E. Savilahti

Correlation of faecal calprotectin and lactoferrin with an endoscopic score for Crohn's disease and histological findings

Background  Faecal calprotectin and lactoferrin increasingly serve as surrogate markers of disease activity in IBD. Data on the correlation of these markers with simple endoscopic score for Crohn’s disease (SES‐CD) and with histological findings are as yet limited.

Epidemiology of childhood diabetes mellitus in Finland-background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus

SummaryA nationwide study of childhood Type 1 (insulin-dependent) diabetes mellitus was established in 1986 in Finland, the country with the highest incidence of this disease worldwide. The aim of the project called “Childhood Diabetes in Finland” is to evaluate the role of genetic, environmental and immunological factors and particularly the interaction between genetic and environmental factors in the development of Type 1 diabetes. From September 1986 to April 1989, 801 families with a newly-diagnosed child aged 14 years or younger at the time of diagnosis were invited to participate in this study. The vast majority of the families agreed to participate in the comprehensive investigations of the study. HLA genotypes and haplotypes were determined in 757 families (95%). Our study also incorporates a prospective family study among non-diabetic siblings aged 3–19 years, and two case-control studies among the youngonset cases of Type 1 diabetes. During 1987–1989, the overall incidence of Type 1 diabetes was about 35.2 per 100,000 per year. It was higher in boys (38.4) than in girls (32.2). There was no clear geographic variation in incidence among the 12 provinces of Finland. Of the 1,014 cases during these 3 years only six cases were diagnosed before their first birthday. The incidence was high already in the age group 1–4-years old: 33.2 in boys and 29.5 in girls. Of the 801 families 90 (11.2%) were multiple case families, of which 66 had a parent with Type 1 diabetes at the time of diagnosis of the proband. The prevalence of Type 1 diabetes in the parents of these newly-diagnosed diabetic children was higher in fathers (5.7%) than in mothers (2.6%).

Increase in gamma/delta T cell receptor bearing lymphocytes in normal small bowel mucosa in latent coeliac disease.

A jejunal biopsy specimen from an asymptomatic 35 year old man was studied because of a low serum titre of reticulin antibody and the finding of coeliac disease in his son. In this specimen villous structure was quite normal as was the total number of intraepithelial lymphocytes, but the number of gamma/delta T cell receptor bearing lymphocytes was 10 times higher than the mean in control subjects. Two years later a further biopsy specimen was obtained because of clinical symptoms and an increased titre of reticulin antibody. This specimen showed villous atrophy with crypt hyperplasia and increased infiltration of intraepithelial lymphocytes compatible with coeliac disease. A control biopsy specimen taken during gluten free diet showed normalisation of the villous architecture. Latent coeliac disease may be characterised by an increase in gamma/delta positive cells similar to that seen in established coeliac disease.

A genetic test which can be used to diagnose adult-type hypolactasia in children

Background/Aims: Adult-type hypolactasia (primary lactose malabsorption) affects most of world’s human population and limits the use of fresh milk due to lactose intolerance. The diagnosis of adult-type hypolactasia has been difficult to establish because of unsatisfactory diagnostic methods. C/T-13910 single nucleotide polymorphism residing 13910 base pairs from the 5′ end of the lactase gene has been shown to be associated with lactase persistence. The aim of the study was to assess the applicability of the C/T-13910 variant as a diagnostic test for adult-type hypolactasia during childhood. Methods: Intestinal biopsies were obtained from 329 children and adolescents of African, Finnish, and other White origins aged 0.1–20 years undergoing upper gastrointestinal endoscopy because of abdominal complaints. The biopsies were assayed for lactase, sucrase, and maltase activity and genotyped for the C/T-13910 variant using polymerase chain reaction minisequencing. Results: The frequency of the C/C-13910 genotype defining lactase non-persistence was well in agreement in this study with published figures for the prevalences of adult-type hypolactasia in Africans and Whites. The C/C-13910 genotype was associated with very low lactase activity (<10 U/g protein) in the majority of children tested at 8 years of age and in every child older than 12 years of age giving a specificity of 100% and sensitivity of 93% for the genetic test. The decline of lactase activity was somewhat earlier in African compared with Finnish children with C/C-13910 genotype (p<0.03). Conclusions: Genetic test of C/T-13910 polymorphism can be used as a first stage screening test for adult-type hypolactasia.

Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation

Background Probiotics are widely studied both in the treatment and prevention of allergic diseases, but their mode of action is poorly known.

Undiagnosed Coeliac Disease Is Common in Finnish Adults

BACKGROUND Large-scale screening for coeliac disease has suggested that the disease is more prevalent than anticipated. In the screening studies published, only a minor proportion of those with a positive result have undergone jejunal biopsy to confirm the diagnosis. Our aim was to search for previously undiagnosed patients with coeliac disease by means of antiendomysium antibodies, which are more specific for the disease than serum antigliadin antibodies, and to study jejunal histology in each with a positive titre. METHODS Serum from 1070 adults working at Helsinki University Central Hospital were screened for untreated coeliac disease with IgA antiendomysium antibodies. All adults with positive titres underwent jejunal biopsy for villous structure analysis and counting of CD3-positive cells and cells bearing the gamma/delta T-cell receptor. RESULTS Coeliac disease was confirmed in a jejunal biopsy specimen from 8 of the 11 subjects with positive antiendomysium titres--that is, a frequency of 1 in 130. Seven of these eight coeliac patients had had minor abdominal discomfort for years, and one patient had a diagnosis of hyperthyroidism. None of the patients had osteoporosis, four had low iron storages, but only two were anaemic; no other nutritional deficiencies were found. The three other adults had a positive antiendomysium titre but a normal villous structure. One of these three was regarded as a false-positive case (titre, 1 in 5). The two other subjects (titres, 1 in 400) had increased numbers of CD3-positive T cells and gamma/delta T-cell receptor-bearing cells, suggesting a predisposition for coeliac disease. CONCLUSIONS Undiagnosed coeliac disease is common in the adult population in Finland; in this study the prevalence was 1 in 130. Screening for coeliac disease is recommended on minor suspicion.

Coeliac disease : Frequent occurrence after clinical onset of insulin-dependent diabetes mellitus

Coeliac disease was searched for in a series of 776 children with newly diagnosed IDDM. During the follow‐up of 2 to 3 years from diagnosis, reticulin and gliadin antibodies were measured, and a jejunal biopsy was performed in those cases with high levels of antibodies; 19 children were identified with coeliac disease, giving the prevalence of 2.4 %. In only one case had coeliac disease been diagnosed before IDDM. Nine patients with proven coeliac disease were negative for antibodies when IDDM was diagnosed, but became positive within 24 months. All patients found to have coeliac disease were positive for IgA reticulin antibodies, but only 12 of 18 (67 %) showed a high level of IgA gliadin antibodies. Of the 18 patients genotyped for HLA DR locus, 14 (78 %) were positive for DR3 and 10 (56 %) were positive for DR4. DQB1*0201 allele was present in 17 of 18 patients (94 %). Coeliac disease in children with IDDM tends to develop soon after diabetes is diagnosed. Routine screening for coeliac disease is recommended repeatedly during the first years after the diagnosis of IDDM.

Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study

Aims/hypothesisWe aimed to assess the feasibility of a dietary intervention trial with weaning to hydrolysed formula in infants at increased risk of type 1 diabetes and to study the effect of the intervention on the emergence of diabetes-associated autoantibodies in early childhood.MethodsWe studied 242 newborn infants who had a first-degree relative with type 1 diabetes and carried risk-associated HLA-DQB1 alleles. After exclusive breastfeeding, the infants underwent a double-blind, randomised pilot trial of either casein hydrolysate (Nutramigen; Mead Johnson) or conventional cow’s milk-based formula until the age of 6–8 months. During a mean observation period of 4.7 years, autoantibodies to insulin, anti-glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured by radiobinding assays, and islet cell antibodies (ICA) by immunofluorescence.ResultsThe feasibility of screening and identifying a cohort of first-degree relatives with HLA-conferred disease susceptibility, enrolling them in a dietary intervention trial and following them for seroconversion to autoantibody positivity is established. The cumulative incidence of autoantibodies was somewhat smaller in the casein hydrolysate vs control formula group, suggesting the need for a larger well-powered study. After adjustment for duration of study formula feeding, life-table analysis showed a significant protection by the intervention from positivity for ICA (p=0.02) and at least one autoantibody (p=0.03).Conclusions/interpretationThe present study provides the first evidence ever in man, despite its limited power, that it may be possible to manipulate spontaneous beta cell autoimmunity by dietary intervention in infancy.

Intestinal γ/δ receptor-bearing T lymphocytes in celiac disease and inflammatory bowel diseases in children. Constant increase in celiac disease

ABSRACT: We studied the numbers of T-cell receptor α/β- and γ/δ-bearing lymphocytes in 27 jejunal specimens from 19 celiac patients, 27 rectal and colonic specimens from 14 ulcerative colitis patients and four patients with Crohns disease, and 24 control specimens. MAb and a three-layer peroxidase staining method were used. Only low numbers of γ/δ+ cells were seen in normal jejunum and rectum of controls, as well as in the specimens of patients with inflammatory bowel diseases. In the lamina propria of celiac patients, the mean number of γ/δ+ cells was significantly higher than in the controls before treatment, during gluten-free diet, and after the gluten challenge. Within the jejunal epithelium, the number of γ/δ+ cells was elevated before and during gluten elimination and after the challenge test. The absolute number of intraepithelial γ/δ+ cells remained constant during gluten elimination and provocation. We infer that the constantly elevated population of γ/δ+ T cells in the epithelium of celiac patients may play an important role in the pathogenesis of celiac disease.

Early recovery from cow's milk allergy is associated with decreasing IgE and increasing IgG4 binding to cow's milk epitopes

BACKGROUND The dynamics and balance of allergen-specific IgE, IgG4, and IgA binding might contribute to the development of tolerance in patients with cows milk allergy (CMA). Profiling of antibody binding to cows milk (CM) protein epitopes might help in predicting the natural history of allergy. OBJECTIVE We sought to investigate differences in IgE, IgG4, and IgA binding to CM epitopes over time between patients with early recovery or with persisting CMA. METHODS We studied serum samples at the time of diagnosis (mean age, 7 months), 1 year later, and at follow-up (mean age, 8.6 years) from 11 patients with persisting IgE-mediated CMA at age 8 to 9 years and 12 patients who recovered by age 3 years. We measured the binding of IgE, IgG4, and IgA antibodies to sequential epitopes derived from 5 major CM proteins with a peptide microarray-based immunoassay. We analyzed the data with a novel image-processing method together with machine learning prediction. RESULTS IgE epitope-binding patterns were stable over time in patients with persisting CMA, whereas binding decreased in patients who recovered early. Binding patterns of IgE and IgG4 overlapped. Among patients who recovered early, the signal of IgG4 binding increased and that of IgE decreased over time. IgE and IgG4 binding to a panel of alpha(s1)-, alpha(s2)-, beta-, and kappa-casein regions predicted outcome with significant accuracy. CONCLUSIONS Attaining tolerance to CM is associated with decreased epitope binding by IgE and a concurrent increase in corresponding epitope binding by IgG4.