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Risk of Thyroid Disease in Individuals with Celiac Disease

Department of Pediatrics (P.E., J.F.L.) and Clinical Research Centre (S.M.M.), Örebro University Hospital, SE-701 85 Örebro, Sweden; Clinical Epidemiology Unit (S.M.M., A.E., J.F.L.), Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden; Department of Medical Sciences (O.K.), Uppsala University, University Hospital, SE-75123 Uppsala, Sweden; and Department of Primary Care and Social Medicine (S.M.M.), Charing Cross Hospital, Imperial College, W6 8RF London, United Kingdom

Address all correspondence and requests for reprints to: Peter Elfström, Department of Pediatrics, Örebro University Hospital, SE-701 85 Örebro, Sweden. E-mail: peter.elfstrom{at}orebroll.se.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background: It has been suggested that celiac disease is associated with thyroid disease. Earlier studies, however, have been predominately cross-sectional and have often lacked controls. There is hence a need for further research. In this study, we estimated the risk of thyroid disease in individuals with celiac disease from a general population cohort.

Methods: A total of 14,021 individuals with celiac disease (1964–2003) and a matched reference population of 68,068 individuals were identified through the Swedish national registers. Cox regression estimated the risk of thyroid disease in subjects with celiac disease. Analyses were restricted to individuals with a follow-up of more than 1 yr and with no thyroid disease before study entry or within 1 yr after study entry. Conditional logistic regression estimated the odds ratio for subsequent celiac disease in individuals with thyroid disease.

Results: Celiac disease was positively associated with hypothyroidism [hazard ratio (HR) = 4.4; 95% confidence interval (CI) = 3.4–5.6; P < 0.001], thyroiditis (HR = 3.6; 95% CI =1.9–6.7; P < 0.001) and hyperthyroidism (HR = 2.9; 95% CI = 2.0–4.2; P < 0.001). The highest risk estimates were found in children (hypothyroidism, HR = 6.0 and 95% CI = 3.4–10.6; thyroiditis, HR = 4.7 and 95% CI = 2.1–10.5; hyperthyroidism, HR = 4.8 and 95% CI = 2.5–9.4). In post hoc analyses, where the reference population was restricted to inpatients, the adjusted HR was 3.4 for hypothyroidism (95% CI = 2.7–4.4; P < 0.001), 3.3 for thyroiditis (95% CI = 1.5–7.7; P < 0.001), and 3.1 for hyperthyroidism (95% CI = 2.0–4.8; P < 0.001).

Conclusion: Celiac disease is associated with thyroid disease, and these associations were seen regardless of temporal sequence. This indicates shared etiology and that these individuals are more susceptible to autoimmune disease.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Celiac disease is an immune-mediated disease characterized by chronic inflammation and destruction of the villous structure of the small intestine (1). It is triggered by the ingestion of gluten. The classic clinical presentation of celiac disease includes abdominal symptoms, malnutrition, and impaired growth in childhood, but many patients have only mild or no symptoms at all. Treatment consists of life-long gluten-free diet (2). Celiac disease has increasingly become considered as a multi-organ disorder and has been linked to a number of diseases including autoimmune disorders (3, 4). About 1% of the population in the Western world is affected by celiac disease (5).

Graves’ disease and different forms of thyroiditis are often referred to as autoimmune thyroid disease and have previously been suggested to be associated with celiac disease (3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). The majority of earlier studies have, however, been cross-sectional, and few of them have included children (12, 15, 19, 20). Several studies have shown a positive association between celiac disease and an increased prevalence of autoimmune thyroid antibodies (10, 19) but not clinically overt disease. Both Italian (17) and Finnish (16) data suggest an increased prevalence of hypothyroidism in individuals with celiac disease. Sategna-Guidetti et al. (18) have also presented an increased risk of overall thyroid disease in individuals with celiac disease. Most other positive studies have either lacked controls (6, 9, 21) or not attained statistical significance (4, 8, 12, 20). To our knowledge, no studies have until now reported a statistically significant risk of increased hyperthyroidism in celiac disease. We only know of one longitudinal study examining the risk of future thyroid disease in individuals with celiac disease (20). This study (20) showed no statistically significantly increased risk of thyroid disease in individuals with celiac disease.

The prevalence of celiac disease is likely increased among individuals with thyroid disease (7, 10, 11, 13, 14). However, although Spadaccino et al. (22) recently reported an increased prevalence of celiac disease in Italian patients with thyroid disease, that study did not use a matched control group. In the current study, we obtained data from the Swedish national registers to conduct a longitudinal study of the risk of thyroid disease in a general population cohort of 14,021 individuals with celiac disease and an age- and sex-matched reference population of 68,068 individuals.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We used the Swedish national inpatient register (IPR) to identify all individuals with a diagnosis of celiac disease on discharge from hospital admissions between 1964 and 2003. Celiac disease was defined according to International Classification of Disease (ICD) codes (ICD-7: 286.00; ICD-8: 269.00, 269.98; ICD-9: 579A; ICD-10: K90.0). The IPR was also used to identify individuals with thyroid disease and diabetes mellitus (DM) (23). The IPR is maintained by the Swedish National Board of Health and Welfare and was set up in 1964. All records in the IPR can be identified through a personal identity number. The personal identity number is a unique number assigned to more than 99.9% of all Swedish residents and immigrants (24). The government agency for demographic statistics, Statistics Sweden, then used the Total Population Register (25) to match each individual with celiac disease with up to five reference individuals for age, sex, calendar year, and area of residence at time of celiac disease diagnosis. This register contains information on, for example, area of residence, vital status, and dates of immigration or emigration. Certain individuals with celiac disease could be matched with only three or four reference individuals due to lack of potential reference individuals with the same age and sex in smaller counties.

Celiac disease and subsequent thyroid disease

In the main analyses, we estimated the risk of subsequent thyroid disease in a general population cohort of 14,021 (9338 children and 4683 adults) individuals with celiac disease and a reference population of 68,068 individuals. We also made stratified analyses of risk estimates in males, females, children, and adults.

Inclusion and exclusion criteria

We identified 15,533 individuals with celiac disease diagnosed between 1964 and 2003. Of these, 94 were excluded due to data irregularities. In the dataset consisting of 15,439 individuals with celiac disease, we identified 153 (1.0%) individuals with hyperthyroidism, 370 (2.4%) with hypothyroidism, and 52 (0.3%) with thyroiditis before or after diagnosis of celiac disease. Among the 76,910 individuals in the reference population, the corresponding figures were as follows: hyperthyroidism, 280 (0.4%); hypothyroidism, 375 (0.5%); and thyroiditis, 52 (0.1%).

In the main analyses, we then excluded all individuals with thyroid disease before study entry and diagnosis of celiac disease (233 individuals with celiac disease and 1386 in the reference population). Finally, 1185 individuals with celiac disease and 7456 in the reference population were excluded due to 1) thyroid disease within the first year of follow-up, 2) death or emigration in that time, or 3) in the reference population only, exclusion of all reference individuals belonging to a stratum where the index individuals with celiac disease were excluded (because we used internal stratification).

The main analysis in this study was hence based on 14,021 individuals with celiac disease and a reference population of 68,068 individuals without a diagnosis of celiac disease (Table 1).

Follow-up started 1 yr after study entry (equal to the date of first inpatient diagnosis of celiac disease or corresponding date in the matched reference population). Because we used Cox regression, which is a survival analysis, the length of follow-up for each study participant is not known at study entry. Follow-up time ended on date of first discharge diagnosis of thyroid disease, emigration, death, or end of the study period (December 31, 2003), whichever occurred first.

Socioeconomic index (SEI)

In a subset of individuals (8642 individuals with celiac disease and 35,843 without celiac disease), Statistics Sweden had data on SEI (26). Some 6500 of these were children who had been assigned a socioeconomic code on the basis of the occupation of their mother.

Statistical methods and analyses

Cox regression estimated the hazard ratios (HRs) for subsequent thyroid disease in celiac disease. These analyses were conditioned on risk-set so that an individual with celiac disease was compared only with his or her age-and sex-matched reference individuals.

In separate analyses, we stratified for sex and age at study entry (15 and 16 yr).

To increase the specificity of our outcome measure, we specifically calculated 1) HRs for thyroid disease when listed as main diagnosis, 2) HRs for thyroid disease when the same individual had received the same thyroid diagnosis at least twice, and 3) HRs for thyroid disease when the diagnosis had been recorded in Departments of Pediatrics, Internal Medicine, Surgery, or Endocrinology because diagnostic investigations for thyroid disease are most often carried out in these departments.

We also estimated the risk of thyroid disease after adjusting for DM and after excluding all individuals who had a diagnosis of DM before the end of follow-up. We also calculated crude and adjusted risk estimates for thyroid disease in a subset of individuals with data on SEI. In a separate analysis, we included the first year after study entry in the follow-up to see whether this would affect the risk estimate.

In post hoc analyses, we estimated the risk of subsequent thyroid disease in individuals with celiac disease compared with a reference population who had been admitted to hospital within less than 1 yr before or after the first diagnosis of celiac disease in the matched individual with celiac disease. To maximize the power, we included the first year of follow-up in the post hoc analyses. This was deemed reasonable because all individuals in the post hoc analyses had been admitted to hospital and were therefore at risk of being investigated for thyroid disease due to hospital admission. We chose to adjust for sex, age, and calendar period instead of using internal stratification because some strata consisted of only one individual with celiac disease (and no reference individuals).

The 95% confidence intervals (CI) for HRs not including 1.00 were considered statistically significant.

Statistics were calculated using SPSS 11.0 (SPSS Inc., Chicago, IL).

Thyroid disease and subsequent celiac disease

From the original cohort of 15,439 individuals with celiac disease and the corresponding reference population, we used conditional logistic regression to estimate the odds ratio (OR) for celiac disease (the dependent variable) in individuals with a prior diagnosis of thyroid disease. We performed this analysis to evaluate whether the positive association between celiac disease and thyroid disease was restricted to patients with celiac disease preceding thyroid disease. The end of follow-up was defined as date of first celiac disease diagnosis and the same date in the matched reference population without celiac disease. Those with 1 yr or less between the date of first thyroid disease diagnosis and celiac disease diagnosis, and corresponding reference individuals, were excluded.

Power calculation

This study had the power (80%) to detect a risk increase for hyperthyroidism at 5% significance level if the HR for hyperthyroidism exceeded 1.6. For hypothyroidism, we needed a HR above 1.5 and for thyroiditis a HR above 2.2.

Ethics

This study was approved by the Research Ethics Committee of the Karolinska Institutet. None of the participants was contacted. Subject information was anonymized before the analyses.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Characteristics of the study participants are presented in Table 1. The majority of study participants were female (58.2%), and the median (range) age at study entry (age at first recorded celiac disease diagnosis and the corresponding date in the reference population) was 2 (0–94) yr. Study participants have been divided according to four calendar periods due to the potential change of diagnostic algorithms of celiac disease and thyroid disease over time.

Celiac disease and subsequent thyroid disease

Celiac disease was associated with hypothyroidism (HR = 4.4; 95% CI = 3.4–5.6; P < 0.001), thyroiditis (HR = 3.6; 95% CI = 1.9–6.7; P < 0.001), and hyperthyroidism (HR = 2.9; 95% CI = 2.0–4.2; P < 0.001) (Tables 2–4). The highest risk estimates were found in children (hypothyroidism HR = 6.0 and 95% CI = 3.4–10.6; thyroiditis HR = 4.7 and 95% CI = 2.1–10.5; and hyperthyroidism HR = 4.8 and 95% CI = 2.5–9.4). The risk estimates remained statistically significant when we used the following outcome measures: 1) receiving at least two hospital discharge diagnoses of thyroid disease, 2) thyroid disease listed as main discharge diagnosis, or 3) thyroid disease diagnosed in a department of Pediatrics, Internal Medicine, Surgery, or Endocrinology (Tables 2–4). The relative risk of hypothyroidism in individuals with celiac disease was higher in males than in females (HR = 11.2 vs. 3.5). The same gender difference could not be seen in hyperthyroidism and thyroiditis. Adjustment for SEI did not affect our risk estimates (data not shown). Risk estimates were similar in the different calendar periods (data not shown).

Incidence rates (per 100,000 person-years) for thyroid disease were consistently higher in individuals with celiac disease than in matched reference individuals: hypothyroidism, 67 vs. 20; thyroiditis, 9 vs. 3; and hyperthyroidism, 25 vs. 10 (Table 5).

Thyroid disease and subsequent celiac disease

Conditional logistic regression showed an increased risk of celiac disease in individuals with prior hypothyroidism (OR = 3.8; 95% CI = 2.8–5.2; P < 0.001), thyroiditis (OR = 4.0; 95% CI = 2.2–7.2; P < 0.001), and hyperthyroidism (OR = 2.0; 95% CI = 1.5–2.8; P < 0.001) (Table 6).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The association between celiac disease and thyroid disease probably reflects the general increase of autoimmune disease seen in celiac disease (4, 23) and might be explained by the presence of shared genetic traits. Both human histocompatibility leukocyte antigen (HLA) DQ2 (HLA-DQA1*05-DQB1*02) and DQ8 (HLADQA1*03-DQB1*0302) are common both in thyroid disease (21, 27) and celiac disease (28), and patients with overlapping disease are often HLA DQ2 positive (3, 15). In a recent study by Hadithi et al. (21), 53 of 104 consecutive patients with Hashimoto’s thyroiditis were HLA DQ2 positive. We have previously examined celiac disease and the risk of type 1 DM (23) in this cohort. After excluding the first year after celiac disease diagnosis, the risk of later DM in individuals with celiac disease (and no prior DM) was similar to that in any HLA-DQ2-positive individual (29). Considering that a vast majority of individuals with celiac disease are HLA DQ2 positive (28), we suggest that shared HLA is a plausible explanation also for the increased risk of thyroid disease in celiac disease. Another potential explanation may be found in the increased expression of T lymphocyte-associated antigen 4 (CTLA4). CTLA4 is a T cell surface molecule involved in control of T cell proliferation. An increased expression of CTLA4 has been seen in both Graves’ disease (30, 31) and hypothyroidism (30) as well as other autoimmune diseases such as DM (32). CTLA4 is also more common in celiac disease (33, 34). The presence of shared genetic risk factors might hence explain the positive association between celiac disease and thyroid disease.

Our study confirms the positive association between celiac disease and thyroid disease. Although earlier studies have suggested a positive association between celiac disease and thyroid disease (3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22), the majority of these studies have been cross-sectional (3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 21, 22), lacked controls (6, 9, 21, 22), or failed to attain statistical significance (4, 8, 12). In 2005, Viljamaa et al. (20) conducted a longitudinal study of thyroid disease in a cohort of individuals with celiac disease. This study indicated an increased incidence of thyroid disease in celiac disease, but results did not reach statistical significance.

To the best of our knowledge, our study is the first study to present a statistically significant risk increase of hyperthyroidism in individuals with celiac disease.

The study participants were identified through the national IPR. Misclassification of celiac disease is uncommon in the IPR (>85% of individuals with IPR diagnoses of celiac disease and concomitant lymphoma were correctly classified with regard to celiac disease) (35) due to the well-established practice to carry out a small-bowel biopsy before the celiac disease diagnosis (36). This has been done in an inpatient setting during most of the study period and still is still done in small children who often need general anesthesia during endoscopy. Not all individuals with celiac disease will be identified through a hospital-based register, but this should be no major drawback because we nevertheless had access to morbidity data in more than 14,000 individuals with celiac disease. There is also a risk that individuals with celiac disease identified through a hospital-based register have more severe disease than the average individual with celiac disease and are therefore at increased risk of any disease. However, the positive association between celiac disease and subsequent thyroid disease remained statistically significant when we restricted our reference population to inpatients. This means that ascertainment bias due to hospital admission in individuals with celiac disease is unlikely to explain the positive association between celiac disease and thyroid disease. Although we cannot rule out the risk of misclassification, this should be a concern only if it differs between those with celiac disease and the reference population (i.e. differential misclassification). To our knowledge, there are no validation studies of thyroid disease in the IPR. Nilsson et al. (37), in their systematic analysis of the reliability of diagnosis of ICD-8 in the IPR, however, found that 88–90% of listed main diagnoses were correct. In ICD-9 and -10 this percentage should be even higher, and incorrect diagnoses are also likely to result in conservative risk estimates. To reduce the risk of differential misclassification, we also validated our diagnosis through estimating the risk of having at least two hospital discharge diagnoses of thyroid disease and receiving the diagnosis in Departments of Pediatrics, Internal Medicine, Surgery, or Endocrinology (where misclassification is supposed to be low). Restricting our outcome measure in this way did not influence our risk estimates. The highest risk estimates of thyroid disease in individuals with celiac disease were seen in children. A possible explanation for this might be that autoimmune thyroid disease dominates in children, whereas in adults, non-autoimmune causes of thyroid disease are common. However, we cannot rule out that children with thyroid disease were more likely to be admitted to hospital than adults and that this partly accounts for the age-specific differences in the risk of thyroid disease. A protective effect of gluten-free diet in celiac disease has previously been reported by Ventura et al. (4). This could not be confirmed in the current study where risk estimates were similar both before and subsequent to diagnosis and presumed gluten introduction.

This study concludes that celiac disease is associated with hypothyroidism and thyroiditis as well as hyperthyroidism. These associations were seen regardless of temporal sequence, and we therefore suggest that the increased risk of thyroid disease in celiac disease is an expression of a more general increase in autoimmunity that characterizes many individuals with celiac disease. The positive association between celiac disease and thyroid disease may be due to shared genetic or immunological traits.

	Footnotes

 
P.E. was supported by the Örebro University Hospital and the Örebro University while carrying out this study. J.F.L. was supported by the Swedish Research Council and the Örebro University Hospital while supervising this study. The project was supported by the Swedish Research Council, the Swedish Society of Medicine, the Örebro Society of Medicine, the Majblomman Foundation, the Sven Jerring Foundation, the Clas Groschinsky Foundation, the Samariten Foundation, the Juhlin foundation, the Karolinska Institutet, and the Swedish Celiac Society.

J.F.L. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

This project (04-030/1) was approved by the Research Ethics Committee of the Karolinska Institutet, Stockholm, Sweden, on March 18th, 2004.

Conflict of Interest: The authors declare no conflict of interest.

First Published Online July 8, 2008

Abbreviations: CI, Confidence interval; CTLA4, T lymphocyte-associated antigen 4; DM, diabetes mellitus; HLA, human histocompatibility leukocyte antigen; HR, hazard ratio; ICD, International Classification of Disease; IPR, inpatient register; OR, odds ratio; SEI, socioeconomic index.

Received April 14, 2008.

Accepted July 2, 2008.

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