Celiac disease, a gluten-sensitive enteropathy, is the most common autoimmune disorder worldwide (1). The global prevalence of celiac autoimmunity, defined as a positive anti–tissue transglutaminase type 2 IgA antibodies (anti‐tTG2) test, is between 1.1% and 1.4% and as high as 8% in some countries (2–10). The anti–tissue transglutaminase (anti-tTG) antibody is a key criterion for establishing the diagnosis of celiac disease and monitoring the adherence to a gluten-free diet (GFD) (1). The presence of anti-tTG autoantibodies is associated with small bowel mucosal damage, whereas celiac serology normalization is associated with mucosal healing and improvement in metabolic outcomes such as anemia and bone density (11,12). Celiac autoimmunity has been associated with other comorbidities and subsequent poor health outcomes, aside from small intestinal inflammation. Evidence suggests that patients with anti-tTG antibodies have an increased risk of cardiovascular disease, cancer, and mortality (7,13). Anti-tTG antibodies are common in patients with autoimmune endocrine disorders such as type 1 diabetes mellitus (T1DM), multiple sclerosis, and autoimmune thyroid diseases in both children and adults (14–17). The association between celiac autoimmunity and patients diagnosed with celiac disease with the diagnosis of hypothyroidism is well established (14,16,18–22). The pathogenesis of this relation is not known; however, HLA type, which is a predisposing gene to autoimmune state, and immune-regulatory gene such as cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) haplotype are common in both diseases (23). The effect of celiac serology normalization on disease outcomes other than gastrointestinal disorders is not widely studied. Patients with T1DM and subclinical celiac disease who started a GFD, which is associated with celiac serology normalization, showed a reduction in hypoglycemic episodes and better glycemic control than those who stayed on a normal diet (24). Similarly, a GFD may reverse thyroid abnormalities in patients with newly diagnosed CD (25); however, this effect is inconsistent (26). These findings suggest that celiac serology normalization might be associated with better outcomes even among nongastrointestinal diseases. In this cohort study, we used a comprehensive electronic medical record database in Israel to evaluate the association of celiac serology status with the risk of hypothyroidism.
Study population and design
This was a retrospective cohort study of Clalit Health Services (CHS) members, the largest of 4 integrated health care organizations in Israel, including 4.7 million members (53% of the population) (27). We included subjects aged 1–80 years with a positive anti-tTG test between January 2008 and December 2012 and a repeat anti-tTG test within 6–36 months. We excluded subjects without continuous membership in CHS for 5 years before the first serology test and subjects diagnosed with thyroid disorders or abnormalities before the first serology test. This included subjects who had a diagnosis of hyper/hypothyroidism, thyroid resection, thyroid-associated therapy (propylthiouracil, methimazole, radioactive iodine, levothyroxine, and other thyroid replacement therapy), and amiodarone-treated subjects based on a comprehensive database search of Anatomical Therapeutic Chemical Classification codes, International Classification of Diseases (ICD-9) diagnosis codes, and drug prescription history since 1999. The CHS institutional review board approved this study, and the study was exempt from the requirement for informed consent.
Celiac serology status was determined by the last serology test performed within 6–36 months of the first serology date. Subjects were categorized into either normalized serology (normalization of both anti-tTG and anti–endomysial antibody [EMA], if performed) or persistent-positive serology (a positive anti-tTG or a positive anti-EMA). We defined the initial anti-tTG levels as previously described (28) (1–3 times upper limits of normal [ULN], 3–5 times ULN, 5–9.9 times ULN, and 10 times ULN or above). We also determined the time interval between the first and last anti-tTG tests as a continuous variable and the number of subsequent anti-tTG tests.
Selected baseline variables considered confounders were collected as of the index date. These included age, sex, ethnicity (Jewish/other), socioeconomic status (classified according to the Clalit clinic classification and grouped into high, medium, and low), diagnosis of T1DM (documented either with ICD-9 codes or at least one prescription of insulin before the index date), and diagnosis code of celiac disease (ICD-9 code 579.0). Data were missing in the socioeconomic classification in 16 cases (0.3%).
All subjects were followed for incident diagnosis of hypothyroidism, defined as a new record of ICD-9 244.9 and at least 1 prescription of thyroid replacement treatment during the follow-up period; the first date of drug issue was determined as the diagnosis date. Subjects were also followed for incidence diagnosis of hyperthyroidism, defined as ICD-9 242 or the prescription of antithyroid treatment (propylthiouracil, methimazole, and radioactive iodine).
Differences in baseline characteristics between the normalized and persistent-positive groups were conducted using the χ2 and Mann-Whitney tests. The association of celiac serology status with the risk of hypothyroidism was calculated using time-dependent (model I) and time-independent (model II) models. In model I, a Kaplan-Meir survival analysis was initially performed; the time to event was defined as the time between the last serology date and diagnosis of hypothyroidism. For patients who did not diagnose hypothyroidism, the observation was censored at the study end or death (log-rank test). Then, after evaluating the proportionality assumption using the Log minus Log function, an unadjusted and adjusted Cox proportional analysis was conducted. The estimates were presented as hazard ratios (HRs) and 95% confidence intervals (95% CIs). In model II, binary logistic regression analysis was used, and the risk was presented as odds ratios (ORs) along with CIs. The cohort was divided into the pediatric population (age <21 years) and adult population (age≥ 21 years, the age of military discharge, and reenrollment to civilian health care organizations in Israel), as the analyses showed a different magnitude of association between celiac serology status and outcome. We also conducted a sensitivity analysis for subjects diagnosed with celiac disease. Data analysis was performed using SPSS statistical software (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY). P < 0.05 was reported as statistically significant.
A total of 217,985 subjects aged 1–80 years were tested for celiac serology between January 1, 2008, and December 31, 2012. As shown in Figure 1, the final pediatric cohort included 2,687 subjects, and the adult cohort included 1,286 subjects. In both cohorts, most subjects were females from all socioeconomic status levels (Table 1). Diagnosis of celiac disease was evident in 28.7% of the pediatric cohort and 39.4% of the adult cohort. Persistent-positive serology was evident in 25.3% (681/2,687) of the pediatric population and 34.4% (442/1,286) of the adult population (P < 0.001). In both the pediatric and the adult cohorts, compared with subjects with normalized serology, subjects with persistent-positive serology were more likely to carry a diagnosis of celiac disease, have higher anti-tTG levels, and belonged to low socioeconomic status and of non-Jewish ethnicity (Supporting Tables 1 and 2, Supplementary Digital Content 1 and 2, https://links.lww.com/AJG/C560 and https://links.lww.com/AJG/C561.
Hypothyroidism among the pediatric cohort
During a median follow-up of 64 months (interquartile range [IQR] 48–80 months), 2.3% (16/681) of the persistent-positive serology and 1.0% (20/2,006) of the normalized serology groups developed hypothyroidism, log-rank test (P = 0.027). The median time to hypothyroidism was 31.5 months (IQR 16–61 months). In the time-dependent model, compared with celiac serology normalization, persistent-positive serology was significantly associated with the diagnosis of hypothyroidism in the univariate analysis (HR 2.07 [95% CI 1.07–4.44]) and nonsignificantly elevated in the multivariate model (adjHR 1.77 [95% CI 0.91–3.46]). In the time-independent model, both the univariate and multivariate analyses were significantly associated with the diagnosis of hypothyroidism (OR 2.39, 95% CI 1.23–4.64; adjOR 2.03, 95% CI 1.02–4.02). Female sex and T1DM were also significantly associated with the diagnosis of hypothyroidism (Figure 2; Table 2). In a sensitivity analysis among the pediatric cohort with an established diagnosis of celiac disease, the rate of hypothyroidism was 3.4% (10/486) of the subjects with persistent-positive serology and 1.0% (5/481) of the subjects with normalized serology. The risk associated with persistent-positive serology was nonsignificantly elevated in the time-dependent model (HR 2.83 [95% CI 0.96–8.32], adjHR 1.77 [95% CI 0.91–3.46]) and significantly elevated in the time-independent model (OR 3.89 [95% CI 1.14–10.0], adjOR 2.03 [1.02–4.02]) (Supplementary Table 3, Supplementary Digital Content 3, https://links.lww.com/AJG/C562).
Hypothyroidism among the adult cohort
During a median follow-up of 71 months (IQR 53–84 months), 4.5% (20/442) of the persistent-positive group and 3.9% (33/811) of the normalized serology group developed hypothyroidism. The median time to hypothyroidism was 26 months (IQR 14–50 months). Compared with celiac serology normalization, persistent-positive serology was not associated with the diagnosis of hypothyroidism in both models (HR 1.13 [95% CI 0.65–1.97], adjHR 1.13 [95% CI 0.65–1.98]; OR 1.16; 95% CI 0.66–2.05; adjOR 1.17 [95% CI 0.66–2.06]) (Figure 3, Table 3). The sensitivity analysis for patients with a diagnosis of CD also showed no association of celiac serology category with the diagnosis of hypothyroidism (Supplementary Table 4, Supplementary Digital Content 4, https://links.lww.com/AJG/C563).
Hyperthyroidism alone was documented in 4 patients (0.1%) of the pediatric cohort and 9 patients (0.7%) of the adult cohort. The paucity of events precluded further analysis.
In this study, we aimed to evaluate the association between celiac serology normalization with the risk of hypothyroidism. Although limited by size and the retrospective design, our findings suggest that among the pediatric population, compared with subjects with celiac serology normalization, subjects with persistent-positive serology have a 2-fold increased risk of an incident diagnosis of hypothyroidism. Our estimates were comparable in both the time-dependent and time-independent models, although the adjusted analysis was significant only in the time-independent model. Similar results were observed among the pediatric cohort with established celiac disease, although the risk was significant only in the time-independent model.
As stated earlier, the association between celiac disease and celiac autoimmunity with the diagnosis of hypothyroidism is well established (18–20,29). Genetic, serologic, and immunologic aspects may potentially explain this relation. Predisposing genes of autoimmune diseases and immune-regulatory genes are common in both disorders (23,30,31). Also, gut dysbiosis and increased gut permeability were suggested to result in abnormal host-microbiome interaction, which contributes to intestinal and thyroidal autoimmunity relations (10,21).
Several reports have shown that GFD, which leads to celiac serology normalization, may improve thyroid functionality. This relation indirectly supports the hypothesis that serology normalization may improve thyroid-related outcomes. Krysiak et al. (32) reported that patients with autoimmune thyroiditis and positive celiac serology who adopted a GFD had reduced thyroid antibody titers compared with those who consumed a regular diet. Likewise, a prospective multicenter study from Italy has shown that patients with newly diagnosed celiac disease who adhere to 1 year of a GFD had higher rates of antithyroid antibody normalization (25). On the contrary, Metso et al. showed that a GFD did not reverse autoimmune thyroiditis among subjects with newly diagnosed CD (26). Choung et al. reported that patients who normalized their serology had similar rates of autoimmune disease compared with patients with persistent-positive serology or celiac disease (5). However, this study referred to many pooled autoimmune disorders and not only autoimmune hypothyroidism (5).
A positive anti-tTG test can occur among patients without celiac disease, representing an autoantibody reaction (30). In our current study, only a third of the pediatric cohort had a diagnosis of celiac disease or a positive anti-EMA serology. Yet, both the time-dependent and time-independent did not show significant differences in the risk of hypothyroidism according to celiac disease diagnosis or a positive anti-EMA serology. Furthermore, the sensitivity analysis among the pediatric cohort for the association of celiac serology status with the risk of hypothyroidism suggested that the risk is even higher, although significant only in the time-independent model.
As stated in the Methods section, we divided the population into pediatric and adult cohorts by the age of 21 years old, the age of military discharge, and reenrollment to civilian health care organizations in Israel. Interestingly, the analyses of the association between celiac serology status with the incidence of hypothyroidism showed a different magnitude of association in the pediatric and adult cohorts. Also, in the pediatric cohort, female sex was associated with a 7-fold increased risk of hypothyroidism, whereas in the adult cohort, the female sex was associated with only a 2-fold increased risk. In the pediatric cohort, T1DM was associated with a 5-fold increased risk of hypothyroidism, whereas in the adult cohort, T1DM was not associated significantly with hypothyroidism. These findings suggest that the pediatric and adult cohorts have different biologic characteristics. Indeed, among subjects with celiac disease, adults have a lower clinical response and histologic recovery following GFD (33).
In the current study, patients from low socioeconomic class and non-Jewish ethnicity were more likely to have persistent-positive serology status. These findings may reflect a lack of adherence to diet, resulting from educational gaps and disparities in health care resources (28,34).
The main strength of this study is the unique design and use of laboratory, pharmacy, and electronic medical records of a large HMO. Hence, we could imply a reliable methodology, capturing incident cases based on ICD codes and thyroid replacement treatment (drugs issued) while excluding all known instances defined by drugs administered or ICD-9 diagnosis.
This study has some limitations. First, our study is limited by the retrospective nature of the design and the relatively low number of outcomes. Second, the information about GFD is lacking. Finally, we also lacked data about TSH levels and the presence of antithyroid antibodies, limiting our ability to refer to subclinical hypothyroidism and autoimmune hypothyroidism.
In conclusion, in this retrospective, age-stratified analysis, we report that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population. Undoubtedly, as our study was limited by size and design, further studies are needed to validate our observation and evaluate whether other outcomes are associated with persistent-positive celiac serology.
CONFLICTS OF INTEREST
Guarantor of the article: Zohar Levi, MD.
Specific author contributions: Conception and design: Z.L., B.F., and R.S.; data extraction: B.F.; analysis and interpretation of the data: M.H., M.A., Z.L., and B.F.; drafting of the article: M.A., R.B.G., and Z.L.; critical revision of the article for important intellectual content: M.H. and R.S.; final approval of the article: Z.L. All authors included in the authorship list approved the final version of the article.
Financial support: None to report.
Potential competing interests: None to report.
WHAT IS KNOWN
- ✓ Celiac autoimmunity, defined as positive celiac serology, is associated with other autoimmune disorders.
- ✓ Population-based studies report that a significant proportion of the population with positive celiac serology remains persistently positive when followed up with repeated tests.
WHAT IS NEW HERE
- ✓ In this retrospective, age-stratified analysis, we report that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population.
- ✓ Our study offers a possible association between persistent-positive celiac serology and disease states. Prospective cohorts are needed to validate our findings.
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