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.     

Screening for celiac disease in diabetic children from Iran

Celiac disease has been shown to be associated with type 1 diabetes mellitus. We conducted this study to determine the frequency of celiac disease in a group of Iranian diabetic children. Ninety-six patients with type 1 diabetes mellitus were tested for anti-tissue transglutaminase antibodies. Six patients (6.25%) were seropositive, and histopathological changes were compatible with celiac disease in intestinal biopsy.     

Screening by anti-endomysium antibody for celiac disease in diabetic children and adolescents in Austria

BACKGROUND: Unrecognized celiac disease (CD) may be found in a substantial proportion of patients with type I diabetes mellitus. METHODS: A cohort of 403 Austrian children and adolescents with type I diabetes mellitus (210 males and 193 females; age range, 1-22 years) was screened for celiac disease using the IgA anti-endomysium antibody test (EMA) and the immunoglobulin (Ig)G anti-gliadin (AGA-IgG) and IgA anti-gliadin (AGA-IgA) antibody test. RESULTS: Twelve patients' sera (2.98%) yielded positive EMA results and two patients' sera (0.49%) with IgA deficiency had high AGA-IgG values. All but one of these patients underwent intestinal biopsy. Six (1.49%) had clear histologic evidence of CD (flat mucosa), whereas three (0.74%) showed minor histologic changes (increase in intraepithelial lymphocytes) and four (0.99%), including the EMA-negative patients with IgA deficiency, had a normal mucosa. When the cases with silent and potential CD were combined, the overall prevalence in the current cohort was 2.98%. There was no difference in the hemoglobin (Hb)A1c level between antibody-positive and -negative patients, and subsequent gluten-free diet did not change this metabolic parameter. CONCLUSION: The prevalence of clinically unrecognized CD, found by EMA screening, is much higher in Austrian children with diabetes than in a comparable population without diabetes. The prevalence of CD in diabetic children in Austria is distinctly lower, however, than in several other countries.     

Type 1 diabetes mellitus in a 3 1/2 year-old girl with Turner's syndrome

Turner's syndrome is associated with autoimmune disorders. Autoimmune endocrinopathy in Turner's syndrome seems to be limited to autoimmune thyroiditis. A small number of patients with Turner's syndrome has also been associated with celiac disease, inflammatory bowel disease and juvenile rheumatoid arthritis. Type 1 diabetes mellitus in Turner's syndrome has been rarely reported. We present here the youngest patient with Turner's syndrome who developed type 1 diabetes mellitus. At the age of 3.5 years she was hospitalized with diabetic ketoacidosis. Anti-islet cell and anti-insulin antibodies were positive and C-peptide level was low. When she was investigated for recurrent urinary tract infections, horseshoe kidney was detected by ultrasonography. Karyotype analysis revealed 45,XO. She has been followed for 2 years with an insulin dose of 0.9 U/kg per day. The prevalence of type 1 diabetes mellitus associated with Turner's syndrome is still unknown.     

Early onset of type I diabetes mellitus, Hashimoto's thyroiditis and celiac disease in a 7-yr-old boy with Down's syndrome

Abstract:  Patients with Down's syndrome are at higher risk for developing autoimmune diseases than those of the general population. Autoimmune diseases like Hashimoto's thyroiditis, Graves' disease, diabetes mellitus type I, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo and hypoparathyroidism are recognized associations with Down's syndrome. We describe the case of a very young boy with Down's syndrome who was diagnosed with diabetes mellitus type I, Hashimoto's thyroiditis and celiac disease before 8 yr of age. Unspecific symptoms like weight loss, unstable blood sugar with high amplitudes, behavioural problems and dry skin were suspicious for other endocrine disorders or celiac disease in our case. The boy was showing the typical human leukocyte antigen profile for these autoimmune diseases. The prevalence of these autoimmune diseases is higher in Down's syndrome than in general population. Therefore, we advice to follow children with Down's syndrome who develop more than two autoimmune diseases very carefully.     

Increased levels of bovine serum albumin antibodies in patients with type 1 diabetes and celiac disease-related antibodies

OBJECTIVES: To detect the presence of antibodies against bovine serum albumin in a cohort of Spanish patients with type 1 insulin-dependent diabetes. METHODS: Antibodies were measured using an in-house enzyme-linked immunosorbent assay test in 80 patients with type 1 diabetes, subdivided according to the presence or absence in their serum of celiac disease-related antibodies. For comparison, 30 patients with celiac disease (nondiabetic), 13 patients with autoimmune thyroiditis, and 45 healthy volunteers were used. RESULTS: Thirty-one percent of patients with diabetes yielded a positive result, with a mean value of 26.1 +/- 21.8 arbitrary units (AU). If the group was split into those with celiac disease-related antibodies and those lacking them, the percentages were 53% and 25%, respectively, with a mean value of 39.6 +/- 28.4 AU and 22.4 +/- 18.3 AU (P = 0.003), respectively. Seventy-three percent of celiac patients showed bovine serum albumin antibodies with a mean level of 38.8 +/- 27.7 AU, comparable to that of patients with diabetes with celiac antibodies, but higher than the group lacking them (P = 0.001). Although 46% of patients with autoimmune thyroiditis had positive results, the level detected (22.1 +/- 8.7 AU) was significantly lower than that recorded in patients with type 1 diabetes who had celiac disease antibodies (P = 0.04) and celiac patients (P = 0.04). Healthy volunteers showed no antibodies against bovine serum albumin. CONCLUSIONS: These data suggest that bovine serum albumin antibodies appears in patients with a compromised epithelial permeability, and they reflect a general defect in the process of immunologic tolerance associated with a predisposition to autoimmunity, rather than immunity specific to beta cells.     

Celiac disease in children and adolescents with type I diabetes: importance of hypoglycemia

BACKGROUND: Symptomatic hypoglycemia is an unavoidable problem in the treatment of type I diabetes. Celiac disease is associated with malabsorption and may therefore represent an important risk factor. METHODS: The frequency of symptomatic hypoglycemia in patients with type I diabetes and celiac disease (cases) was compared with those of patients who had diabetes without celiac disease (controls). For this purpose, each case was matched for age, sex, and duration of disease with one to two control patients. Indices of metabolic control (hemoglobin [Hb]A1c, frequency of hypoglycemia, and total insulin requirement) were retrieved for the 18 months before and after diagnosis of celiac disease. RESULTS: Eighteen patients (6 males and 12 females) had diagnosed celiac disease and were matched with 26 control patients (10 males and 16 females). There was no difference in age (11.0 years; range, 1.8-21.9 vs. 13.1 years; range, 2.3-22; P = 0.3) and duration of disease (8.4 years; range, 1.2-19.3 vs. 8.3 years; range, 1.1-18.7; P = 0.3) between the two groups. During the 6 months before and after diagnosis of celiac disease the cases had significantly more hypoglycemic episodes than the controls (means +/- SD; 4.5+/-4 vs. 2.0+/-2.2 episodes/months, P = 0.01). This was reflected by a progressive reduction in insulin requirement over the 12 months before diagnosis reaching a nadir at time 0 (0.6+/-0.2 vs. 0.9+/-0.3, P = 0.05). CONCLUSION: These data suggest that underlying celiac disease is associated with an increased risk of symptomatic hypoglycemia and that the introduction of a gluten-free diet with normalization of the intestinal mucosa may reduce its frequency.     

Small intestinal permeability and orocaecal transit time in cystic fibrosis.

Cellobiose and mannitol were used as probe molecules to measure intestinal permeability in 36 children with cystic fibrosis, and 25 age matched controls. Orocaecal transit was also evaluated for each subject using the lactulose/hydrogen breath test. There was a fourfold increase in permeability to disaccharide (cellobiose) in patients with cystic fibrosis, but permeability to the monosaccharide (mannitol) was similar to controls. The orocaecal transit time of lactulose was prolonged in patients with cystic fibrosis, but was unrelated to the percentage excretion of cellobiose or mannitol in cystic fibrosis patients or control subjects.     

Symptomless celiac disease in type 1 diabetes: 12‐year experience in Estonia

Background: We aimed to determine the prevalence and characteristics of celiac disease in children with type 1 diabetes in Estonia, a country with a formerly low frequency of both diseases. Methods: Altogether, 271 patients with diabetes were studied over 12 years (1995–2006): 122 at diagnosis and 149 patients 0.1–14.8 years after diagnosis. In addition, 73 patients were followed up over 1–6 years. Immunoglobulin A type endomysium and tissue transglutaminase antibodies were determined. Patients with antibodies and/or with celiac‐disease‐related symptoms were invited for a small‐intestinal biopsy. Results: At the primary screening, celiac disease was histologically confirmed in nine patients (all without symptoms), that is, in 3.3% (95% confidence interval: 1.63–6.42) of type 1 diabetes cases. At follow up, celiac disease was additionally detected in two (2.7%) of 73 diabetic patients, that is, in 0.016 (95% confidence interval: 0–0.072) celiac disease cases per follow‐up year. Conclusion: The prevalence of celiac disease among type 1 diabetes patients in Estonia is similar to that in countries with a high incidence of celiac disease and type 1 diabetes. As celiac disease is mostly symptomless, all children with type 1 diabetes, irrespective of their geographic origin, should be regularly screened for celiac disease.     

Intestinal permeability to inert sugars and different-sized polyethyleneglycols in children with celiac disease

Intestinal permeability was measured in a total of 42 children, 29 of whom had celiac disease. The celiac children were studied at presentation, during gluten-free diet, and/or at gluten challenge. The permeability was assessed by oral lactulose/L-rhamnose in all 42 children and also by different-sized polyethylene glycols (PEG) in 36 children. Results were compared with the findings of small intestinal biopsy. The mean of the permeability tests in children with enteropathy was significantly abnormal compared with the result in children with a normal mucosal morphology. The lactulose/L-rhamnose test and the PEG test gave equivalent results in the same child. In the celiac children abnormal permeability properties at presentation normalized during gluten-free diet and reappeared during gluten challenge. It is concluded that measurement of intestinal permeability may be a valuable tool in monitoring children with celiac disease, preferably when serial measurements are available in the same child.     

Anti-alpha-gliadin antibodies are not predictive of celiac disease in juvenile chronic arthritis

Some authors have recently reported an increased level of antigluten antibodies in rheumatoid arthritis, both in the adult and juvenile form. The real meaning of these antibodies is still unclear. We ascertained the levels of antigluten antibodies in a group of children with juvenile chronic arthritis to determine if these antibodies were linked with celiac disease and/or to increased intestinal permeability. In 18 of 53 patients (33.9%), the levels of antigluten antibodies (IgA or IgG) were higher than normal. No correlation was found between the increase in antigluten antibodies and the positive lactulose/ mannitol test, used for determining increased intestinal permeability. In all eight patients undergoing intestinal biopsy due to abnormal levels of antigluten antibodies (IgA class), intestinal mucosa was normal. In conclusion, our study shows that in patients with juvenile chronic arthritis, immunological response to gluten is neither related to celiac disease nor to increased intestinal permeability.     

Immunologic and biochemical factors of coincident celiac disease and type 1 diabetes mellitus in children

The objective of the study was to investigate whether immunologic and biochemical events occurring in the course of type 1 diabetes mellitus might play a role in the development of the celiac disease. The study was carried out on 223 children with long-standing diabetes mellitus type 1 (DM1). All the patients had TSH, fT4, fT3, urinary albumin secretion rate, IgA, level of antigliadin antibodies (AGA) IgA and IgG, antitissue transglutaminase IgA antibodies, antiendomysium (EmA) IgA and IgG antibodies and antitireoglobulin antibodies, antithyroid peroxidase antibodies evaluated. Serum TNF-alpha, IL-6, and IL-10 levels were also measured. The group of children with coincident DM1 and celiac disease and without autoimmune thyroiditis was characterized by significantly higher glycosylated hemoglobin, higher serum TNF-alpha, IL-6 but lower serum IL-10 in relation to the remaining diabetic patients. A statistically significant positive correlation was observed between IgA-anti-tTG and serum TNF-alpha (R = 0.28, p = 0.026); between IgG AGA and serum IL-6 (R = 0.31, p = 0.023); and between glycosylated hemoglobin and IgA-anti-tTG (R = 0.21, p = 0.001) and IgA antiendomysium (R = 0.22, p = 0.001). Poor metabolic control, persistent elevated levels of proinflammatory cytokines, and decreased level of antiinflammatory cytokines occurring in the course of type 1 diabetes mellitus might influence the incidence of celiac disease.     

Role of physical exercise in children and adolescents with diabetes mellitus

During the past 50 years several studies have underlined the central role of physical exercise in the management of patients with both type 1 and type 2 diabetes mellitus. The numerous benefits described in normal individuals who practise regular exercise have also been demonstrated in patients with diabetes who obtained significant physical and psychological advantages for the care of the underlying disease. Despite physical and psychological benefits, the occurrence of acute complications and some important effects on diabetes-related vascular complications may often discourage patients from participation in sports activities. However, even though adverse events may occur, exercise is still judged one of the most important components in the treatment of patients with diabetes. Thus, children, adolescents and young adults with diabetes must be educated on the metabolic changes occurring during physical activity in order to be able to acquire the ability to individually modulate their diet and insulin therapy before and after exercise. Appropriate education may allow a proper and correct approach to physical exercise.     

Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management

Type 1 diabetes (T1DM) is often associated with autoimmune diseases such as: autoimmune thyroid disease (ATD), celiac disease (CD), autoimmune gastritis (AIG), pernicious anemia (PA) and vitiligo. Autoimmune thyroid disease is the most prevalent endocrinopathy among diabetic patients. Hypothyroidism, celiac disease or Addison's disease in patients with type 1 diabetes may deteriorate glycemic control and can lead to an increased rate of hypoglycemia. Autoimmune gastritis, pernicious anemia and celiac disease can cause malabsorption and anemia which additionally impair the quality of life in patients with T1DM. The presence of organ-specific autoantibodies can be used to screen patients who are at higher risk of developing autoimmune diseases. Such procedure can help to identify patients, who need to undergo treatment in order to decrease the rate of possible complications in the future. In this clinical review we present current opinions in terms of diagnosis, management and screening in the most common type 1 diabetes-associated autoimmune diseases.     

Embryonal risks in gestational diabetes mellitus

Diabetes mellitus is generally associated with a higher incidence of early pregnancy loss and congenital anomalies, though this relationship should be strictly restricted to patients with previously existing diabetes. In gestational diabetes mellitus, which often develops during the third trimester, no such relationship should exist, though the birth of a previous infant with a congenital anomaly is often assumed to be a risk factor for gestational diabetes. OBJECTIVE: The study attempts to analyse the congenital anomaly rate in women with gestational diabetes and compare this to the rates in women known to have normal glucose tolerance. RESULTS: The prevalence of infants/fetuses with congenital anomalies born to women with gestational diabetes amounted to 4.48%, a rate similar to that recorded in women with normal glucose tolerance (4.54%). CONCLUSIONS: The development of gestational diabetes, in contrast to pre-existing diabetes, does not appear to be associated with an increased risk for teratogenesis.     

Latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and Celiac disease

Latent autoimmune diabetes mellitus in adults (LADA) is characterized by clinical presentation as type 2 diabetes mellitus after 25 years of age, initial control achieved with oral hypoglycemic agents for at least 6 months, presence of autoantibodies and some immunogenetic features of type 1 diabetes mellitus. An 8.3 year-old girl was referred to our pediatric endocrinology department because of incidental glucosuria. She did not complain of polyuria, polydipsia, or weight loss. Her body mass index (BMI) was at the 80th percentile. Fasting glucose was 126 mg/dl, and OGTT glucose level at 120 min was 307 mg/dl. Although C-peptide levels were normal, her first phase insulin response (FIR) was lower than the 1st percentile. Anti-insulin antibody (AIA), islet cell antibody (ICA), and anti-glutamic acid decarboxylase (antiGAD) were negative. According to the clinical and laboratory findings, she was diagnosed as having type 2 diabetes mellitus. She was started with oral anti-diabetic treatment for a period of 1 year. Insulin had to be initiated for worsening of HbA1c levels. In the fourth year of follow-up, she was admitted to our hospital with diabetic ketoacidosis although she was on an intensive insulin regimen. At this time, C-peptide levels were low, antiGAD and AIA were positive with HLA DR3/DQ2 haplotype. In addition, her thyroid peroxidase antibody and endomysium antibody were found to be high at follow-up. Small intestinal biopsy revealed celiac disease. This patient may represent the first case of latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and celiac disease.     

Features of children with positive celiac serology and type 1 diabetes mellitus

Prior studies have reported disparate clinical presentations between children with celiac disease and type 1 diabetes mellitus and those with celiac disease alone. Studies focusing on differences in endoscopic and histopathological findings, however, are limited. We reviewed children aged 2–18 years, presenting for an initial evaluation between January 2000 and December 2010. Data on medical history, serologic markers, upper endoscopy, and histopathology were collected. Only the children with positive celiac serology who had upper endoscopy performed within 3 months of the initial visit were included. We identified 294 children who fulfilled the criteria, 21 of whom had diagnosed type 1 diabetes mellitus. Diabetic children were more likely to have absence of gastrointestinal symptoms. Erythematous duodenal and esophageal mucosa on endoscopy, and histopathology suggestive of reflux esophagitis were more common in the diabetes group. Diabetic children with positive celiac serology had different histopathological features as compared with their non‐diabetic counterparts.     

Incidence of enteropathy-associated T-cell lymphoma in celiac disease: implications for children and adolescents with type 1 diabetes

Abstract: The long-term consequences of screening for celiac disease in diabetic children are not known. Routine screening is not practiced in our pediatric diabetic population. This study of the incidence of the most severe and specific long-term complication of untreated celiac disease, i.e., enteropathy-associated T-cell lymphoma (EATCL) and its association with diabetes, is done in order to justify our strategy not to practice routine screening. In the first phase of this study, a questionnaire was sent to all Swiss pathologists. The second phase consisted of a search in the cancer registry of the canton of Zurich. The incidence of EATCL in the general population of a Swiss region and the theoretical risk for a diabetic patient to develop this type of lymphoma were calculated.
Ten cases of EATCL were found. Five had a long history of malabsorption, three of them since childhood. The mean age of the patients was 61.9 yr. None suffered from diabetes mellitus. The incidence of EATCL was 0.07/100 000 inhabitants/year. The expected risk for EATCL in patients with type 1 diabetes is 12.4/100 000 diabetic patients over a period of 60 yr.
The data suggest that the risk for EATCL is small in diabetic patients. Therefore, we restrict the investigation for celiac disease to patients with typical and atypical symptoms, but do not perform routine screening.     

Prediction of silent celiac disease at diagnosis of childhood type 1 diabetes by tissue transglutaminase autoantibodies and HLA

Abstract: Aims: The aims were to estimate the diagnostic sensitivity and specificity of autoantibodies to tissue transglutaminase (IgA‐ and IgG‐tTG), gliadin (AGA) and endomysium (EMA) in relation to human leukocyte antigen (HLA)‐DQB1 alleles to identify silent celiac disease at diagnosis of type 1 diabetes. Methods: IgA‐ and IgG‐tTG were measured in radioligand binding assays in 165 type 1 diabetic patients. Data on HLA‐DQB1 were available for 148 patients and on both AGA and EMA for 164 patients. For patients considered positive for AGA or EMA, or both, an intestinal biopsy was suggested. HLA‐DQB1 typing was carried out by polymerase chain reaction and hybridization with allele specific probes. Results: Three patients, left out from further study of antibodies, but not from HLA‐DQB1 analysis, had treated celiac disease at diagnosis. Out of the other 162 type 1 diabetic patients tested, nine had IgA‐tTG, six IgG‐tTG, eight EMA, and 11 AGA. Biopsy was suggested for nine patients, of whom six showed villous atrophy, one did not and two refused to participate. Thus, silent celiac disease was probable in 8/162 and biopsy‐verified in 6/162, where five patients were AGA‐positive and six either EMA‐, IgA‐tTG‐ or IgG‐tTG‐positive. Of the 11 patients with celiac disease (three with treated and eight with silent celiac disease), 10 were HLA‐DQB1‐typed, of whom 65% (13/20) had the DQB1*02 allele, compared with 36% (100/276; p = 0.011) of those without celiac disease. IgA‐tTG levels were higher in patients having either *02 or *0302 (0.6; ?1.3–112.4 RU) compared with those not having these alleles (0.4; ?0.7–3.4 RU; p = 0.023). Conclusion: IgA‐tTG are HLA‐DQB1*02‐associated autoantibodies with high sensitivity and specificity for silent celiac disease at diagnosis of type 1 diabetes.     

Value of the intestinal permeability test with lactulose-mannitol for screening and monitoring of celiac disease in children]

An intestinal permeability test (IPT) analysing the mannitol (M) and lactulose (L) clearances and the L/M ratios was performed in 15 children followed for celiac disease, before the onset of exclusion diet, during the gluten-free diet and after the reintroduction of gluten. The results showed a significant increase of the L/M ratios under normal diet, with respect to a control population. This increase was related to an increased L urinary excretion and to a decrease in M excretion. During gluten-free diet a normalization of the L/M ratios was observed. Reintroducing gluten altered the L/M ratios by increasing the L intestinal permeability and decreasing the M intestinal permeability. This study shows the value of the non invasive L/M IPT for the screening and monitoring of celiac disease in children.