Abstract
Background:
Hashimoto’s thyroiditis (HT) and celiac disease (CD) are commonly associated with type 1 diabetes (T1DM). There is no consensus on screening, however, the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend testing for thyroid function (TFT), thyroid antibodies and anti-tissue transglutaminase antibodies (TTG) IgA soon after diagnosis. TFT should be repeated every 1–2 years while TTG IgA should be tested for within 2 and 5 years. We hypothesize that the rate of HT and CD in our T1DM children is lower, so screening may need to be revised to reflect their underlying risk.
Methods:
An Institutional Review Board (IRB)-approved retrospective chart review was conducted on children with T1DM in the past 10 years. Age, sex, race, A1C, TFT, thyroid and celiac antibodies were obtained. t-Tests, the Wilcoxon-Mann-Whitney test and stepwise regression were performed.
Results:
Of 222 children with T1DM, with a mean age of 15.8±5.53 years, followed for 6.1±4.0 years, 53% female, mean A1C 11.1±1.9% and 87% African American (AA). Three had Graves’ disease (1.3%), three had HT (1.3%) and 97% were euthyroid. TFT were assessed on average every 1.3 years and thyroid antibodies every 2.5 years. Positive thyroid antibody was found in 11%, negative in 57% and unknown in 32%. The positive antibody group had higher mean A1C and TSH. No biopsy confirmed cases of CD (0%) were found when screened every 2.3 years.
Conclusions:
The number of individuals who screened positive for hypothyroid HT and CD was lower than expected in our population. Further studies are needed to assess the optimal screening frequency for HT and CD in minority children with T1DM.
Introduction
Comorbid autoimmune conditions such as Hashimoto’s thyroiditis (HT) and celiac disease (CD) are more prevalent in patients with type 1 diabetes (T1DM) than in the general population. It is important to screen for these autoimmune conditions in children and adolescents early as identification and treatment of these disorders can have an intense benefit on growth and glycemic control.
Autoimmune thyroid disorders (ATD) are the most prevalent endocrinopathy, occurring in 14–25% of children with T1DM [1], [2], [3], [4], [5], [6]. The two ATDs include Graves’ disease (GD) and the more common HT, both of which are characterized by infiltration of the thyroid by T and B cells reactive to thyroid antigens leading to the production of thyroid autoantibodies and by abnormal thyroid function, hyperthyroidism in GD and hypothyroidism in HT. While the exact etiology of thyroid autoimmunity is unknown, it is believed to develop when a combination of genetic susceptibility and environmental factors lead to breakdown of tolerance. Among a large cohort of 25,759 children and adults with T1DM in the Type 1 Diabetes Exchange Clinic Registry, ATD occurred in 20% of the participants where HT was more prevalent (19%) than GD (1%) [7].
The current guidelines by the American Diabetes Association (ADA) recommend “testing children and adolescents for antithyroid peroxidase (TPO Ab), antithyroglobulin antibodies (TG Ab) and thyroid function tests (TFT) soon after diagnosis of T1DM. If normal, consider rechecking every 1–2 years or sooner if the patient develops symptoms of thyroid dysfunction, thyromegaly, an abnormal growth rate, or an unexplained glycemic variation [8]”. The International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines 2014 Compendium recommended “screening of thyroid stimulating hormone (TSH) and anti TPO Ab at the diagnosis of diabetes and thereafter, every second year in asymptomatic individuals without goiter or in the absence of thyroid autoantibodies. More frequent assessment is indicated otherwise [9]”.
CD is an autoimmune enteropathy that results in small intestinal inflammation, villous atrophy and malabsorption which occurs in genetically predisposed individuals and is precipitated by the ingestion of dietary gluten, a protein found in wheat, rye and barley [10]. The clinical picture of CD can be silent with the absence of gastrointestinal signs or symptoms, therefore it is important to screen for CD [11]. CD occurred in 6% of children and adults in the T1DM exchange registry [7]. Screening studies in children with T1DM in Europe, Asia, Africa, Australia, Middle East and America have demonstrated varied prevalence of CD affecting 0.97–16.4 % [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Anti-tissue transglutaminase antibodies (TTG) along with documentation of normal total serum IgA levels is the preferred single test for the detection of CD [22]. In asymptomatic children, the ADA recommends “measuring TTG IgA at the time of diagnosis of T1DM and repeated 2 and 5 years thereafter [8]”. The ISPAD guidelines recommend “screening at the time of T1DM diagnosis, and every 1–2 years thereafter [9]”.
Most of the previous studies investigated European and North American populations and there are few studies on the rate of HT and CD in minority populations such as African Americans with T1DM. There is no consensus on how often screening should be performed in asymptomatic individuals with T1DM for HT or CD. In our practice, we have traditionally screened according to existing guidelines or earlier if symptomatic. We hypothesize that regular screening for HT and CD among the T1DM children and adolescents at our institution in Central Brooklyn results in few new cases of asymptomatic HT and CD. The purpose of this study is to determine the rate of HT and CD in minority children and adolescents with T1DM in Central Brooklyn.
Materials and methods
An Institutional Review Board (IRB)-approved retrospective chart review was performed on 226 children and adolescents with T1DM, ages 1–21 years, seen by pediatric endocrinologists at our institution in the past 10 years (2005–2015). Data collected included age, sex, race, A1C, thyroid-stimulating hormone (TSH), free thyroxine (FT4), TPO Ab, TG Ab, TTG IgA, and frequency of screening. A1C values were averaged over whole study period for each participant. We included only children and adolescents with T1DM, defined by the presence of one or more autoimmune markers: islet cell autoantibody, GAD 65 antibody, or insulin antibody. We excluded those with type 2 diabetes, maturity-onset diabetes of the young (MODY), steroid induced diabetes and those with an unclear type of diabetes. We defined HT as those with positive thyroid antibody measurements (TPO Ab or TG Ab) irrespective of being euthyroid, hypothyroid or hyperthyroid. GD was defined as those with biochemical hyperthyroidism along with positive thyroid stimulating immunoglobulin (TSI) or thyroid binding inhibitory immunoglobulin (TBII). FT4 and TSH were analyzed by chemiluminescence immunoassays (Architect ci2800 integrated system, Abbott Diagnostics, Abbott Park, IL), with normal ranges 0.70–1.48 ng/dL and 0.35–4.94 μIU/mL, respectively. TPO Ab and TG Ab were analyzed by chemiluminescence immunoassays with normal range 0–34 IU/mL and <40 IU/ mL, respectively. TSI and TBII were analyzed by Immulite 2000/2000 XPi TSI assay and binding inhibition assays, with normal ranges <125% and <16%, respectively.
Statistical analysis
The characteristics of study subjects were presented as descriptive statistics. For subjects with known TPO Ab and/or TG Ab status, univariate analysis for continuous variables was conducted via independent t-tests and Wilcoxon-Mann-Whitney tests. Chi-squared (χ2)-tests were conducted for categorical variables. To identify predictors of A1C levels, crude and stepwise backward multiple regression analysis model was conducted with age, sex, race, TSH, FT4 and thyroid antibody status as predictors. TSH was removed from the backward regression model as it was non-significant and only changed the R2 by 0.004.
Results were analyzed using Statistical Package for Social Sciences 23 (SPSS Inc. Chicago, IL, USA) and Excel 2013 (Microsoft, Redmond, WA, USA). The significance level was set at p<0.05.
Results
We identified 226 children and adolescents with T1DM who ranged in age from 1 to 21 years, with an average age of 15.8±5.53 years. They were followed for 6.1±4.0 years at our center and had an average A1C 11.1±1.9%.
For ATD assessment, baseline clinical characteristics are summarized in Table 1. Four subjects were excluded for missing TFTs (n=222). The majority of our subjects were African American (87%) while 9% were Hispanic, 3% were White and 1% were of unknown race. Subjects were 53% female and 47% male. Screening for TFT occurred on average every 1.3 years, and for thyroid antibodies every 2.5 years. Positive TPO Ab and/or TG Ab were found only in 11% (25/222) while 57% (125/222) had negative TPO Ab and/or TG Ab antibodies and unknown in 32% (72/222). After excluding one with GD, positive TPO Ab and/or TG Ab status was seen in 10.8% (24/222), of which only three had hypothyroid HT (1.3%). Even among those with unknown TPO Ab and/or TG Ab status, hypothyroidism was not noted during TFT screening and follow-up. Thus, in the entire group, 1.3% (3/222) had hypothyroid HT, 1.3% (3/222) had GD and the rest – 97.3% (216/222) were euthyroid. There were no subjects with subclinical hypo- or hyperthyroidism. In Table 2, we compared subjects with positive and negative TPO Ab and/or TG Ab status, after excluding one GD subject who had positive TPO Ab (the other two GD subjects belonged to the unknown TPO Ab and/or TG Ab status group). Baseline characteristics for those with known thyroid antibody status (n=149, data not shown) are similar to Table 1. The positive TPO Ab and/or TG Ab group had a higher mean A1C and a higher TSH compared to the negative group (p<0.05). None of the other parameters were different (number of years known to our institution, FT4, antibody titers, frequency of screening) between the two groups.
Baseline characteristics of the subjects screened for ATD (n=222).
| n | % | |
| Gender | ||
| Male | 104 | 47 |
| Female | 118 | 53 |
| Race | ||
| African American | 192 | 86.5 |
| Hispanic | 20 | 9.0 |
| White | 7 | 3.1 |
| Unknown | 3 | 1.3 |
| Thyroid antibody status TPO Ab and/or TG Ab | ||
| Negative | 125 | 56.3 |
| Positive | 25a | 11.3 |
| Unknown | 72 | 32.4 |
| Thyroid function | ||
| Hyperthyroid (Graves’) | 3 | 1.35 |
| Hypothyroid Hashimoto’s | 3 | 1.35 |
| Euthyroid | 216 | 97.3 |
aIncludes one GD subject.
Group comparison by thyroid Ab (TPO and TG Ab) status (n=149c).
| Antibody negative (n=125) | Antibody positive (n=24) | p-Value | |||||
|---|---|---|---|---|---|---|---|
| Mean | SD | Range | Mean | SD | Range | ||
| Age, years | 15.48 | 5.63 | 2–21 | 16.88 | 4.73 | 8–21 | 0.256a |
| Average A1C, % | 10.89 | 1.84 | 7.05–15.8 | 11.79 | 1.85 | 8.34–16.1 | 0.028a |
| Number of years known to our institution | 6.65 | 4.22 | 1.0–20 | 6.50 | 4.34 | 0.3–14 | 0.872a |
| TFTs checked per year | 0.78 | 0.22 | 0.25–1.0 | 1.18 | 1.28 | 0.33–3.33 | 0.081b |
| Average TSH, mIU/L | 1.61 | 0.88 | 0.29–4.39 | 4.28 | 10.6 | 0.45–53.7 | 0.021b |
| Average FT4, ng/dL | 1.09 | 0.15 | 0.80–1.58 | 1.07 | 0.17 | 0.59–1.34 | 0.936b |
| After excluding the three subjects with hypothyroid HT from antibody positive group | |||||||
| Average A1C, % | 10.89 | 1.84 | 7.05–15.8 | 11.91 | 1.93 | 11.0–2.79 | 0.020a |
| Average TSH, mIU/L | 1.61 | 0.88 | 0.29–4.39 | 1.85 | 0.87 | 0.45–3.62 | 0.142b |
| Average FT4, ng/dL | 1.09 | 0.15 | 0.80–1.58 | 1.11 | 0.13 | 0.85–1.34 | 0.371b |
aIndependent t-test. bWilcoxon-Mann-Whitney test. cOne GD subject excluded.
Bold values – statistically significant i.e. p-value <0.05
For CD assessment, 58 subjects were excluded as neither TTG IgA nor gliadin Ab was assessed; only 168 subjects were included in this analysis. Screening for CD occurred on average every 2.3 years. Only one subject had a positive TTG IgA (levels repeated several times: 33, 37, 40 U/mL, reference range <4.0 U/mL) but biopsy results were normal with no villous atrophy. Interestingly, positive gliadin Ab was found in 3.6% (6/168), all of whom had negative TTG IgA. Therefore, no biopsy-confirmed cases of CD were found in our study (0%).
Discussion
Hypothyroid HT among children and adolescents in our study was 1.3% (3/222) and positive TPO Ab and/or TG Ab status was seen in 10.8% (24/222) among those with known Ab status. Among those with positive TPO Ab and/or TG Ab, most of them had positive antibodies since diagnosis, only three patients had antibodies that turned from negative to positive. Among African-American children (n=192) in our study, only one (0.52%) had hypothyroid HT, which is lower than that reported in other studies while positive thyroid antibody status was seen in 8.3% (16/192) of the entire group and in 12.6% (16/127) among those whose thyroid antibodies were assessed. In the T1DM Exchange Clinic Registry, similar positive thyroid antibody status was reported in 8% (104/1315) of the African-American subgroup which included children and adults, and they defined thyroiditis without distinguishing between those who were euthyroid, hypothyroid or subclinically hypothyroid [7]. It is important to note that the predominant ethnicity in our study was African American (87%) while the subjects from the T1DM Exchange Clinic Registry were predominantly White (82%) and only 5% were African American. The rate of hypothyroid HT in our study was also lower than the 27.6% (37/134) of hypothyroid HT children with T1DM reported in a US cohort [23] and the 16% (n=1530) of a German cohort [3]. However, both studies did not discuss the racial background of their subjects. In 1990, Burek et al. compared White and Black children with T1DM, and found that 50% (41/82) of White children had positive thyroid antibodies compared to only 16% (12/77) of Black children. HT was seen in 12% (10/82) of the White children and 5.2% (4/77) of the Black children [24]. Muhame et al. found positive thyroid antibody status in 7.3% (5/69) of Ugandan children with T1DM [25].
In our study, even though 24 subjects had positive thyroid antibody titers, 97% of the group remained euthyroid throughout the follow-up period (6.1±4.0 years) with TFT screened on average every 1.3 years. There are few longitudinal studies that assess the risk of HT if thyroid antibodies are positive during screening. Kordonouri et al. noted that 8.9% (59/659) of German children and adolescents with T1DM developed HT after the diagnosis of diabetes within a median time of 3.4 years (range 0–12 years) [26]. Lorini et al. noted that out of the 90 Italian children with T1DM, six had positive thyroid antibodies at diagnosis, an additional 10% (9/90) developed positive thyroid antibodies during a 3–10 year follow-up, of which three were diagnosed with HT [27]. In our study, 25% (6/24) had positive thyroid antibodies at T1DM diagnosis and the rest developed positive antibodies at an average of 3.96 years after T1DM diagnosis. Not surprisingly in our study, the positive antibody group had higher TSH compared to the negative antibody group as the positive antibody group included the three subjects with hypothyroid HT. When the three hypothyroid HT subjects (Table 3) were excluded from the positive antibody group, TSH levels were not different between the antibody groups, indicating that they were all euthyroid. The average A1C in our study was also noted to be significantly higher among those with positive thyroid antibodies compared to those with negative thyroid antibodies (even after eliminating the three with HT), possibly suggesting that poorer control of T1DM may be associated with positive thyroid antibodies.
Clinical parameters for three hypothyroid HT subjects.
| Subject | TSH at diagnosis | FT4 at diagnosis | TPO Ab | TG Ab | Treatment | Thyroid ultrasound |
|---|---|---|---|---|---|---|
| 1 | 12.7 | 0.78 | 236 | 1634 | Levothyroxine 50 μg daily, increased to 62.5 μg after 9 months | 0.6×0.4 cm hypoechoic nodule in inferior pole of left thyroid lobe. Thyroid size upper limits of normal |
| 2 | 9.0 | 0.8 | >600 | 327.5 | Levothyroxine 25 μg daily, increased to 37.5 μg after 6 months and then increased to 50 μg after 1 year | Not done |
| 3 | 100.0 | 0.4 | 729 | 36 | Levothyroxine 88 μg daily | Not done |
Reference ranges: TPO Ab 0–34 IU/mL, TG Ab <40 IU/ mL.
In the backward stepwise regression model for A1C (Table 4), predictors such as age, sex, race, TSH, FT4 and thyroid antibody status (positive or negative) were entered into the model. Only FT4 and thyroid antibody status remained significant predictors of A1C. TSH, age, race and sex were eliminated, as they were not associated with A1C. The resultant significant model (Figures 1 and 2) containing FT4 and thyroid antibody status explained 7.1% (R2) of the variability seen in A1C. Positive thyroid antibody status increased A1C by 1%, compared to negative thyroid antibody status. Similarly, a one unit increase in FT4 increases A1C by 2.33%. Consistent with the group results mentioned previously, this model also linked high A1C with positive thyroid antibody status. In addition, the model linked A1C with high FT4 level, although the clinical significance for the FT4 level is unclear as 97% of the cohort had normal FT4 level.
Stepwise regression model for A1C (n=149).
| β | SE | t | p-Value | |
|---|---|---|---|---|
| Age | 0.00 | 0.02 | −0.00 | 0.99 |
| Sex | −0.06 | 0.30 | −0.22 | 0.82 |
| Race | 0.01 | 0.26 | 0.04 | 0.96 |
| FT4 | 2.34 | 0.99 | 2.34 | 0.02 |
| Thyroid antibody status | 0.99 | 0.42 | 2.35 | 0.02 |
Bold values − statistically significant i.e. p-value<0.05
Scatter plot of relationship between FT4 and A1C by stepwise regression modeling (p=0.015).
Box plot of thyroid antibody status and A1C by stepwise regression modeling (p=0.014).
HT is associated with discrete micronodules that need serial monitoring as benign and malignant nodules are known to coexist in HT [28]. Among our three patients with HT (Table 3), only one had a thyroid ultrasound that showed a nodule 0.6×0.4 cm, and he was euthyroid after treatment. Studies have shown that those with positive thyroid antibody status with euthyroidism demonstrated similar ultrasound features to those with HT [29], hence it is important to continue monitoring even those who are euthyroid.
The rate of GD is much lower in children and adolescents with T1DM compared to HT in previous studies. Our patients with GD are summarized in Table 5. The African-American subgroup in the T1DM Exchange Clinic Registry which included children and adults had a lower incidence of GD (19/1315, 1%) compared to HT (104/1315, 8%) [7]. GD affected 0.4% (4/987) of a US cohort of children with T1DM [23], which is similar to the German and Austrian cohort (0.46%, 276/60,456) [30] and Italian cohort (0.53%, 7/1323) [31]. However, Burek et al. noted a higher prevalence of GD among Black children (3.9%, 3/77) compared to the White children (0/82) [24]. We noted an equal number of children affected with GD and HT (1.3%, 3/222) in our study.
Clinical parameters for three Graves’ disease subjects.
| Subject | TSH at diagnosis | FT4 at diagnosis | TSI | TBII | Treatment | Thyroid ultrasound |
|---|---|---|---|---|---|---|
| 1 | 0.05 | 3.27 | 159% | 29% | Unknown | Mild thyromegaly, heterogeneous and hyperemic |
| 2 | 0.01 | 2.89 | – | 45.8% | Methimazole 10 mg BID | Mild thyromegaly and heterogeneous |
| 3 | <0.008 | 3.11 | 429% | – | Methimazole 7.5 mg BID | Massive thyromegaly, multinodular and hyperemic Largest nodule measures 2.2 cm, benign appearing |
TSI, thyroid stimulating immunoglobulin; TBII, thyroid binding inhibitory immunoglobulin. Reference values: TSI<125%, TBII<16%.
Screening for CD in our asymptomatic subjects occurred on average every 2.3 years. Only one (0.58 %) subject who was asymptomatic for CD had a positive TTG IgA which could be either a false positive or latent CD. A positive CD serology in subjects with villous atrophy confirms the diagnosis of CD. This subject underwent an upper endoscopy with resulting histological analysis that revealed no villous atrophy, which means that TTG IgA was a false positive screen. Thus, no one was found to have CD in our population. There have only been a few studies that have looked at prevalence of CD in the African-American population. In the recent National Health and Nutrition Examination Survey (NHANES) [32], the prevalence of CD among the African-American subgroup in the general population was low, 0.15% (5/3233) and among the <20 year age group, 0.1% was affected. However, this survey did not mention if there was associated T1DM. Also, our rate was lower than reported by the recent T1DM Exchange Clinic Registry with 0.7% (10/1315) of their African-American children and adults affected [7] and even lower than the worldwide prevalence of 0.97–16.4% as mentioned previously. Even though 3.6% of the children in our study tested positive for gliadin Ab, they had negative TTG IgA. Gliadin Ab is less accurate for CD diagnosis as there is a wide variability in their diagnostic accuracy. Gliadin Ab testing has lower sensitivity and specificity, 87.8% and 94.1%, respectively, when compared to 93% and 96.5% for TTG IgA based on a meta-analysis [33].
Kaukinen et al. suggested testing for HLA-DQ2 and HLA-DQ8 as CD is unlikely if both haplotypes are negative [34], however, more recent guidelines do not recommend haplotype testing at initial diagnosis of CD [22]. At our center, in a previously published study, 82% of 31 children with T1DM had the predisposing haplotype (HLA-DQ2 or DQ-8 or both) for CD. However, none had biopsy-proven CD, which is consistent with this study [35].
Most cases of CD are diagnosed within the first 5 years of T1DM diagnosis [8], however, not many longitudinal studies have been performed to investigate the development of new cases of CD during long-term follow-up. Barera et al. found that an additional 2.6% of Italian children developed CD after being screened annually for 6 years after the initial screening [36]. Among our population of minority children and adolescents who were followed for 6.1±4.0 years, no new cases of CD were detected when screening occurred on average every 2.3 years.
Our study has limitations. Even though the documented race of our population in the medical records is African American, some of our patients in Central Brooklyn are of mixed Afro-Caribbean descent. The Caribbean population includes a mixture of African, South Asian, Chinese, European and Middle Eastern descent. There is paucity of information on the prevalence of HT and CD among children and adolescents with T1DM within populations of Afro-Caribbean ethnicity. Another limitation is that it is a retrospective study so unknown thyroid antibody status was found in 32% and celiac status was unknown in 25% of our children and adolescents with T1DM even though all were euthyroid except for three with hypothyroidism during follow-up at our center. As our study was a retrospective study, the unknown thyroid antibody status may have led to an underestimate of the true rate of autoimmune thyroiditis in our population. None of these children with unknown Ab status had overt clinical features suggestive of HT and their thyroid function was normal. Additionally, it is not clear why certain individuals did not have TTG IgA checked for CD screening, as this is a retrospective chart review. Also, a negative TTG IgA result in an untreated patient does not always rule out CD, therefore results of this assay should be used in conjunction with clinical findings [37]. Another limitation was that there was large variability in the follow-up period, with a mean follow-up of 6.1±4.0 years. Those with shorter follow-up periods may not have developed positive thyroid antibodies, celiac antibody or hypothyroidism yet, but only three subjects had less than 1-year follow-up period.
Conclusions
The association between T1DM with HT and CD has been well established in other populations but relatively few studies have assessed the risk of these conditions in minority children and adolescents. Among the minority African-American children and adolescents with T1DM in Central Brooklyn who had screening tests regularly done, the number with hypothyroid HT and CD was lower than expected. The rate of autoimmune HT which includes both hypothyroid and euthyroid subjects is similar to other studies. Further studies are needed to assess the optimal screening frequency and cost-effectiveness of screening for HT and CD in our population of minority children with T1DM.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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