A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders
Authors: Jonas F. Ludvigsson, Abraham Reichenberg, Christina M. Hultman, Joseph A. Murray
Journal: JAMA Psychiatry (2013)

utism or autistic spectrum disorder (ASD) is a complex developmental disorder characterized by the triad of symptoms of impaired social interaction, impaired communication, and repetitive behaviors.Previously, ASD was estimated to occur in fewer than 1 per 1000 individuals, 1 but increasing disease awareness, new diagnostic criteria, and a potentially true increase in ASD incidence have led some to suggest that more than 1% of the population of US children have some kind of ASD. 2 Typically apparent before age 3 years, ASDs include infantile autism, Åsperger syndrome, and pervasive development disorders (atypical autism). 3Many children with ASDs have feeding symptoms from infancy. 3 Although there is a strong genetic component in ASDs 4,5 (siblings of individuals with ASDs are at a highly increased risk of having an ASD themselves), 6 no single mutation has been identified that can explain more than a small percentage of all disorders, and emerging research has linked various determinants, including an array of toxicant exposures with subsequent ASDs. 7,8The fact that not only pregnancy-related and neonatal adverse events 9 but also intrauterine exposure to certain teratogenic drugs may increase the risk of ASDs 10 strongly suggests that ASD begins early in life.We have recently demonstrated a link between parental autoimmunity and ASDs. 11eliac disease (CD) is an immune-mediated disorder that occurs in 1% to 2% of the Western population. 12It is triggered by gluten exposure in genetically susceptible individuals. 12Individuals with CD usually have small intestinal villous atrophy (VA) and inflammation, but in the past years it has be-IMPORTANCE Most case reports suggest an association between autistic spectrum disorders (ASDs) and celiac disease (CD) or positive CD serologic test results, but larger studies are contradictory.OBJECTIVE To examine the association between ASDs and CD according to small intestinal histopathologic findings.DESIGN AND SETTING Nationwide case-control study in Sweden.MAIN OUTCOMES AND MEASURES Through 28 Swedish biopsy registers, we collected data about 26 995 individuals with CD (equal to villous atrophy, Marsh stage 3), 12 304 individuals with inflammation (Marsh stages 1-2), and 3719 individuals with normal mucosa (Marsh stage 0) but positive CD serologic test results (IgA/IgG gliadin, endomysium, or tissue transglutaminase) and compared them with 213 208 age-and sex-matched controls.Conditional logistic regression estimated odds ratios (ORs) for having a prior diagnosis of an ASD according to the Swedish National Patient Register.In another analysis, we used the Cox proportional hazards regression model to estimate hazard ratios (HRs) for future ASDs in individuals undergoing small intestinal biopsy.RESULTS A prior ASD was not associated with CD (OR, 0.93; 95% CI, 0.51-1.68)or inflammation (OR 1.03; 95% CI, 0.40-2.64)but was associated with a markedly increased risk of having a normal mucosa but a positive CD serologic test result (OR, 4.57; 95% CI, 1.58-13.22).Restricting our data to individuals without a diagnosis of an ASD at the time of biopsy, CD (HR, 1.39; 95% CI, 1.13-1.71)and inflammation (HR, 2.01; 95% CI, 1.29-3.13)were both associated with moderate excess risks of later ASDs, whereas the HR for later ASDs in individuals with normal mucosa but positive CD serologic test results was 3.09 (95% CI, 1.99-4.80).CONCLUSIONS AND RELEVANCE Although this study found no association between CD or inflammation and earlier ASDs, there was a markedly increased risk of ASDs in individuals with normal mucosa but a positive CD serologic test result.