98 degree bio

OBJECTIVE--To investigate the prevalence of autoimmune diseases in young patients (probands) with type 1 diabetes and their first-degree relatives, and to determine the spectrum of extrapancreatic manifestations in these subjects.

RESEARCH DESIGN AND METHODS--The study population included 109 probands age 13 [+ or -] 4.9 years and 412 first-degree relatives age 28.7 [+ or -] 16.2 years. The prevalence rates of autoimmune thyroiditis and celiac disease were determined in all probands and in 100 of the 412 first-degree relatives. Control groups included 78 subjects age 14.9 [+ or -] 10.4 years for the prevalence of autoimmune thyroiditis and 120,000 youth ages 16-17 years for the prevalence of celiac disease. Thyroiditis and celiac disease were diagnosed by abnormally high thyroid peroxidase (TPO), thyroglobulin (TG), antigliadin, and antiendomysial antibody titers. Celiac was confirmed by biopsy. A questionnaire was used to interview probands and relatives to determine the spectrum of autoimmune manifestations.

RESULTS--The prevalence of autoimmune thyroiditis determined by high TPO and/or TG titers was 27 and 25% for probands and relatives, respectively. These rates were higher than those for control subjects (P < 000.1). The prevalence of celiac disease among probands and screened relatives was 8.3 and 6%, respectively. These rates were higher than those for control subjects and the 312 family members interviewed only (0.1 and 0.3%, respectively; P < 0.0001). Interviews of participants revealed a wide range of associated autoimmune diseases. The risk of developing an autoimmune disease was higher (P < 0.00 1) in families with a proband who had an additional autoimmune manifestation.

CONCLUSIONS--Screening for autoimmune thyroiditis and celiac disease should be performed in patients with type 1 diabetes and their first-degree relatives, especially when the probands have an additional autoimmune manifestation.

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Type 1 diabetes, a common autoimmune endocrine disease in children and adolescents, is frequently associated with other autoimmune diseases and autoantibodies (1). The most prevalent autoimmune disease associated with type. 1 diabetes is Hashimoto thyroiditis. Its prevalence varies from 8 to 50% depending on the age, sex, and ethnic origin of the subjects (2-10). Because of this high prevalence, most investigators recommend screening children and adolescents with type 1 diabetes for autoimmune thyroid disease (2,3,6,7).

Celiac disease coexists with type 1 diabetes less frequently than does Hashimoto thyroiditis. Its prevalence in children and adolescents with type 1 diabetes ranges from ~3 to 8% (11-16), a much higher prevalence than that found in the general population. Thus routine screening of type 1 diabetes patients for celiac disease is also recommended (12,16,17).

In a study based solely on serological data, thyroid antibodies were found more frequently in both type 1 diabetic patients and their first-degree relatives (18). Thus, family members of type 1 diabetic patients may also be at high risk for developing type 1 diabetes and associated autoimmune diseases. The prevalence of autoimmune disorders, especially thyroid and celiac diseases in first-degree relatives, remains mostly unknown. Except for this study (18), no previous study has evaluated the prevalence of thyroid (4,6,19-22) and celiac diseases (23,24) in the same cohort. Moreover, previous studies have not examined the full extent of associated autoimmune diseases beyond a few conditions.

The present multicenter study was carried out in a cohort of type 1 diabetes patients and first-degree relatives with the following objectives: 1) to determine the prevalence of both autoimmune thyroid and biopsy-proven celiac diseases, and 2) to investigate the range of associated autoimmune manifestations by obtaining a detailed family history.

RESEARCH DESIGN AND METHODS

Study population

Pediatric endocrinology clinics from four medical centers participated in this multicenter study, carried out from 1997 to 2000. The study population included 109 type 1 diabetic patients who were diagnosed before age 18 years and 412 first-degree relatives. All patients and 100 of the 412 first-degree relatives were screened to determine the prevalence of autoimmune thyroid and celiac diseases. (Screening was offered to all relatives, but only 100 gave their consent.) In addition, the patients and their first-degree relatives were interviewed by the one investigator (A.M.) to detect autoimmune diseases, using a detailed questionnaire that included all signs and symptoms suggestive of autoimmune diseases. Medical history and data regarding autoimmune diseases in young children were obtained from their parents. The diagnosis of an autoimmune disease was confirmed by physical examination and/or review of the subject's medical charts.

A group of 78 healthy subjects with no family history of autoimmune disease served as a control group to assess the prevalence of autoimmune thyroid disease. This group consisted of medical staff and their children and subjects from pediatric outpatient clinics with no underlying medical pathology.

Data on the prevalence of celiac disease in Israel were based on two sources: Israel Defense Forces (IDF) draft board data and a recently published screening study in blood donors (25). The IDF data, gleaned from 120,000 consecutive candidates for army service ages 16-17 years (collected by A.L. in cooperation with the IDF), served as an additional control group to assess the prevalence of celiac disease in Israel. In this group, the diagnosis of celiac disease was based on clinical symptoms suggestive of celiac disease and positive serology (antigliadin and antiendomysial antibodies). The diagnosis was further confirmed by intestinal biopsy. The prevalence rate of celiac disease among the blood donor group was determined by serological screening of 1,570 healthy subjects (median age 38 years) with no known celiac disease. The blood samples were screened for celiac disease by antigliadin IgG, human tissue transglutaminase, and antiendomysial antibodies. The final diagnosis was based on intestinal biopsy (25) .

Immunological and biochemical assays

Thyroid antibodies directed to thyroglobulin (TG) and to microsomal antigens (TG and TPO) were determined by enzymelinked immunosorbent assay (Enzymun-Test, Boehringer Mannheim). TG and TPO titers >1/180 and 1/80, respectively, were considered diagnostic for autoimmune thyroid disease. In all patients screened for thyroid antibodies, free T4 and thyrotropin concentrations were also determined.

IgA antiendomysial antibodies (AEAs) were detected on the smooth muscle of monkey esophagus by an indirect immunofluorescence test (ImmuGlo; IMMCO Diagnostics, Buffalo, NY). All sera with fluorescence (titer [greater than or equal to]1/5) were considered to be positive. Antigliadin antibodies (AGAs) of IgA and IgG were determined by an indirect solid-phase enzyme immunometric assay. IgA and IgG antibody levels [greater than or equal to]12 units/ml were considered positive.

The diagnosis of celiac disease was based on the presence of positive AEA and AGA titers. The final diagnosis was confirmed by performing jejunal biopsy in all probands and family members tested positive for AEA and/or AGA.

GAD antibodies were determined by a commercial radioimmunoassay (CIS Bio International, Gif-Sur-Yvette Cedex, France). Levels of >1 unit/ml were considered positive. Islet cell antibodies (ICAs) were detected on monkey pancreas sections by an indirect immunofluorescence antibody test (BioSystems, Barcelona, Spain). Fluorescence at a dilution [greater than or equal to]25% was considered positive. Sera for these antibodies were obtained usually within days after the diagnosis, but not later than 3 months.

The E. Wolfson Hospital local ethics committee approved the study protocol. Informed consent for withdrawal of blood was obtained from all participants.

Statistical analysis

Data were stored on Excel 97 program (Microsoft). Data were analyzed using SPSS 9.0 statistical analysis software (SPSS, Chicago, IL). Frequencies of autoimmune diseases were simultaneously compared across groups (patients, first-degree relatives, and healthy subjects) using a [chi square] test. Tests were considered significant at P < 0.05.

RESULTS--The characteristics of the study population are shown in Table 1. The mean ages of type 1 diabetic patients and healthy subjects screened for the presence of thyroid antibodies were not significantly different. Similarly, the mean age and ethnic origins of the 100 first-degree screened relatives did not differ significantly from the mean age and ethnicity of the whole group.

Prevalence of ICAs and GAD antibodies