Heterogeneity of vitamin D receptor gene association with celiac disease and type 1 diabetes mellitus.

OBJECTIVE: Vitamin D has been shown to exert multiple immunomodulatory effects and is known to suppress T-cell activation by binding to the vitamin D receptor (VDR). To determine whether VDR gene polymorphisms are related to the susceptibility to celiac disease, we investigated its implication as a candidate gene in the Basque population. Because celiac disease and type 1 diabetes share common susceptibility loci, we also analyzed families with type 1 diabetes mellitus. METHODS: A total of 37 families with celiac disease and 64 type 1 diabetic families of Basque origin with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (Fok I, Bsm I, Apa I and Taq I). The AFBAC approach was used to test for association. RESULTS: Comparison of VDR genotypes of the patients with those of 88 healthy individuals identified "ff" as a risk genotype for celiac disease [p = 0.01; OR = 3.45 (1.12-10.79)]. On the other hand, a significantly higher frequency of haplotype "fBAt" was observed in the type 1 diabetic group [p(c) = 0.02; OR = 4.4 (1.5-15.3)]. CONCLUSION: Our findings suggest that polymorphisms within the vitamin D receptor gene are markers of susceptibility to or protection from autoimmune diseases, although, at least in the Basque population, association of VDR variants with celiac disease and type 1 diabetes seems to be heterogeneous.

Dental enamel defects in celiac patients.

OBJECTIVE: The incidence and distribution of enamel defects among patients with celiac disease were examined. STUDY DESIGN: The oral cavity was explored in 137 patients with celiac disease (mean age 16.2 years; age range 5 to 68 years) and in 52 control patients (mean age 19.8 years; age range 5 to 64 years). Permanent dentition enamel defects were recorded, along with their number and locations. The decayed, missing, and filled teeth index rates were also established, and an investigation was made of the human leukocyte antigens among the patients with celiac disease. The results obtained were analyzed with the chi-squared test, statistical significance being regarded for p < or = 0.05. RESULTS: Enamel defects were observed in 72 (52.5%) of the patients with celiac disease (52 patients had systematic defects) and in 22 (42.3%) of the control patients (9 patients had systematic defects). Systematic defects were significantly more common in the celiac disease group. In the patients with celiac disease, 72.2% were symmetrical, compared with 40.9% of the defects in the control patients. The incisors were the most frequently affected teeth, the extent of involvement being significantly greater in the celiac disease group. In patients with celiac disease, DR7, DR3, and DQ2 were the most commonly observed human leukocyte antigens. The mean decayed, missing, and filled teeth index rates were 4.8 and 6.2 in the celiac disease group and the control group, respectively. CONCLUSIONS: Enamel defects are common among patients with celiac disease. They tend to be bilateral and symmetrical, and they are chronologically distributed. The lesions affect mainly the incisors and the molars. Patients with such characteristics should be evaluated for possible celiac disease.

[Cholelithiasis in childhood. Proposals based on a multicentric study]. / Colelitiasis en la infancia. Propuestas de un estudio multicéntrico.

Fifty six cases of cholelithiasis in patients aged two months to 15 years (mean age 7.65 years) concerning to 11 hospitals are reviewed. The study protocol followed was the same in all medical records, although own criterions were considered on management performed in each center. From the cases, it follows: 1. Male/female rate is 1/1.5. 2. Symptomatology in infancy is relatively poor and pain localization is not orientative. 3. It was an incidentally finding in 41 per 100 of the cases. 4. Ultrasonography is the best examination procedure rendering diagnosis in the 51 cases it was underwent. 5. Hematologic study was abnormal in six of 46 cases. 6. Medical treatment was not performed in any hospital. 7. Existence of "lithogenic families" seems to be demonstrated. 8. The presence of four patients with Down syndrome in this series must be pointed out. 9. Among total 56 cases, 21 underwent surgical treatment, 29 were conservatively treated, two have died and four patients had spontaneous stone resolution. 10. In the face of these, we propose: A) Surgical treatment in symptomatic cases, porcelain gallbladder and nonfunctionating gallbladder. B) Expectant management and sonographic monitoring in asymptomatic cases. C) Carefully evaluation in patients with predisposing factors and patients with recurrent abdominal pain.

[Nutritional profile of foods offered and dietary intake in school canteens in Biscay]. / Perfil nutricional de los menús e ingesta dietética en comedores escolares de Vizcaya.

INTRODUCTION: Nowadays the school canteen occupies a central place in the supply and in the nutritional education of the children in school age. OBJECTIVES: To assess the nutritional adequacy of the school menus and the food intake of the children. METHODS: 1,500 trays were selected in six school dining rooms of Biscay. Dietary intake was evaluated by means of the technique of double weighed and visual estimation of the residues. RESULTS: Evaluation of the menus: Macronutrients: carbohydrates 48%, proteins 20%, lipids 32%. Weekly offer: The first plate: vegetables 1.1; legumes 1.8; potatoes 0.4; pasta-rice 1.7. The second plate: meat 2.5; fish 1.4; eggs 0.6; precooked fried food 0.5. Garnish: potatoes 0.5; sauces 0.8; lettuce 1.7; cooked vegetables 1; no garnish 1. Dessert: fruit 2.8; dairy product 2; other 0.2. Significant changes have been observed in 4% of the menus. The vegetable garnish is not served in 40% of the occasions. 70% do not eat the vegetable garnish. CONCLUSIONS: Though the theoretical offer of vegetables is appropriate, due to the fact that frequently the vegetables are not served in garnish and to that when they are served children do not eat them, their final intake is poor. The protein contribution to the diet is higher than the recommended. Meaningful changes take place often in the composition of the menus.

The functional R620W variant of the PTPN22 gene is associated with celiac disease.

The functional (R620W) variant of human PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been implicated in the risk to several autoimmune disorders, including type 1 diabetes, Graves' disease, rheumatoid arthritis and systemic lupus erythematosus. In an association study of this single nucleotide polymorphism with celiac disease (CD), comparison of 262 young diagnosis patients and 214 adult controls from Spain showed a higher frequency of the minor allele in the CD group (9.7% vs 5.6% in controls; P = 0.018), suggestive of an increased genetic risk to the disease (odds ratio = 1.82; 95% confidence interval 1.1-3.0). These results support the role of PTPN22 as a general autoimmunity locus involved in tolerance induction in the thymus.

Association of KIR2DL5B gene with celiac disease supports the susceptibility locus on 19q13.4.

Genome-wide scans have detected linkage to celiac disease (CD) in several genomic locations, including 19q13.4. Killer immunoglobulin-like receptor (KIR) genes map to the region and encode receptors of natural killer (NK) cells and certain T cells that modulate cytolitic activity through interactions with HLA class I ligands, participating in the innate immune response. We performed KIR genotyping in a group of 70 CD patients of Basque origin and compared gene content, genotype and haplotype frequencies to ethnically matched blood-donors. The frequency of gene combination KIR2DL5B(+)/KIR2DL5A(-) was significantly higher in the disease group, and this result was confirmed in a second group of 343 CD patients and 160 controls of Spanish origin, suggesting an implication of this 'unexpressed' gene with increased susceptibility to CD (combined OR of 3.63 (95% CI: 1.76-7.51; P=0.0004)), possibly due to the lack of an efficient inhibitory signal. Our results support the role of the KIR gene cluster in celiac disease and replicate the CD-susceptibility locus at 19q13.4.

Toll-like receptor 4 (TLR4) gene polymorphisms in celiac disease.

Toll-like receptors (TLRs) participate in the first line of immune defense through antigen pattern recognition, and ligands include exogenous and host-derived molecules. Coding variants in TLR4 have been associated with autoimmune diseases like ulcerative colitis, Crohn's disease, and rheumatoid arthritis. Our aim was to determine whether these polymorphisms are associated with celiac disease (CD). Two coding single nucleotide polymorphisms of TLR4 (Asp299Gly and Thr399Ile) were genotyped in 95 family trios with CD as well as in 186 patients and 186 unrelated controls. There were no differences in allele, genotype or haplotype distribution, or transmission between patient and control groups. Our results do not support association of these TLR4 variants with CD.

Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease.

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10(-5)) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

[Jaundice associated with congenital hypertrophic pyloric stenosis (author's transl)]. / Ictericia asociada a estenosis hipertróifica de píloro

The clinical and biological findings in six infants with congenital hypertrophic pyloric stenosis with associated jaundice are described. Pathogenesis of this association is not known but current hypothesis are based on either a decrease in the activity of hepatic glucuronyl transferase or an increase in the activity of intestinal glucuronidase. Correction of dehydration and alkalosis does not modify the hyperbilirubinemia which only disappears after pyloromiotomy.

[Crohn's disease in childhood. Comments on one case (author's transl)]. / La enfermedad de Crohn en la infancia. Comentarios a propósito de una observación.

Chronic inflammatory diseases of the bowel are specially frequent in the adult, with peak incidence during adolescence and early adulthood. There are, however, increasing number of reports in the pediatric age group, mainly coming from anglosaxon countries although more recently also from countries of Southern Europe. Authors present a case of Crohn disease occuring in a child, with typical clinical, radiological and pathological features, since they are not aware of any report in the Spanish literature. Comments are made upon pathogenesis, clinical features and pathological findings and specially upon the treatment established in the present case in relation with the indications of other authors.

[Results of the sweat test, carried out by 2 methods, for the diagnosis of cystic fibrosis]. / Resultados de la prueba del sudor, efectuada por dos métodos, para el diagnóstico de la fibrosis quística.

Un review the results of the sweat test for the diagnosis of cystic fibrosis performed by 2 methods: Electric conductivity of the sweat (2,517 test in non-cystic fibrosis and 114 in 37 cystic fibrosis children) and skin chloride electrode (121 test in non-cystic fibrosis and 20 in cystic fibrosis children). A 1% rate of false positive results was obtained with the former along with 6,1% falsely negative results in cystic fibrosis patients. The skin chloride electrode method was much less specific and sensitive. The diagnosis of cystic fibrosis should only be made once repeatedly altered sweat chloride concentrations are obtained together with careful correlation with the clinical findings. We think that both the implications of the diagnosis and the thoroughness needed in the proper performance of the sweat test warrant that the diagnosis should always be confirmed in a centre with experience in the disease.

Use of serological markers as a screening test in family members of patients with celiac disease.

That symptomatic celiac disease (CD) can occur in several members of a family has long been recognized. Given the possible complications of untreated CD, it is also important to diagnose those family members with "silent" disease, to offer them the benefit of a gluten-free diet. We studied 642 first-degree relatives of 210 patients with CD, two of the latter belonging to the same family. IgA and IgG antigliadin antibodies and IgA antiendomysium antibodies were studied in all. Jejunal biopsy was performed in 59 subjects, 47 with positive and 12 with negative serological markers. Celiac disease was diagnosed de novo in 18 cases (2.8%). Diagnosis in a symptomatic mother was made by jejunal biopsy despite the negativity of all immunological markers. We conclude that the risk of having CD is higher in siblings than in parents of patients with CD, that the most useful marker for diagnosis is the study of IgA antiendomysium antibodies, and that the absence of positive serological markers does not completely exclude the diagnosis of CD.

Chloride deficiency as a presentation or complication of cystic fibrosis.

Thirteen children with cystic fibrosis (CF), aged 1.5 months-15 years, had 18 episodes of hypochloraemia and metabolic alkalosis over the period 1983-1991. Five patients were not known to have CF prior to developing these electrolyte disturbances. There were two distinct clinical presentations: 5 patients had an acute isolated picture of heat exhaustion while 8 patients (all infants) had a more chronic course associated with failure to thrive. Many episodes were not associated with particularly high environmental temperatures, although most occurred during the summer and early autumn months. Serum electrolytes should be assessed regularly in children with CF, and this diagnosis should be considered in any infant presenting with unexplained hypochloraemic metabolic alkalosis.

[Malabsorption of carbohydrates in children (author's transl)]. / Malabsorción de los hidratos de carbono en el niño

Physiological bases of digestion and absorption of carbohydrates are reviewed, as a preliminary step, in order to draw a general scheme of its patholophysiology. Clasification of different types of carbohydrate malabsorption is presented. Various exploration methods are discussed in terms of autors' own experiences. Relationship between a sugar screening test, faecal lactic acid contents and a simplified lactose tolerance test, is described in detail. Systematic diagnoses of these diseases are established. Different clinical pictures are reviewed. It is not yet well defined if a starch malabsorption can be caused by either a primary or secondary duodenal amylase deficiency. The clinical forms of congenital sucrose-isomaltose intolerance may be more attenuated than its classical form; incertain cases, secondary sucrose intolerance may also be present due to mucosa anatomic lesions. Maltose malabsorption has no clinical implications. As compared to other alpha-glycosidades, the trehalase activity has been not more affected by not using trehalose in feeding. Primary congenital lactase deficiency is not frequent, whereas secondary forms as much more usual and appear, in primary malabsorption syndromes and in the coeliac disease, very often along with clinical tolerance to lactose. In Spain, lactose nonabsorbers in 16.5% for adults 11.2% for adolescents and 18.3% for children, meaning, that it is being favored by environmental factors in the latter. The unspecified sugar malabsorption during the child's first year is still the most frequent cause of carbohydrate intolerance in children and, although certain progress has been achieved in its diagnosis and therapy, its pathogenic mechanism is not satisfactorily known yet.

Enteropathy related to fish, rice, and chicken.

Gastrointestinal symptoms in relation to the ingestion of proteins are common but only in the case of sensitisation to cows' milk protein, soy, or gluten have alterations in the function and structure of the small-intestine been reported. We describe 3 children with cows' milk protein intolerance and associated enteropathy related to fish, rice, and chicken, respectively. Repeated intestinal biopsies before and after an acute challenge with the specific food showed changes in the histological appearance of the intestinal mucosa identical with those observed after the acute administration of cows' milk. These findings support the conclusion that cows' milk-protein intolerance is not an isolated entity; it represents the first part of a broader intolerance of various dietary proteins.

Down's syndrome and celiac disease.

The association between Down's syndrome (DS) and autoimmune diseases has long been recognized. However, its relationship to celiac disease (CD) has only recently been reported, and a clear-cut association remains to be fully established. We have studied the prevalence of CD in a random sample of 70 individuals with DS. IgA anti-gliadin antibodies (IgA AGAs) were determined in all and found to be positive in nine (13%). In eight, anti-endomysium antibodies (AEAs) were investigated, and jejunal biopsies were performed. AEAs were positive in two, and three had flat intestinal mucosa. The class I and II human leukocyte antigens of two patients with CD were determined. Results were as follows: A2/B8 B39/DR1 DR3/DQW1 DQW2 in one case and A2 A28/B44 B17/DR4 DR5/DQW3 in the other. This implies a 43% prevalence of CD in DS, which is well above that previously found by us in our population (0.62/1,000 live births). We conclude that the association between DS and CD is not fortuitous and suggest that the determination of such serologic markers as IgA AGA and AEA should be part of health assessment in DS patients.

[Digestive intolerance in newborn infants with extensive intestinal resections. Nutritional problems and long-term sequelae]. / Intolerancia digestiva en neonatos con grandes resecciones intestinales. Problemas nutricionales y secuelas a largo plazo.

The experience of two neonates with extensive intestinal resection and severe difficulties in the introduction of oral nutrients in presented. The pathophysiology and treatment of short bowel syndrome is reviewed, emphasizing the importance of maintenance of nutritional support as well as the factors that contribute to the readaptation mechanism. Mention is made of the complications and long-term sequelae encountered in these cases, whose body weights and growth were normal at the age of 5.

[Intolerance to cow's milk proteins. An epidemiologic study]. / Intolerancia a proteínas de leche de vaca. Estudio epidemiológico.

The incidence of cow's milk protein intolerance (CMPI) varies depending on the series. The aim of the present investigation was to determine the incidence of this disease in our population and its change over the past the years. Over the period January 1977 to December 1986, 217 patients suspected to have the disease were submitted to a cow's milk challenge test. Diagnosis was confirmed clinically and/or pathologically in 121 patients and was ruled out in 96 patients. The incidence for the whole period was 0.78 cases/1,000 alive newborn infants. However, it fell significantly over the ten years, with a maximum of 1.36/1,000 alive newborn infants in 1979 and a minimum of 0.17/1,000 alive newborn infants in 1986 (r = 0.76, p less than 0.001). We conclude that, similarly to the observation in other diseases of nutritional origin, the incidence in our population of CMPI has clearly decreased, probably as a consequence of changes in the dietary habits.

HLA-DRB1 and MHC class 1 chain-related A haplotypes in Basque families with celiac disease.

The contribution of HLA genes to the genetic risk for celiac disease (CD) has been known for a long time. Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain-related protein A (MICA; located between TNFA and HLA-B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease. On the other hand, a single amino acid change in exon 3 of MICA (M129V) has been shown to strongly reduce MICA binding to NKG2D, an activating natural killer receptor expressed also on T cells, and this could have significant effects on autoimmune reactions. In this study, we have analyzed the contribution of these polymorphisms to CD in 37 Basque families, and have constructed MICA-HLA-DRB1 haplotypes to determine whether MICA has an effect independent from the HLA class II conferred risk. In our population, HLA-DRB1*0301 was associated with an increased risk for CD, while HLA-DRB1*1501 conferred protection from the disease (OR: 7.38 and 0.06, respectively). On the other hand, MICA allele A4 was positively associated with the disease (OR: 4.69) whereas allele A9 showed a trend towards protection (OR: 0.18), although significance did not hold after correction. No association of the exon 3 biallelic polymorphism was observed. A positive allelic association was found for haplotypes A5.1-DRB1*0301 (associated with risk for disease), A4-DRB1*0301 and A6-DRB1*07. In view of our results, both HLA-DRB1 and MICA are associated with CD, but stratification analysis did not show any independent contribution of the MICA polymorphisms analyzed to CD risk. Besides, MICA allele A4 (also A5.1 was associated with risk for CD and other diseases) is in strong linkage disequilibrium with HLA-DRB1*0301. Finally, the major histocompatibility complex region's conferred susceptibility to CD, at least in Basque, is very similar to that observed for DM1, with shared risk and protective haplotypes.