Psychiatric Disorders in Children Linked to Celiac Disease

Children with celiac disease are at a 1.4-fold increased risk for psychiatric disorders, according to a new Swedish study.¹

Agnieszka Butwicka, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institute, Stockholm, Sweden, and colleagues assessed the risk of childhood psychiatric disorders (any psychiatric disorder; psychotic, mood, anxiety, and eating disorders; psychoactive substance misuse; behavioral disorder; ADHD; ASD; and intellectual disability) in 10,903 children age 18 and younger and 12,710 of their siblings.

For each child with celiac disease, the researchers randomly selected 100 general population controls (ie, unexposed individuals) who were matched by gender and year and country of birth, and had been diagnosed with celiac disease at >18 years.

For each sibling of a celiac disease proband, the researchers randomly assigned 100 healthy control siblings from the general population (ie, siblings of people without celiac disease) and matched them in terms of gender and year and country of birth of both siblings. Both sets of siblings were required to be free of celiac disease to age 19.

The researchers obtained histological data on individuals who had exhibited villous atrophy in small intestine biopsy specimens between 1969 and 2008, equating villous atrophy with celiac disease. The median age at the time of intestinal biopsy was 3.0 years (interquartile range [IQR] 1.3-8.9 years). The median duration of follow-up was 9.6 years for children with celiac disease and 17.9 years for their siblings (IQR, 5.3- 15.6 years and 12.8-18.0 years respectively).

In the main cohort study, the researchers estimated the risk for any psychiatric disease, as well as specific psychiatric disorders (ie, mood, anxiety, eating, and behavioral disorders, as well as neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD), autistic spectrum disorders (ASD), and intellectual disability) in children with celiac disease, compared with general population controls. They used a design with sibling analyses to investigate whether underlying familiar factors could account for the associations. As a comparator, the risk for psychiatric disorders in the siblings of probands was compared with the risk in siblings of the general population.

Both univariate and multivariate analyses were conducted, adjusting for maternal/paternal age at the child’s birth, maternal/paternal country of birth, level of education of highest-educated parent, and the child’s gestational age, birthweight, Apgar score, and history of psychiatric disorders prior to recruitment.

During follow-up, 7.7% of children were diagnosed with a psychiatric disorder. A positive association was found in the first univariate analysis between celiac disease and any psychiatric disorder (hazard ratio [HR], 1.4; 95% CI, 1.3-1.4), which remained even after the researchers adjusted for maternal/paternal age at childbirth and country of birth, parental education level, and child’s gestational age, birthweight, Apgar score, and previous history of psychiatric disorders.

Children with celiac disease were found to be at increased risk for specific psychiatric disorders, including mood disorders (HR, 1.2; 95% CI, 1.0-1.4), anxiety disorders (HR, 1.2; 95% CI, 1.0-1.4), eating disorders (HR, 1.4; 95% CI, 1.1- 1.8), behavioral disorders (HR, 1.4; 95% CI, 1.2-1.6), ADHD (HR, 1.2; 95% CI, 1.0-1.4), ASD (HR, 1.3; 95% CI, 1.1-1.7), and intellectual disability (HR, 1.7; 95% CI, 1.4-2.1).

Although a history of previous psychiatric disorders was more common in patients with celiac disease (OR, 1.8; 95% CI, 1.5-2.1;

P <.001), the association was statistically significant only for eating (OR, 2.8; 95% CI, 2.2-3.7; P <.001) and behavioral disorders (OR, 1.8; 95% CI, 1.4-2.3; P <.001).

The overall prevalence of psychiatric disorders in the entire sample in the celiac disease probands was 6.9% (95% CI, 6.4%-7.4%) in the 10 years after biopsy. However, the 10-year prevalence of psychiatric disorders was increased 8-fold over the study period when the researchers analyzed the findings by cohort.

The siblings of celiac disease probands were at no increased risk for any psychiatric disorder, or specific psychiatric disorders.

The study finding that psychiatric disorders “may precede a diagnosis of celiac disease in children” is “important,” according to the investigators in the study. In addition, the study “also provides insight into psychiatric comorbidities in childhood celiac disease over time,” they write.

They note that “the mechanisms underlying the association between celiac disease and psychiatric orders has yet to be established.” However, the lack of increased risk of psychiatric disorders in the siblings of celiac disease probands “suggests an effect of celiac disease per se rather than common genetic or within-family environmental factors.”

Lower body mass and malnutrition in children with celiac disease is one possible pathogenic mechanism, and immune-mediated systemic reaction in celiac disease may be associated with the increased risk for depression and autism, they suggest. The increased risk of neurodevelopmental disorders also suggests a “biological etiology of psychiatric comorbidity in celiac disease.” In addition, psychological aspects of celiac disease and chronic symptoms may contribute to the effect.

“Once celiac disease diagnosis is confirmed, patients and their families need to confront the diagnostic label of chronic disease and the prospect of life-long treatment,” the investigators write. “This can be particularly challenging during the developmental periods of childhood and adolescence.” The gluten-free diet also requires “constant monitoring and attention,” which can be stressful and taxing for patients and their families.

The researchers conclude that their study “underscores the importance of both mental health surveillance in children with celiac disease and a medical workup in children with psychiatric symptoms.”

Reference

Butwicka A, Lichtenstein P, Frisén L, Almqvist C, Larsson H, Ludvigsson JF. Celiac Disease Is Associated with Childhood Psychiatric Disorders: A Population-Based Study [published online March 7, 2017]. J Pediatr. 2017;184:87-93.e1.