Scandinavian Journal of Gastroenterology. 2014; 49: 52–58
ORIGINAL ARTICLE DIABETES
High prevalence of celiac disease in Swedish children and adolescents with type 1 diabetes and the relation to the Swedish epidemic of celiac disease: a cohort study
MARA CERQUEIRO BYBRANT1,2, EVA ÖRTQVIST2,3, SOPHIE LANTZ2,4 & LENA GRAHNQUIST1,2 1
Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden, 2Department of Women’s and Children’s Health, Karolinska Institutet, SE- 17176, Stockholm, Sweden, 3Pediatric Diabetes Clinic, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden, and 4Department of Orthopedics, Västervik County Hospital, SE-59381, Västervik, Sweden (at the time of the study medical student, Karolinska Institutet)
Abstract Aim. The aim was to determine the prevalence and clinical and temporal relationship of celiac disease (CD) in a population of Swedish children with type 1 diabetes mellitus (T1DM) before, during, and after the Swedish epidemic of CD (birth cohorts 1984–1996). Methods. Retrospective chart review between 1995 and 2005 was conducted of 1151 children (0–18 years old, born 1981–2004) with T1DM. Results. A prevalence of 9.1% (95% CI: 7.2–11.2) of CD in T1DM children was found. No significant difference in prevalence of CD was observed in different birth years, in contrast to the Swedish epidemic of CD. Sixty-two percent of children diagnosed with CD after T1DM onset had pathological levels of antibodies within the first 24 months. The presence or absence of gastrointestinal symptoms had no predictable value for biopsy-confirmed CD or not. Conclusion. The onset of CD in the T1DM population does not follow the pattern of the general population during the Swedish epidemic of CD. The shared genetic component in the human leukocyte antigen region in cases with comorbidity of CD and T1DM may overrule other CD-causing factors in the general population. Children with T1DM should be screened for CD at diagnosis and repeatedly at least during the first 2 years, even if asymptomatic.
Key Words: Celiac disease, children, prevalence, screening, type 1 diabetes mellitus
Introduction Co-occurrence of celiac disease (CD) and type 1 diabetes mellitus (T1DM) in children is a challenge for patients, parents, and healthcare professionals. Both CD and T1DM are autoimmune disorders with a shared genetic background, both in human leukocyte antigen (HLA) genes and non-HLA genes [1–4]. Children with T1DM can be screened with auto-antibodies for CD [3,5,6], and the CD diagnosis should be confirmed with small bowel biopsy [7,8]. The prevalence of CD in the general population worldwide is about 1% [1,9] and between 0.7–2.9%
in Swedish children [10,11]. The prevalence has increased over time, and CD is more common in females than males [12,13]. The risk of CD in childhood follows regionalvariations [14]. In the mid-1980s, pediatricians throughout Sweden diagnosed an increasing number of children with CD (most were under 2 years of age). The cumulative incidence of CD reached levels higher than reported previously, from 1 to 4 cases per 1000 births. The incidence continued to be high during ten years and then decreased rapidly to the incidence at baseline. The high incidence rate that was shown in Swedish children born between 1984 and 1996 is known as the Swedish epidemic of CD. It has
Correspondence: Mara Cerqueiro Bybrant, MD, Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 77708. Fax: +46 8 517 77685. E-mail: [email protected]
(Received 3 July 2013; revised 10 August 2013; accepted 15 September 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.846403
Celiac disease and type 1 diabetes in Swedish children been explained as a combination of postponed introduction of gluten until 6 months of age, usually with high gluten concentration due to new commercial formulas at that time and gluten introduced without the breastfeeding protecting effect [10–12,15–17]. In Sweden, incidence of childhood-onset diabetes is, next to Finland, the highest reported in the world [18]. Further, the incidence of T1DM in Swedish children has doubled in the past 25 years and is now higher than 40/100,000 person-years in children aged 0–15 years [19]. Most studies show a five to seven times higher prevalence of CD in children with T1DM compared with the general population [1,9,20]. The prevalence rates of CD in T1DM children range from 1% in Germany to 16.4% in Algeria [1,3,20]. Despite the knowledge of the co-occurrence of CD and T1DM and that CD can have an adverse effect on T1DM [1,21,22], there are still different recommendations about screening tests, frequency of screening, and treatment of asymptomatic children in the consensus-based guidelines from national and international associations [23,24] and global consensus on when and how to screen is lacking [1]. The aim of the present study was to determine the prevalence of CD in a large population of Swedish children with T1DM before, during, and after the Swedish epidemic of CD, to describe possible gender differences, to investigate the temporal relationship between the onset of T1DM and CD, and to study the frequency of reported gastrointestinal (GI) symptoms as a clinical feature. Subjects, materials, and methods Study area and population The present study was performed in Stockholm, the capital of Sweden (mainly urban areas). The total population was rising from 1,500,000 in 1995 to 1,700,000 in 2004. The Karolinska Hospital outpatient and admission area, the central and north part of Stockholm, included ~250,000 children up to the age of 18 years in 1995, and which rose to 275,000 in 2004. This was equivalent to about 15% of the Swedish child population (data from the National Central Bureau of Statistics). In Sweden, all outpatient evaluation and hospital admissions were free of charge for patients up to the age of 18, and all diabetic children were attended in a Pediatric Diabetes Clinic. Study design Since 1995, all T1DM children (0–17.9 years of age) attending the Pediatric Diabetes Clinic at St. Göran
53
Children’s Hospital (from 1998 Astrid Lindgren Children’s Hospital, Karolinska) were registered in a diabetes database (DiaBase). The World Health Organization (WHO) criteria for diabetes diagnosis were used [25]. Follow-up time in the present study started from 1 January 1995 and ended when CD was diagnosed [7] or by study period completion, that is, till December 31, 2004. In total, 1151 children were part of the study population. All T1DM children with persistent pathological antibody test results that had not yet been diagnosed with CD at the study period completion were followed up for at least one more year. A local recommendation to screen all T1DM patients for CD was introduced in 1995. Children with at least one pathological antibody test result were retrospectively studied through all available patient file systems (DiaBase, files in paper and computerized). Immunoglobulin A (IgA)-deficiency patients were also separately searched for. Data collection included antibody tests screening results, gender and age, date and age of onset of T1DM and CD when diagnosed (including biopsy results), recorded information of GI symptoms (abdominal pain, abdominal discomfort, diarrhea, constipation, flatulence, or vomiting) from diabetes diagnosis until the decision of biopsy and/or at CD diagnosis. The study cohort consisted of eight children with known CD before T1DM onset, three children who underwent biopsy previous to screening due to symptoms and the 836 children who were subjected to screening (847/1151). For comparison, we constructed three birth cohorts based on the years of the Swedish epidemic of CD (birth cohort 1984 to 1996 [14–16]), before (birth cohort 1981 to 1983), and thereafter (birth cohort 1997 to 2004). The study was approved by the Regional Ethics Review Board in Stockholm. Laboratory methods Serological test. IgA gliadin antibodies (AGA) were measured using an enzyme-linked immunosorbent assay (ELISA), cut-off being
ORIGINAL ARTICLE DIABETES
High prevalence of celiac disease in Swedish children and adolescents with type 1 diabetes and the relation to the Swedish epidemic of celiac disease: a cohort study
MARA CERQUEIRO BYBRANT1,2, EVA ÖRTQVIST2,3, SOPHIE LANTZ2,4 & LENA GRAHNQUIST1,2 1
Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden, 2Department of Women’s and Children’s Health, Karolinska Institutet, SE- 17176, Stockholm, Sweden, 3Pediatric Diabetes Clinic, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden, and 4Department of Orthopedics, Västervik County Hospital, SE-59381, Västervik, Sweden (at the time of the study medical student, Karolinska Institutet)
Abstract Aim. The aim was to determine the prevalence and clinical and temporal relationship of celiac disease (CD) in a population of Swedish children with type 1 diabetes mellitus (T1DM) before, during, and after the Swedish epidemic of CD (birth cohorts 1984–1996). Methods. Retrospective chart review between 1995 and 2005 was conducted of 1151 children (0–18 years old, born 1981–2004) with T1DM. Results. A prevalence of 9.1% (95% CI: 7.2–11.2) of CD in T1DM children was found. No significant difference in prevalence of CD was observed in different birth years, in contrast to the Swedish epidemic of CD. Sixty-two percent of children diagnosed with CD after T1DM onset had pathological levels of antibodies within the first 24 months. The presence or absence of gastrointestinal symptoms had no predictable value for biopsy-confirmed CD or not. Conclusion. The onset of CD in the T1DM population does not follow the pattern of the general population during the Swedish epidemic of CD. The shared genetic component in the human leukocyte antigen region in cases with comorbidity of CD and T1DM may overrule other CD-causing factors in the general population. Children with T1DM should be screened for CD at diagnosis and repeatedly at least during the first 2 years, even if asymptomatic.
Key Words: Celiac disease, children, prevalence, screening, type 1 diabetes mellitus
Introduction Co-occurrence of celiac disease (CD) and type 1 diabetes mellitus (T1DM) in children is a challenge for patients, parents, and healthcare professionals. Both CD and T1DM are autoimmune disorders with a shared genetic background, both in human leukocyte antigen (HLA) genes and non-HLA genes [1–4]. Children with T1DM can be screened with auto-antibodies for CD [3,5,6], and the CD diagnosis should be confirmed with small bowel biopsy [7,8]. The prevalence of CD in the general population worldwide is about 1% [1,9] and between 0.7–2.9%
in Swedish children [10,11]. The prevalence has increased over time, and CD is more common in females than males [12,13]. The risk of CD in childhood follows regionalvariations [14]. In the mid-1980s, pediatricians throughout Sweden diagnosed an increasing number of children with CD (most were under 2 years of age). The cumulative incidence of CD reached levels higher than reported previously, from 1 to 4 cases per 1000 births. The incidence continued to be high during ten years and then decreased rapidly to the incidence at baseline. The high incidence rate that was shown in Swedish children born between 1984 and 1996 is known as the Swedish epidemic of CD. It has
Correspondence: Mara Cerqueiro Bybrant, MD, Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 77708. Fax: +46 8 517 77685. E-mail: [email protected]
(Received 3 July 2013; revised 10 August 2013; accepted 15 September 2013) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2013.846403
Celiac disease and type 1 diabetes in Swedish children been explained as a combination of postponed introduction of gluten until 6 months of age, usually with high gluten concentration due to new commercial formulas at that time and gluten introduced without the breastfeeding protecting effect [10–12,15–17]. In Sweden, incidence of childhood-onset diabetes is, next to Finland, the highest reported in the world [18]. Further, the incidence of T1DM in Swedish children has doubled in the past 25 years and is now higher than 40/100,000 person-years in children aged 0–15 years [19]. Most studies show a five to seven times higher prevalence of CD in children with T1DM compared with the general population [1,9,20]. The prevalence rates of CD in T1DM children range from 1% in Germany to 16.4% in Algeria [1,3,20]. Despite the knowledge of the co-occurrence of CD and T1DM and that CD can have an adverse effect on T1DM [1,21,22], there are still different recommendations about screening tests, frequency of screening, and treatment of asymptomatic children in the consensus-based guidelines from national and international associations [23,24] and global consensus on when and how to screen is lacking [1]. The aim of the present study was to determine the prevalence of CD in a large population of Swedish children with T1DM before, during, and after the Swedish epidemic of CD, to describe possible gender differences, to investigate the temporal relationship between the onset of T1DM and CD, and to study the frequency of reported gastrointestinal (GI) symptoms as a clinical feature. Subjects, materials, and methods Study area and population The present study was performed in Stockholm, the capital of Sweden (mainly urban areas). The total population was rising from 1,500,000 in 1995 to 1,700,000 in 2004. The Karolinska Hospital outpatient and admission area, the central and north part of Stockholm, included ~250,000 children up to the age of 18 years in 1995, and which rose to 275,000 in 2004. This was equivalent to about 15% of the Swedish child population (data from the National Central Bureau of Statistics). In Sweden, all outpatient evaluation and hospital admissions were free of charge for patients up to the age of 18, and all diabetic children were attended in a Pediatric Diabetes Clinic. Study design Since 1995, all T1DM children (0–17.9 years of age) attending the Pediatric Diabetes Clinic at St. Göran
53
Children’s Hospital (from 1998 Astrid Lindgren Children’s Hospital, Karolinska) were registered in a diabetes database (DiaBase). The World Health Organization (WHO) criteria for diabetes diagnosis were used [25]. Follow-up time in the present study started from 1 January 1995 and ended when CD was diagnosed [7] or by study period completion, that is, till December 31, 2004. In total, 1151 children were part of the study population. All T1DM children with persistent pathological antibody test results that had not yet been diagnosed with CD at the study period completion were followed up for at least one more year. A local recommendation to screen all T1DM patients for CD was introduced in 1995. Children with at least one pathological antibody test result were retrospectively studied through all available patient file systems (DiaBase, files in paper and computerized). Immunoglobulin A (IgA)-deficiency patients were also separately searched for. Data collection included antibody tests screening results, gender and age, date and age of onset of T1DM and CD when diagnosed (including biopsy results), recorded information of GI symptoms (abdominal pain, abdominal discomfort, diarrhea, constipation, flatulence, or vomiting) from diabetes diagnosis until the decision of biopsy and/or at CD diagnosis. The study cohort consisted of eight children with known CD before T1DM onset, three children who underwent biopsy previous to screening due to symptoms and the 836 children who were subjected to screening (847/1151). For comparison, we constructed three birth cohorts based on the years of the Swedish epidemic of CD (birth cohort 1984 to 1996 [14–16]), before (birth cohort 1981 to 1983), and thereafter (birth cohort 1997 to 2004). The study was approved by the Regional Ethics Review Board in Stockholm. Laboratory methods Serological test. IgA gliadin antibodies (AGA) were measured using an enzyme-linked immunosorbent assay (ELISA), cut-off being
