Coeliac Disease Case-Control Study: Has the Time Come to Explore beyond Patients at Risk?

The worldwide prevalence of asymptomatic coeliac disease (CD) is increasing, which is in part due to the routine screening of children with risk factors. Both symptomatic and asymptomatic patients with CD are at risk of long-term complications. The objective of this study was to compare the clinical characteristics of asymptomatic and symptomatic children at the time of CD diagnosis. A case-control study was conducted using data from a cohort of 4838 CD patients recruited from 73 centers across Spain between 2011 and 2017. A total of 468 asymptomatic patients (cases) were selected and matched by age and sex with 468 symptomatic patients (controls). Clinical data, including any reported symptoms, as well as serologic, genetic, and histopathologic data were collected. No significant differences were found between the two groups in most clinical variables, nor in the degree of intestinal lesion. However, the asymptomatic patients were taller (height z-score -0.12 (1.06) vs. -0.45 (1.19), p < 0.001) and were less likely to have anti transglutaminase IgA antibodies ≥ 10 times the upper normal limit (66.2% vs. 758.4%, p = 0.002). Among the 37.1% of asymptomatic patients who were not screened for CD due to the absence of risk factors, only 34% were truly asymptomatic, while the remaining 66% reported non-specific CD-related symptoms. Therefore, expanding CD screening to any child who undergoes a blood test could reduce the burden of care for some children, as many of those considered asymptomatic reported non-specific CD-related symptoms.

Influence of HLA on clinical and analytical features of pediatric celiac disease.

BACKGROUND: Celiac disease (CD) is triggered by gluten and related prolamines in genetically susceptible individuals. We aimed to investigate the influence of HLA-DQ genotypes in clinical, serological and histological features related to CD. METHODS: A retrospective observational study was performed including 463 Spanish patients with biopsy-proven CD. Clinical, serological, histological and HLA-DQ genetic data were collected from each participant. The presence of a family history of CD was also considered. Bivariate (chi-square tests or the Fisher's exact test) and multivariate (logistic regression after adjusting for age and sex) analyses were performed to assess the association between clinical and laboratory parameters with HLA-DQ. RESULTS: A predominance of females (62%), classical clinical presentation (86%) and positive anti-transglutaminase 2/endomysium antibodies (99%) was observed in our sample, with a mean age at onset of 2.6 ± 0.1 years. Five percent of our patients were first-degree relatives of subjects with CD, with HLA-DQ genetics showing increased homozygosity of HLA-DQ2.5 (p = 0.03) and HLA-DQ8 (p = 0.09). In the non-CD family history group, an association between delayed disease onset and HLA-DQ8 carriage was observed (p < 0.001), besides an influence of HLA-DQB1*02 gene dosage on clinical presentation and severity of histological damage (after adjusting for age and sex, p = 0.05 and p = 0.02, respectively) and a trend towards presence of specific antibodies (p = 0.09). These associations could not be evaluated properly in the group of patients with affected first-degree relatives due to the small sample size. CONCLUSIONS: HLA-DQ genotypic frequencies differ slightly between CD patients depending on their family history of CD. In patients lacking CD first-degree relatives, carriage of HLA-DQ2.5 with double dose of HLA-DQB1*02 seems to be associated with classical clinical presentation and more severe histological damage.

Ten years of follow-up of the Spanish cohort of the European PreventCD study: the lessons learned.

AIM: to evaluate the influence of gluten consumption on celiac disease development and to describe its natural history in the Spanish cohort of the European PreventCD study. METHODS: prospective multi-center double blind study of 225 children that were followed up from birth. All cases were HLA-DQ2/HLA-DQ8 positive with a 1st degree relative with celiac disease and were followed up in three centers from Madrid, Reus and Valencia. Gluten intake was determined between four and ten months according to the protocol. Gluten intake was ad libitum between eleven and 36 months and was prospectively quantified by means of dietary records. Clinical visits and specific antibody analysis for celiac disease were performed periodically. RESULTS: twenty-six cases were diagnosed, all had a positive biopsy and serology; 21 had gastrointestinal symptoms and five were asymptomatic. In addition, 2,565 food records were analyzed and statistically significant differences (p < 0.001) were found with regard to gluten consumption among the three centers, although not between celiac and non-celiac children (p = 0.025). The HLA-DQ2.5/DQ2.5 and DQ2.5/DQ2.2 genotypes had a relative risk of 4.7 (95% CI: 0.80-27.55; p = 0.08), which was higher than for the rest of genotypes. Female gender also had a relative risk that was five times higher than that for males. CONCLUSIONS: the amount of gluten intake between 11 and 36 months or the duration of breast feeding were not risk factors for the development of CD in the Spanish population. The HLA genotype and gender were the most relevant associated factors. In this at-risk group, the disease presented before two years of age in the majority of the cases with a weak clinical expression.

Histopathological evaluation of duodenal biopsy in the PreventCD project. An observational interobserver agreement study.

Aim of the current study was to evaluate the inter-observer agreement between pathologists in the diagnosis of celiac disease (CD), in the qualified context of a multicenter study. Biopsies from the "PreventCD" study, a multinational- prospective- randomized study in children with at least one-first-degree relative with CD and positive for HLA-DQ2/HLA-DQ8. Ninety-eight biopsies were evaluated. Considering diagnostic samples with villous atrophy (VA), the agreement was satisfactory (κ = 0.84), but much less when assessing the severity of these lesions. The use of the recently proposed Corazza-Villanacci classification showed a moderately higher level of agreement (κ = 0.39) than using the Marsh-Oberhuber system (κ = 0.31). 57.1% of cases were considered correctly oriented. A number of >4 samples per patient was statistically associated to a better agreement; orientation did not impact on κ values. Agreement results in this study appear more satisfactory than in previous papers and this is justified by the involvement of centers with experience in CD diagnosis and by the well-controlled setting. Despite this, the reproducibility was far from optimal with a poor agreement in grading the severity of VA. Our results stress the need of a minimum of four samples to be assessed by the pathologist.

Efficacy of a point-of-care test based on deamidated gliadin peptides for the detection of celiac disease in pediatric patients.

OBJECTIVE: The objective of the study was to assess the effectiveness of a point-of-care test (POCT) based on deamidated gliadin peptides (DGP) compared to the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) criteria diagnosis in the early detection of celiac disease (CD) in pediatric patients. METHODS: One hundred children (≤ 18 years) with suspected CD were selected, including siblings of celiac children that underwent gastroscopy for other gastrointestinal conditions. Patients with severe disease, following a gluten-free diet (GFD), with gastrointestinal bleeding, coagulopathy and infections in the last month were excluded. All children were evaluated with a POCT that detects immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to DGP and total IgA. The POCT results were compared to CD diagnosis according to current ESPGHAN criteria. This involved the detection of IgA tissue transglutaminase (tTG) antibodies, the results of an intestinal biopsy and genetic testing. RESULTS: The prevalence of CD found in the present study was 48% (95% confidence interval in parenthesis 37.9-58.2%). The results of the POCT were concordant with the CD diagnosis made according to ESPGHAN criteria: 95.8% (85.7-99.4%) sensitivity, 98.1% (89.7-99.7%) specificity, 97.9% (88.7-99.6%) positive predictive value and 96.2% (87.0-99.4%) negative predictive value. Positive and negative likelihood ratios were 49.8 (7.2-347.5) and 0.04 (0.01-0.17), respectively. The POCT showed a 100% diagnostic accuracy in children younger than ten years of age. In total, three discordant results were found. CONCLUSION: Due to the high diagnostic accuracy in the pediatric population, the POCT can be considered as an effective tool for the early diagnosis of CD, especially in patients younger than ten years of age.

Randomized feeding intervention in infants at high risk for celiac disease.

BACKGROUND: A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled dietary-intervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age. RESULTS: Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention. CONCLUSIONS: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.).

The IL6-174G/C polymorphism is associated with celiac disease susceptibility in girls.

The aim of this paper was to study the role of IL6 and IL6R polymorphisms in celiac disease (CD) susceptibility. Because previous literature describes IL-6-related gender differences, sex-stratified analyses were performed. We undertook a case-control study with 374 pediatric CD patients and 853 healthy controls, all white Spaniards, and a family study using an independent sample including 303 trios for replication purposes. Three single-nucleotide polymorphisms tagging most of the variability of the IL6 gene (rs2069827, rs1800795 [-174G/C], and rs2069840) and one functional polymorphism in IL6R (rs8192284, Asp358Ala) were genotyped using TaqMan technology. Case-control comparisons were performed with the chi2 test and family data were analyzed with the transmission disequilibrium test. No association was observed between any tested polymorphism and overall CD. However, after sex stratification, we found that the IL6 promoter variant -174C increases the risk of developing CD specifically in female patients. This effect was observed both in the case-control and in the family studies (considering girls included in both studies vs boys: p = 0.021, odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.03-1.66; and vs controls: p = 0.003, OR = 1.30, 95% CI 1.09-1.55). The functional -174G/C IL6 polymorphism seems to influence CD susceptibility in girls. The gender-specific role of IL-6 in this pathology must be further investigated.

Detección de anticuerpos antimaláricos en un grupo de escolares del municipio del El Bagre, Antioquia / Antimalaric antiobodies in school children in El Bagre, Colombia

En 1996, en el municipio de El Bagre (Antioquia-Colombia), zona endémica para malaria y con altos niveles de desnutrición, se realizó un estudio de casos y controles con el objeto de determinar la relación entre el estado nutricional y la respuesta inmune humoral de niños con y sin malaria. Se trabajó con un grupo de 100 niños entre 4 y 9 años de edad, 51 con malaria y 49 sin ella, al cual se le determinaron los niveles de anticuerpos antimaláricos IgG e IgM por la técnica de inmunofluorescencia indirecta (IFI), empleando antigenos de P. falciparum cepa FCB 2 mantenida en cultivo continuo. El estado nutricional se evaluó por comparación de las medidas antropométricas con la referencia de crecimiento del National Center for Health Statistics (NCHS) de los Estados Unidos. Los resultados mostraron diferencias en la tasa de positividad de anticuerpos IgG entre los niños maláricos y los no maláricos. En efecto: Veintinueve niños maláricos (56.9 por ciento) y sólo 4 de los no maláricos (8.2 por ciento) tenían dichos anticuerpos (P<0.00001 ); la diferencia también fue significativa para el antecedente de malaria en el último año que fue de 70.6 por ciento en los niños maláricos y 10.2 por ciento en los no maláricos (p<0.00001 ). Todas las determinaciones de IgM fueron negativas. Por último, de los 29 seropositivos con malaria, 20 (69 por ciento) eran desnutridos (p<0.01 ).

A cases and controls study was carried out in1996 in El Bagre, Colombia, endemic zone for ma.laria, in order to determine the relationship betweennutritional situation and immune response to mala-ria in 51 children with malaria and 49 without it; IgGand IgM antibodies were determined by means ofindirect inmunofluorescence .against P. falciparumantigens (Strain FCB2). Nutritional situation wasevaluated according to USA National Center forHealth Statistics.No child was found positive for IGM antibodies;concerning IgG response, it was positive in 29(56.9%) malaric children but only in 4 (8.2%) of thenon-malaric ones (p<0.00001 ). Difference was alsosignjficant (p<0.00001) for malarja antecedents inthe previous year (70.6% in malaric children vs10.2% jn the nonmalaric ones). Of the 29 malaricseropositive children 20 (69%) were malnourrished(p<0.01 )

Familia y salud familiar: un enfoque para la atención primaria

Tomando en cuenta la importancia de los factores psicosociales en la consulta del nivel primario de atención, así como la importancia que cobra en la actualidad el mejoramiento de la calidad de dicha atención, el enfoque familiar es como una vía estratégica para las acciones del médico general y el equipo de salud. Dentro de un marco conceptual con aportes de las ciencias de la conducta, la utilización del concepto de familia en salud y el significado de la salud familiar es objeto de discusión. La descripción de un proceso de intercambio academico asistencial en la aplicación del modelo de análisis incluye los resultados de investigaciones de las funciones e instrumentos asistenciales incorporados a una ficha familiar. Por último se plantea la búsqueda de parámetros para la medición de la salud familiar y el estudio del impacto de la enfermedad individual sobre las relaciones familiares, y vice-versa