Magda Bahia

Prevalence of celiac disease in Brazilian children with type 1 diabetes mellitus

Objective: Although the relationship between celiac disease and diabetes mellitus type 1 is well recognized, there are no studies of this association in Brazil. This study aims to identify the prevalence of celiac disease in a group of children with diabetes mellitus type 1 undergoing treatment in the pediatric endocrinology division of a university hospital in Minas Gerais, Brazil. Methods: Immunoglobulin (Ig)A and IgG antigliadin antibodies (enzyme-linked immunoadsorbent assay) were measured in blood collected from 236 children and adolescents with diabetes mellitus type 1. Patients with antigliadin antibodies then had jejunal biopsy and determination of antiendomysial antibodies by indirect immunofluorescence. Results: Twenty-one patients had IgA or IgG antigliadin antibodies. Nineteen underwent jejunal biopsy. Six had mucosal alterations compatible with celiac disease; four had nonspecific histologic changes; nine had normal biopsies. Thirteen antigliadin antibody-positive patients were antiendomysial antibody-negative; one antiendomysial antibody-negative patient had celiac disease. The prevalence of celiac disease was 2.6% among 234 patients. Conclusions: Measurement of antigliadin antibodies in patients with diabetes mellitus type 1 helped in the selection of patients to undergo jejunal biopsy. Antiendomysial antibodies were highly specific and moderately sensitive in predicting celiac disease. The prevalence of celiac disease was higher in diabetics than in the general population, suggesting the need for regular screening assessment of diabetic children.

Prevalence of serological markers for celiac disease (IgA and IgG class antigliadin antibodies and IgA class antiendomysium antibodies) in patients with autoimmune rheumatologic diseases in Belo Horizonte, MG, Brazil

CONTEXT Patients with autoimmune rheumatologic conditions and celiac disease tend to have a variety of autoantibodies, many of which have no clear pathogenic role. The literature contains frequent reports of celiac disease being more prevalent in patients with rheumatologic diseases, although this remains controversial. OBJECTIVES To investigate the prevalence of positive serum tests for celiac disease, particularly IgA and IgG antigliadin (AGA) antibodies and IgA antiendomysium antibodies (EmA) in patients with autoimmune rheumatologic diseases. A second aim was to correlate positive serum tests with prednisone and immunosuppressant medication. METHODS A total of 190 adults and pediatric patients with a variety of autoimmune rheumatologic diseases (systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis and spondyloarthrophathies) were evaluated and tested for IgA and IgG antigliadin-antibodies and IgA antiendomysium antibodies. Patients with positive serum tests underwent endoscopic duodenal biopsies for pathology studies. RESULTS There were four positive sera (2.1%) for AGA IgA, all of which tested negative for AGA IgG and EmA. Three sera (1.6%) tested positive for AGA IgG; all were negative for AGA IgA and EmA. The EmA test at a 1:2.5 serum dilution tested positive in 94 patients (49.5%); at a 1:5 serum dilution it was positive in 41 patients (21.6%). Eleven subjects tested positive for EmA at 1:40 dilution; and all of these tested negative for IgA tissue antitransglutaminase (tTG) antibodies. Nine of the 11 EmA-positive patients and all 7 patients with positive antigliadin antibodies tests underwent duodenal endoscopic biopsies, and no significant changes were demonstrated in their duodenal mucosa. A positive EmA was associated with elevated optical density AGA IgA readings; however, there was no relationship between positive EmA and AGA IgG optical density readings. Prednisone and immunosuppressant use were unrelated to AGA IgA optical density readings or AGA IgG readings. These drugs were associated with fewer positive EmA tests. CONCLUSIONS Positive AGAA, AGAG or EmA results are probably nonspecific for the presence of celiac disease among autoimmune rheumatologic disease patients. The intake of prednisone and immunosuprressant drugs seems to reduce the prevalence of IgA EmA, but it does not interfere with antigliadin antibodies tests.Further studies are required to estimate more accurately the prevalence of this disease in rheumatologic patients.

Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis

Infantile myofibromatosis (IM) is a rare disorder characterized by the development of benign tumors in the skin, muscle, bone, and viscera. The incidence is 1/150,000 live births and the disease is the most common cause of fibrous tumors in infancy. Cases which lack visceral involvement generally have a more benign course, usually with spontaneous regression of the tumors. On the other hand, the prognosis tends to be unfavorable when there is involvement of vital organs, which can lead to significant mortality. The identification of rare variants in genes that may cause IM is the first step towards the possibility of targeted treatments; however, the molecular pathogenesis of IM is poorly understood. In the present study, we report the results of exome sequence analysis of two brothers diagnosed with visceral multicentric infantile myofibromatosis, and their healthy consanguineous parents. In the two brothers we identified novel homozygous variants in NDRG4 gene (N-myc downregulated gene family member 4) and in RLTPR gene (RGD motif, leucine rich repeats, tropomodulin domain and proline-rich containing). The healthy parents were heterozygous for both variants. Consistent with the phenotype of IM, NDRG4 is a tumor-related gene; its expression has been shown to be decreased in numerous tumor types, suggesting that it might be a tumor suppressor gene. Additionally, studies have demonstrated that NDRG4 may have a role in cell survival and tumor invasion. We thus propose that this homozygous variant in NDRG4 may be the causative variant of the autosomal recessive form of IM in the studied family and that it should be investigated in other cases of autosomal recessive infantile myofibromatosis.

Determining IgA and IgG antigliadin, IgA antitransglutaminase, and antiendomysial antibodies in monkey esophagus and in umbilical cord for diagnosis of celiac disease in developing countries.

Objectives: To assess the efficiency of determining IgA and IgG antigliadin antibodies (IgA- and IgG-AGA, respectively), antitransglutaminase (TgA), and anti-endomysial antibodies (AEA) in human umbilical cord (CO) and monkey esophagus for diagnosis of celiac disease; to determine the correlation between serological markers and celiac disease. Patients and Methods: A total of 400 patients were divided in 3 groups: group 1 with 37 patients with celiac disease, group 2 with 208 patients with no enteropathies, and group 3 with 155 patients with other enteropathies. IgA-AGA, IgG-AGA, and TgA were assessed using enzyme-linked immunosorbent assay, whereas AEA was evaluated by indirect immunofluorescence. Results: Sensitivity and specificity of IgA-AGA were 81.1% and 95.2%, of IgG-AGA 89.2% and 95.2%, of TgA 83.9% and 96.8%, of AEA-CO 87.9% and 100%, and of AEA of monkey esophagus 88.6% and 100%, respectively. Positive predictive values were 75.0%, 76.7%, 83.9%, and 100%. Negative predictive values were 96.6%, 98.0%, 96.8%, and 97.7% for IgA-AGA, IgG-AGA, TgA, and AEA, respectively. Multivariate analysis showed a strong association between AEA-CO and celiac disease and a good correlation with other markers (TgA, IgA-AGA, and IgG-AGA). Conclusions: TgA has been recommended for screening patients with celiac disease. Considering the similar sensitivity and specificity of IgA-AGA and TgA and their correlations in the multivariate analysis, both are applicable for this purpose. However, because TgA tests are highly costly and celiac disease is associated with IgA deficiency, the determination of IgA-AGA and IgG-AGA, followed by AEA-CO, is suitable for screening in developing countries, provided a cutoff point for these examinations is established. The results of antiendomysial antibodies in umbilical cord overlapped those in monkey esophagus. Therefore, umbilical cord should be used as a substrate instead of specimens from endangered species.

Serum antigliadin antibody levels as a screening criterion before jejunal biopsy indication for celiac disease in a developing country

The objective of the present study was to determine the efficacy of detection of antigliadin immunoglobulins G and A (IgG and IgA) for the diagnosis of celiac disease in a developing country, since other enteropathies might alter the levels of these antibodies. Three groups were studied: 22 patients with celiac disease (mean age: 30.6 months), 61 patients with other enteropathies (mean age: 43.3 months), and 46 patients without enteropathies (mean age: 96.9 months). Antigliadin IgG and IgA ELISA showed sensitivity of 90.9 and 95.5%, respectively. With the hypothetical values of prevalence ranging from 1:500 to 1:2000 liveborns, the positive predictive value varied from 8.5 to 2.3% for IgG and from 4.8 to 1.1% for IgA. Considering the patients without enteropathies, specificity was 97.8 and 95.7% for IgG and IgA, respectively. In patients with other enteropathies, specificity was 82.0 and 84.1%, respectively. When patients with and without other enteropathies were considered as a whole, specificity was 88.8 and 91.6%, respectively. The specificity of positive IgG or IgA was 93.5% in children without enteropathies and 78.7% in the presence of other enteropathies. The negative predictive value for hypothetical prevalences varying from 1:500 to 1:2000 liveborns was 99.9%. Thus, even in developing countries where the prevalence of non-celiac enteropathies is high, the determination of serum antigliadin antibody levels is a useful screening test prior to the jejunal biopsy in the investigation of intestinal malabsorption.

Estudo da prevalência da doença celíaca em crianças e adolescentes com diabetes melito tipo 1: resultado de 10 anos de acompanhamento

OBJECTIVE To estimate the prevalence of celiac disease (CD) in children and adolescents with type 1 diabetes mellitus (T1DM) treated in the Childrens Division of Endocrinology, at the Universidade Federal de Minas Gerais Hospital das Clínicas. SUBJECTS AND METHODS Children and adolescents diagnosed with T1DM, aged 0 to 18 year, were included in this study performed from March 1999 to April 2009. All patients were screened for CD at their first visit and, again, annually. The investigation was performed through the measurement of IgA (AGAA) and IgG (AGAG) antigliadin antibodies. Patients with values of AGAA and/or AGAG above two times the cutoff mark undertook intestinal biopsy. RESULTS A group of 21 patients were excluded from the initial total of 384 patients. Out of the remaining, 50 patients had positive serology and 29 underwent intestinal biopsy. The prevalence index was 3.1%. CONCLUSION The periodic screening of CD in diabetic patients should be encouraged, due to its high prevalence.

Discordância de apresentação da doença celíaca em gêmeos monozigóticos

CONTEXTO: A doenca celiaca e uma enteropatia autoimune causada pela sensibilidade ao gluten em individuos geneticamente predispostos. Apesar da caracteristica genetica da doenca, estudos demonstram discordância de 30% na sua apresentacao em gemeos monozigoticos. OBJETIVO: Apresentar dois pares de gemeos monozigoticos, comprovados por estudos geneticos, discordantes para apresentacao da doenca celiaca. METODO: Os pacientes foram acompanhados no Servico de Gastroenterologia Pediatrica do Hospital das Clinicas da Universidade Federal de Minas Gerais desde 1990, sendo submetidos a exames clinicos periodicos, biopsias intestinais e sorologia para anticorpos IgG e IgA antigliadina, determinados pela tecnica de ELISA (ensaio imunoenzimatico), e anticorpos classe IgA antiendomisio, determinados pela tecnica de imunofluorescencia indireta. Estudos geneticos foram realizados atraves da tecnica de amplificacao por PCR e posterior tipagem de loci de microssatelites do tipo STR (short tandem repeats). RESULTADOS: Em cada par de gemeos, apenas um apresentou doenca celiaca ate o momento, mostrando que, apesar do genotipo identico, este nao foi o unico determinante para a expressao da doenca. CONCLUSAO: Outros fatores, ambientais e geneticos, parecem contribuir para determinacao da doenca.

“Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis (Linhares et al., 2014)” turns out to be EBV+ leiomyomatosis caused by CARMIL2 mutations

In 2014 we published in the European Journal of Medical Genetics the article entitled “Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis” (Linhares et al., 2014).” We reported in the paper that “In the two brothers we identified novel homozygous variants in NDRG4 gene and in RLTPR gene. [...] Consistent with the phenotype of IM [Infantile Myofibromatosis], NDRG4 is a tumor-related gene; its expression has been shown to be decreased in numerous tumor types, suggesting that it might be a tumor suppressor gene. Additionally, studies have demonstrated that NDRG4 may have a role in cell survival and tumor invasion. We thus propose that this homozygous variant in NDRG4 may be the causative variant of the autosomal recessive form of IM in the studied family and that it should be investigated in other cases of autosomal recessive infantile myofibromatosis.” Further investigation of these children, in collaboration with Fabian Hauck, Christopher Klein and their associates at the Ludwig-Maximilians-Universit€ at (LMU) in Munich, showed that our conclusion was not correct. The children, in fact, did not have Infantile Myofibromatosis, but the almost pathologically indistinguishable EBV þ Leiomyomatosis. Moreover, the gene responsible was shown to be RLTPR (recently renamed CARMIL2), which we had mentioned, but did not value as a candidate. These facts have been reported in a recent article entitled “A human immunodeficiency syndrome caused by mutations in CARMIL2” (Schober et al., 2017). In this case, even though the conclusions of our article were not correct, its publication helped in the characterization of this novel and fascinating immunodeficiency syndrome. Thus, it should be counted as successful according to the spirit of the “Exome Reports” of the European Journal of Medical Genetics. However, I believe that a correction might be published by the European Journal of Medical Genetics, pointing the potential readers of our article (Linhares et al., 2014) to the newer publication in Nature Communications (Schober et al., 2017).

Anthropometric profile of patients with celiac disease tended at the Pediatric Gastroenterology Clinic of UFMG, Belo Horizonte

Objective: celiac disease is characterized by being autoimmune, triggered by the presence of wheat gliadin and barley and rye proteins in the diet of susceptible people. The non-adherence to proper diet can lead to nutritional deficiency and alteration in body composition. This study evaluated the anthropometric profile and body composition of children, adolescents, and young adults with celiac disease. Methods: 31 patients with celiac disease and 31 control persons, within the age range from 3 to 23 years, were evaluated. Weight, height, waist and hip circumference were compared and body mass index was calculated. The percentage of body fat, muscle mass, and total water was obtained by electrical bioimpedance. Food frequency and food record questionnaires were applied to evaluate its relationship with body composition. The Fisher, Student’s t, and Wilcoxon tests were used for comparison of groups. Results: the anthropometric and body composition analyses did not show significant differences (p < 0.05) between the two groups. The proportions of individuals with bodily parameters above, below, or at the healthy appropriate level were similar. Conclusion: the patient with celiac disease following a gluten-free diet has normal body composition. In this study, the gluten-free diet has not been proved detrimental to the body composition of these individuals.