If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New YorkDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenDepartment of General Practice, Institute of Health and Society, University of Oslo, Oslo, NorwayVårdcentralen Årjäng, Centre for Clinical Research, County Council of Värmland, Värmland, SwedenFaculty of Medicine and Health, Örebro, Sweden
Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenChild and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Stockholm, SwedenDepartment of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland
Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New YorkDepartment Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenDepartment of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden
Few studies have explored the link between childhood celiac disease and long-term psychiatric comorbidities. We performed a population-based cohort study of associations between childhood celiac disease and psychiatric disorders and investigated whether risk persists into adulthood.
We performed a nationwide study in Sweden using data from the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. In this cohort, 19,186 children with a diagnosis of biopsy-verified celiac disease from 1973 through 2016 were identified from Sweden’s 28 pathology departments. Each patient was matched with as many as 5 reference children (controls, n = 94,249). Data on psychiatric disorders were obtained from the patient register. We used Cox proportional modeling to estimate hazard ratios (HRs).
During a median follow-up period of 12.3 years, 3174 children (16.5%) with celiac disease received a new diagnosis of a psychiatric disorder, compared with 13,286 controls (14.1%). Corresponding incidence rates were 12.2 per 1000 person-years (95% CI, 11.8–12.7) vs 10.3 per 1000 person-years (95% Cl, 10.2–10.5). Childhood celiac disease was associated with a 19% increase in risk of any psychiatric disorder (95% CI, 1.14–1.23); the increase in risk was observed in all childhood age groups. The highest HRs were seen in the first year after celiac diagnosis (HR, 1.70; 95% CI, 1.41–2.05). The risk increase persisted into adulthood (age, >18 y: HR, 1.11; 95% CI, 1.04–1.17). We found increased risks of mood disorders (HR, 1.20; 95% CI, 1.12–1.28), anxiety disorders (HR, 1.12; 95% CI, 1.06–1.19), eating disorders (HR, 1.34; 95% CI, 1.18–1.51), attention deficit hyperactivity disorder (HR, 1.29; 95% CI, 1.20–1.39), and autism spectrum disorder (HR, 1.47; 95% CI, 1.32–1.64). We found no statistically significant risk increase for psychotic disorders, psychoactive substance misuse, behavioral disorders, personality disorders, suicide attempt, or suicide. Celiac disease also was linked to an increased use of psychiatric drugs (HR, 1.34; 95% CI, 1.24–1.43). A conditional logistic regression found that psychiatric disorders also were more common before a diagnosis of celiac disease (odds ratio, 1.56; 95% CI, 1.39–1.76).
Childhood celiac disease is associated with an increased risk of subsequent psychiatric disorders, which persists into adulthood. Mental health surveillance should be integral in the care of celiac disease.
Little is known about the association between childhood celiac disease and long-term psychiatric comorbidities.
A population-based study in Sweden found that childhood celiac disease is associated with a 19% increase in risk of subsequent psychiatric disorders, which persists into adulthood. Children with celiac disease have an increased risk of mood disorders, anxiety disorders, eating disorders, attention deficit hyperactivity disorder, and autism spectrum disorder.
Implications for patient care
Mental health surveillance should be integral in the care of celiac disease.
In celiac disease, an immune-mediated enteropathy is triggered by intake of dietary gluten in genetically susceptible individuals. The prevalence is approximately 1% to 2% in Western populations
However, that study did not specifically evaluate the risk of psychiatric disorder in adulthood. Although a few studies have reported an increased prevalence of neuropsychiatric disorders before a celiac disease diagnosis,
these generally lacked power to provide precise risk estimates.
The aim of this study was to investigate the connection between a childhood diagnosis of celiac disease and later psychiatric morbidity including suicide, and to assess if any such risk increases persist into adulthood.
The Epidemiology Strengthened by histoPathology Reports in Sweden cohort consists of 6.1 million gastrointestinal biopsy reports from 2.1 million individuals. Biopsy reports were classified according to the Systematized Nomenclature of Medicine Clinical Terms, and originated from 1965 to 2017 from Sweden’s 28 pathology departments. Data collection took place between October 12, 2015, and April 10, 2017.
Through a computerized search of the Epidemiology Strengthened by histoPathology Reports in Sweden cohort (Supplementary Table 1 lists the topography codes equivalent to the duodenum and jejunum, and relevant Systematized Nomenclature of Medicine codes) we identified individuals with villus atrophy (Marsh III, in this study equivalent to celiac disease). An earlier patient chart validation found that 108 of 114 (95%) patients with villus atrophy had celiac disease.
Because that validation was performed on individuals who underwent a biopsy up until 2008, one of the authors (J.F.L.) re-reviewed the free text of 100 randomly selected biopsy reports with villus atrophy originating from 2009 to 2017. Of these, 98 had sufficient information to be validated, and 97 had celiac disease (positive predictive value, 99.0%; 1 patient had misclassified microscopic colitis; personal communication, March 23, 2020).
Because our outcome measure was any psychiatric disorder, we restricted our study to patients diagnosed during the years spanning from 1973 (the onset of psychiatric diagnosis availability in the National Patient Register) through 2016, the latest availability of follow-up data.
For each individual with celiac disease, the government agency Statistics Sweden identified up to 5 reference individuals (n = 94,249) matched for age, sex, county, and calendar year from the Swedish Total Population Register.
None of the reference individuals had celiac disease at a matching date, and if they developed celiac disease their follow-up evaluation was censored at the date of diagnosis.
Secondary reference individuals
In a separate analysis we compared 13,015 individuals with celiac disease with their nonceliac siblings (n = 18,024). Sibling analyses takes shared intrafamilial confounding, including genetic and early environmental factors, into account.
Our primary outcome was any psychiatric disorder. Secondary outcomes were psychiatric disorders defined according to International Classification of Diseases codes (suicide attempts, psychotic disorders, mood disorders, anxiety disorders, psychoactive substance misuse, eating disorders, behavioral disorders, attention-deficit hyperactivity disorder [ADHD], autism spectrum disorders, and personality disorders), suicide, and suicide attempt (Supplementary Table 2). Psychiatric disorder data were obtained through the National Patient Register. For selected psychiatric disorders, this register has a positive predictive value of 85% to 95%.
Although data on suicide attempts were retrieved from the Patient Register, data on suicides were obtained from the Cause of Death Register. ADHD was defined as having a relevant ADHD medication in the Prescribed Drug Register.
We began follow-up evaluation on the date of celiac disease diagnosis (or corresponding date in the reference group). Follow-up evaluation ended with a psychiatric diagnosis/suicide, death, emigration, or December 31, 2016, whichever occurred first.
Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% CIs for psychiatric disorders. Stratified analyses were performed according to years of follow-up evaluation (<1, 1 to <5, 5 to <10, 10 to <20, and ≥20 y), age at celiac disease diagnosis (<2, 2 to <6, 6 to <11, 11 to <16, and 16 to <18 y) sex, level of parental education (≤9, 10–12, and ≥13 y), and country of birth (Nordic, other). We repeated the analysis, restricting the outcome definition to patients with a prescription for a psychiatric drug in the Prescription Drug Register (Supplementary Table 3 contains a list of included drugs). Because the Prescribed Drug Register started on July 1, 2005, this sensitivity analysis was performed in celiac patients diagnosed from July 1, 2006, or later. In separate analyses we examined the risk of psychiatric disorders in patients with celiac disease vs siblings. In that study, only celiac individuals with a sibling (n = 13,015) were included. Given that persistent villus atrophy after a celiac disease diagnosis is associated with adverse outcomes including lymphoproliferative disease
we compared those children who had persistent villus atrophy with those whose villi healed in the subset of subjects who underwent a follow-up biopsy.
We also explored the risk of psychiatric disorders in adulthood in patients diagnosed with celiac disease in childhood in an analysis restricted to patients who reached the age of adulthood (age, 18 y) during the follow-up evaluation. As a sensitivity analysis, we also evaluated this risk when including all patients, even those with a psychiatric diagnosis preceding the diagnosis of celiac disease or preceding age 18 years. To rule out that any association between celiac disease and psychiatric disorder was not caused by an underlying intellectual disability (triggering celiac testing and predisposing to a psychiatric disorder), we excluded anyone with a diagnosis of an intellectual disability in a sensitivity analysis.
We used SAS v.9.4 (Cary, NC) and STATA v.16.0 (College Station, TX) for all statistical analyses.
The current study was approved by the Stockholm Ethics Review Board (2014/1287-31/4) on August 27, 2014. The ethics review board did not require informed consent because this was strictly a register-based study.
We identified 19,583 individuals with celiac disease diagnosed in childhood (age, <18 y) during the years spanning from 1973 to 2016. In the primary analysis, 397 were excluded because of a previous history of a psychiatric disorder. The remaining 19,186 patients were matched with 94,249 comparators without any history of a psychiatric disorder (Figure 1).
Baseline Characteristics of the Main Study Cohort
The mean age at the time of celiac disease diagnosis was 6.6 years (SD, 5.2 y) with almost 30% diagnosed at younger than 2 years of age (Table 1). Follow-up time ranged from 0 to 42 years, with a median follow-up time of 12.2 years in individuals with celiac disease.
Table 1Baseline Characteristics of Study Cohort
Celiac disease (n = 19,186)
Matched comparators (n = 94,249)
Girls, n (%)
Boys, n (%)
Age at celiac disease diagnosis, y
Categories, n (%)
2 to <6 y
6 to <11 y
11 to <16 y
16 to <18 y
Country of birth, n (%)
Highest attained level of education by parents, n (%)
Starting year of follow-up evaluation
Psychiatric diagnoses in family before index date, n (%)
Celiac disease diagnosed in childhood was associated with a 19% increased risk of any psychiatric disorder (95% CI, 1.14–1.23) (Table 2), with the most increased risk within the first year after a celiac diagnosis (HR, 1.70; 95% CI, 1.41–2.05). Restricting follow-up evaluation until the age of 18 years, celiac disease was linked to a 26% increased risk of any psychiatric disorder (95% CI, 1.20–1.33) (Supplementary Table 4).
Table 2Risk of Any Psychiatric Disorder Overall and by Subgroup in Patients With Celiac Disease and Matched General Population Comparators
The risks of each psychiatric disorder in celiac disease patients vs controls are listed in Table 3. Children with celiac disease were at an increased risk of developing mood disorders, anxiety disorders, eating disorders, ADHD, and autism spectrum disorder.
Table 3Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators
In analyses of adults (age, ≥18 y) with celiac disease diagnosed in childhood and free of psychiatric disease as of age 18, we matched 11,207 celiac disease patients with 49,252 reference individuals (Supplementary Table 5). The median follow-up time after age 18 was 6.4 years for the celiac disease patients and 6 years for the comparators. The overall risk of any psychiatric disorder was increased in celiac disease patients by 11% (HR, 1.11; 95% CI, 1.04–1.17). Having a family history of psychiatric disorder yielded a 1.25-fold increase (HR, 1.25; 95% CI, 1.08–1.46) (Supplementary Table 6).
Adults with childhood celiac disease had an increased risk later for mood disorders, ADHD, and autism spectrum disorder (Supplementary Table 7). When repeating the analysis, now including all subjects regardless of whether they had been diagnosed with psychiatric disease before a celiac disease diagnosis or before reaching the age of 18 years, the association of childhood celiac disease and psychiatric disorders in adulthood was strengthened (HR, 1.17; 95% CI, 1.11–1.22). When excluding individuals with a diagnosis of intellectual disability before study entry (celiac patients, 19,101; controls, 93,612), the positive association with psychiatric disorders remained (HR, 1.18; 95% CI, 1.14–1.23).
We repeated the earlier-described analyses using celiac-free siblings as comparators (n = 18,024), restricting our cohort to 13,015 children with celiac disease and at least 1 sibling (Supplementary Table 8 shows participant characteristics). After conditioning on matching set (within family) and further adjustment for age and sex, celiac disease patients were at a 12% increased risk of a psychiatric disorder compared with siblings (95% CI, 1.05–1.20). Sibling analyses yielded very similar data to those of our main analyses with general population reference individuals (Supplementary Table 9). Sibling comparisons found a positive association between celiac disease and mood disorders, anxiety disorders, eating disorders, and autism spectrum disorder (Supplementary Table 10).
Mucosal Healing and Psychiatric Disorder
During follow-up evaluation, 2604 children with celiac disease had a follow-up biopsy (mucosal healing: n = 2071, 79.5%; persistent villus atrophy: n = 533, 20.5%) (Supplementary Table 11). We found no association between mucosal healing and a subsequent psychiatric disorder (HR, 1.21; 95% CI, 0.95–1.53) (Supplementary Table 12).
In sensitivity analyses, we defined a psychiatric disorder as having a prescription for a psychiatric drug (Supplementary Table 3). Because of the construction of the Swedish Prescribed Drug Register, this analysis was restricted to children diagnosed between July 2006 and December 2016 (Supplementary Table 13). Using this definition, the incidence rate for any psychiatric disorder was 26.9 (95% CI, 25.3–28.6) per 1000 person-years in celiac disease and 20.5 (95% CI, 19.8–21.2) in the reference group (Supplementary Table 14). The HR for any psychiatric disorder was 1.34 (95% CI, 1.24–1.43) (Supplementary Table 14).
The increased risk was significant in all categories of psychiatric drugs: antidepressants (HR, 1.35; 95% CI, 1.25–1.46), anxiolytics, hypnotics and sedatives (HR, 1.32; 95% CI, 1.23–1.42), and antipsychotics (HR, 1.34; 95% CI, 1.23–1.46) (Supplementary Table 15).
History of Psychiatric Disorder Preceding Celiac Disease
In children with celiac disease a prior history of a psychiatric disorder (preceding the diagnosis of celiac disease) was more common compared with controls (odds ratio [OR], 1.56; 95% CI, 1.39–1.76) (Table 4). This association was statistically significant for mood disorders (OR, 2.05; 95% CI, 1.54–2.72), anxiety disorders (OR, 1.51; 95% CI, 1.20–1.91), and eating disorders (OR, 3.10; 95% CI, 2.39–4.02).
Table 4Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators Before Start of Follow-Up Evaluation
In this nationwide and population-based cohort study, we followed up more than 19,000 individuals with childhood celiac disease diagnosed during the years spanning from 1973 to 2016. During follow-up evaluation, we found a 19% increased risk of any psychiatric disorder. The overall risk increase is consistent with earlier findings correlating psychiatric comorbidity with celiac disease in children, as well as in adults.
The overall risk for psychiatric disorder was highest in the first year after diagnosis. This may be owing in part to surveillance bias, but it also is possible that the systemic inflammatory response is mediating this relationship. In addition to these purported mechanisms, the psychosocial stress associated with adapting to a gluten-free diet may account for the early increase in the risk of psychiatric disorders. Unlike most chronic medical conditions that are managed via pharmaceutical approaches, a diagnosis of celiac disease mandates a major lifestyle change for the patient, with a new requirement to attend to ingredient lists, restaurant menus, and social circumstances, given the intermingling of diet with socializing, and the ubiquity of gluten. This treatment has been rated by patients to be highly burdensome,
The stress associated with this burden may contribute to the increased incidence of psychiatric disorders in both the short and long term. However, this risk is unlikely to be owing to the gluten-free diet alone because we also observed an increased risk of psychiatric disorders preceding the diagnosis of celiac disease, possibly related to the systemic inflammatory response described earlier.
Specific Psychiatric Disorders
The specific psychiatric disorders found to be increased in this study of childhood-diagnosed celiac disease include mood and anxiety disorders, eating disorders, ADHD, and autism-spectrum disorders. The association between celiac disease and depression and anxiety has been studied extensively, largely in the adult population.
Through data retrieval from Sweden’s all 28 pathology departments, we were able to identify 19,101 children with celiac disease, with follow-up evaluation through 2016. This compares with 10,903 children followed up through 2010 in a previous population-based study in Sweden.
This expanded sample size and follow-up period allowed us to evaluate additional outcomes including long-term, adult-onset, psychiatric disease; this study examined the development of psychiatric disorders, particularly in adults with celiac disease diagnosed in childhood. The large sample size and long-term follow-up period (a total of 259,633 person-years in people with childhood-diagnosed celiac disease) allowed us to detect even minor risk increases for specific psychiatric disorders. We also were able to perform sensitivity analyses including a comparison with siblings and evaluation of mucosal healing. Our access to follow-up biopsy data allowed us to examine potential mechanisms behind the association with psychiatric disorders; however, we found no link between mucosal healing (at least in the short term) and psychiatric disorders.
This study also had some limitations. The International Classification of Diseases codes and thus the criteria used for psychiatric diagnoses (Supplementary Table 1) have changed throughout the years, and this might influence the rates of psychiatric diagnosis. Because this was an observational study, we cannot rule out that residual confounding contributed to the association between celiac disease and psychiatric disorders.
The lack of association between mucosal healing and psychiatric risk in our study contrasts with a study of 53 patients that found that deterioration of quality of life after a diagnosis is associated with lower adherence to a gluten-free diet.
This may be because mucosal healing is an imperfect marker of adherence, particularly given the possibility of gradual healing (ie, persistent villus atrophy that eventually resolves with further time while maintaining the gluten-free diet).
This study showed that although small in absolute magnitude, there is an increased risk of a psychiatric disorder in individuals diagnosed with celiac disease in childhood with an increased risk in the long term, emphasizing the importance of not just somatic surveillance but also mental health surveillance for timely support and intervention.
In conclusion, this nationwide population-based study including more than 19,000 children with celiac disease found an increased risk of psychiatric disorders. This risk was highest in the first year after celiac disease diagnosis but persisted over a long time and into adulthood. Mental health surveillance should be integral in the care of celiac disease.
This project (2014/1287-31/4) was approved by the Research Ethics Committee in Stockholm, Sweden, on August 27, 2014.
Other researchers can apply for our data through the different Swedish pathology departments, and through the Swedish National Board of Health and Welfare.
The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
CRediT Authorship Contributions
LH wrote the first draft of the paper. All authors conceived and designed the study. JFL and BL supervised the project. PG and JFL funded the study. JS carried out the statistics. All authors interpreted the data and contributed to the writing of the paper. All authors revised and approved the final version. JFL takes responsibility for the integrity of the data and the accuracy of the data analyses. JFL is the guarantor of the data.
Supplementary Table 1Definitions of Celiac Disease and Normal Mucosa Using SNOMED Codes
ADHD, attention-deficit hyperactivity disorder; ICD-8, International Classification of Diseases, 8th revision; ICD-9, International Classification of Diseases, 9th revision; ICD-10, International Classification of Diseases, 10th revision.
Supplementary Table 4Risk of Any Psychiatric Disorder Overall and by Subgroup in Patients With Celiac Disease and Matched General Population Comparators, With Follow-Up Evaluation Ending at Age 18 Years
Supplementary Table 6Analysis Limited to Those With Available Follow-Up Evaluation Starting at Age 18 Years: Risk of Any Psychiatric Disorder Overall and by Subgroup in Patients With Celiac Disease and Matched General Population Comparators
Supplementary Table 7Analysis Limited to Those With Available Follow-Up Evaluation Starting at Age 18 Years: Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators
Supplementary Table 14Outcomes Restricted to Those With a Psychiatric Medication Prescription (July 2006–December 2016): Risk of Any Psychiatric Disorder Including Drug Use Overall and by Subgroups in Patients With Celiac Disease and Matched General Population Comparators
Supplementary Table 15Outcomes Restricted to Those With a Psychiatric Medication Prescription (July 2006-December 2016): Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators
Conflicts of interest This author discloses the following: Jonas Ludvigsson coordinates a study on behalf of the Swedish IBD quality register (SWIBREG). The remaining authors disclose no conflicts.
Funding Supported by a Celiac Disease Foundation Young Investigator Research Grant, and the Louis and Gloria Flanzer Philanthropic Trust (B.L.); by the Karolinska Institutet (J.F.L.); and by the Janssen corporation. The funders did not influence the study or the decision to submit the study.