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. 2014 Sep 4;178(1):57–64. doi: 10.1111/cei.12395

Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity

K A Ponto *,†, D Schuppan ‡, I Zwiener §,†, H Binder §, A Mirshahi *, T Diana ‡, S Pitz *, N Pfeiffer *, G J Kahaly ‡
PMCID: PMC4360194  PMID: 24903731

Abstract

Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid–eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren's syndrome were ‘protective’ for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO.

Keywords: autoimmune co-morbidity, autoimmune gastritis, autoimmune thyroid diseases, coeliac disease, thyroid-associated orbitopathy

Introduction

Autoimmune thyroid diseases (AITD) encompass Graves' disease (GD) and Hashimoto's thyroiditis (HT). Their prevalence is fivefold higher in females than in males 1,2. Diagnosis of AITD is based on clinical features, thyroid sonography and tests for anti-thyroid autoantibodies 3,4. Thyroid-associated orbitopathy (TAO) is the most prevalent extrathyroidal manifestation of AITD 2,4,5

Common autoimmune disorders tend to co-exist in the same subjects, and cluster in families 6. For GD and HT it has been shown that the relative risk of nearly all other relevant autoimmune diseases is increased significantly 7. However, clustering of associated autoimmunity is different between HT and GD 8. The exact aetiology of the deregulated immune response of the thyroid in patients with AITD is still unknown, but patients usually have a complex genetic predisposition [e.g. human leucocyte antigen (HLA)-DR3/DR4 or HLA-DQ2/DQ8] 9. Patients with AITD may also be affected by other autoimmune endocrine diseases 10, such as type 1 diabetes and autoimmune type A gastritis 6, but coeliac disease has also been frequently observed 11,12. The aetiopathogenesis of AITD is multi-factorial 13, and additional endogenous hormonal and various exogenous factors are suspected triggers of disease manifestation. Exogenous factors comprise environmental influences such as smoking, iodine intake and infections 14.

The objective of this study was to provide data on the association between TAO versus non-TAO in consecutive and unselected patients with AITD and the prevalence of other autoimmune endocrine and non-endocrine diseases. We hypothesized that these different manifestations of AITD, affecting the periorbital extracellular matrix in GD, should be reflected by a variant spectrum of associated autoimmune co-morbidity.

Methods

The medical records or files of 1310 consecutive unselected patients with AITD (n = 777 with GD and n = 533 with HT) were analysed within this retrospective cross-sectional study. No matching was performed. All patients were followed on a regular basis at a specialized out-patient clinic for autoimmune (endocrine) diseases of the Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany, between January 1999 and July 2012.

The primary outcome measure was the prevalence of associated autoimmunity in patients with AITD with and without orbital disease. Complete endocrine investigation was performed in all patients; all patients were subsequently screened for signs and symptoms of orbital involvement. In the presence of clinical signs, patients were managed at our combined thyroid–eye clinic or (in the presence of a mild and inactive TAO) were seen by an ophthalmologist close to their home town on a regular basis. Diagnosis and clinical evaluation of TAO were performed according to the consensus statement of the European Group on Graves' orbitopathy (EUGOGO) 15,16.

A comprehensive interview regarding their medical history was performed, and blood samples were drawn for both functional and autoantibody testing in all patients. The standard reference ranges of the JGU Central Laboratory were used as cut-offs. Whenever suspected and if clinically indicated (positive autoantibodies and/or suggestive symptoms), endocrine function tests, measurement of specific autoantibodies and/or additional diagnostics (e.g. endoscopy of the gastrointestinal tract and/or magnetic resonance imaging) were performed. Data acquisition from patients with AITD was performed using standardized clinical and laboratory diagnostic criteria. The patients had clinically and biochemically confirmed AITD, either GD or HT. Cases that could not be defined clearly as GD or HT were not included into the analysis. A thyroid ultrasound was performed in all subjects with thyroid dysfunction, specific autoantibodies and in patients with a (family) history for thyroid diseases. The presence of thyroid stimulating hormone (TSH) receptor blocking autoantibodies (TBAb) in patients with HT was evaluated as published previously 17.

The definitions and diagnostic criteria of the various autoimmune diseases are listed in Table 1. All subjects were tested for all autoimmune diseases that are listed in this table. The adult autoimmune polyglandular syndrome encompassed type II (Addison's disease with another autoimmune endocrine disorder), type III (autoimmune thyroid disease and type 1 diabetes) as well as type IV (two autoimmune endocrine disorders excluding types I–III).

Table 1.

Definitions and diagnostic criteria of the various autoimmune diseases

Endocrine autoimmune diseases
 Graves' disease Hyperthyroidism, presence of thyroid-stimulating hormone (TSH) receptor autoantibodies, typical thyroid ultrasound pattern with enhanced vascularization of the thyroid gland
 Hashimoto's thyroiditis At least fivefold increased serum level of thyroid peroxidase autoantibodies, a typical hypoechoic ultrasound pattern, and eu- or hypothyroidism
 Type I diabetes mellitus Insulin dependency; positive autoantibodies against the islet cell antigens and/or tyrosine phosphatase IA-2 (IA2A) and/or insulin (IAA) and/or glutamic acid decarboxylase-65 (GADA), a pathological serum glycaemic haemoglobin > 6·5% and fasting serum glucose > 120 mg/dl
 Addison's disease Suppressed baseline serum cortisol levels (<0·1 μg/dl), pathologically elevated baseline serum adrenocorticotrophic hormone (ACTH) levels, markedly elevated stimulated serum ACTH levels (delta > 50 pg/ml) and the presence of cytochrome P450-21 hydroxylase autoantibodies
 Autoimmune primary hypoparathyroidism Serum baseline parathyroid hormone levels < 15 pg/ml with positive anti-calcium-sensing receptor autoantibodies, baseline serum calcium < 2 mmol/l and elevated serum phosphate levels > 5 mg/dl
 Autoimmune primary hypogonadism Suppressed serum peripheral sexual hormone levels, elevated serum gonadotrophic hormone levels (FSH > 15 IU/l, LH > 10 IU/l, pathological luteinizing hormone-releasing hormone stimulation test (delta FSH and LH > 10 IU/l) and positive 17-hydroxylase autoantibodies
Autoimmune diseases of the gastrointestinal tract
 Coeliac disease Presence of serum immunoglobulin (Ig)A (in case of IgA-deficiency IgG) autoantibodies to tissue transglutaminase and histological confirmation by Marsh stage III (endoscopic biopsy of the small bowel)
 Autoimmune type A gastritis Presence of gastric parietal cell autoantibodies with histological atrophy of the gastric mucosa and intestinal metaplasia
 Autoimmune hepatitis Elevated anti-nuclear and/or anti-alpha smooth muscle actin or anti-soluble liver antigen antibodies in the presence of usually ≥2-fold elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values and subsequent histological confirmation
Dermatological autoimmune diseases
 Vitiligo Clinical inspection
 Alopecia Clinical picture and root hair analysis
 Urticaria Clinical phenotype
Further autoimmune diseases
 Rheumatoid arthritis Clinical criteria (e.g. morning stiffness); laboratory tests: positive rheumatoid factor and cyclic citrullinated peptide (CCP)
 Sjögren′s Syndrome Dry eye syndrome and positive anti-SS-A-and SS-B-antibodies. If clinically required an additional positive biopsy of the salivary gland was performed
 Systemic lupus erythematosus Presence of DNS and ds-DNS- and anti-smooth-muscle antibodies together with a classical phenotype
 Scleroderma Clinical phenotype and biopsy; laboratory tests: positive serum anti-nuclear, anti-SCL 70 and anti-centromere autoantibodies
 Sarcoidosis Laboratory tests: elevated angiotensin converting enzyme (ACE), elevated blood sedimentation rate; clinical and radiological criteria, i.e. swelling of lymph nodes and lung fibrosis
 Myasthenia gravis Positive serum acetylcholine receptor autoantibodies, Simpson's (ice-pack) test and tensilon test
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The protocol was consistent with the principles of the Declaration of Helsinki. Because this study was observational, did not include any interventions aside from those commonly falling within the daily routine, and because no decoded patient-related data were passed to third parties, the responsible Ethics Committee of the Medical Association of the State Rhineland Palatinate, Germany, decided that no approval was required.

Statistical analyses

Statistical analyses were performed using spss (Statistical Package for the Social Sciences, version 18; SPSS Inc., Chicago, IL, USA). A χ2 test was used to calculate dependencies between two categorical variables. A binary regression analysis was used for multivariable analysis yielding odds ratios (OR), 95% confidence-intervals (OR and P-values, respectively). None of the autoimmune diseases was defined as the primary outcome measure, so all analyses that were performed were exploratory. No significance level was fixed.

Results

Demographic data and associated co-morbidities

Of 1310 consecutive and unselected patients with AITD followed regularly at the autoimmune out-patient clinic, a total of 777 had GD (59%) and 533 (41%) had HT. Of these 1310 AITD patients, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome (APS types II–IV), 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) autoimmune type A gastritis, 57 (4·4%) vitiligo and 25 (1·9%) had Addison's disease. Listed in Table 2 are all associated autoimmune endocrine and non-endocrine diseases observed in patients with GD and HT. A positive association with GD was found for coeliac disease and for autoimmune gastritis, whereas type I diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis, autoimmune hepatitis and Sjögren's syndrome were linked to HT.

Table 2.

Associated autoimmune diseases in patients with autoimmune thyroid diseases. Frequencies of co-morbidities in patients with Graves' disease and Hashimoto's thyroiditis, respectively, with P-values according to χ2 test and odds ratios (ORs), 95% confidence intervals (CIs) and P-values according to binary logistic regression analysis. ORs >1 indicate a positive association with ‘Graves’ disease

Frequency in 777 patients with Graves' disease n (%) Frequency in 533 patients with Hashimoto's thyroiditis n (%) P-value (χ2 test) OR 95% CI P-value (logistic regression analysis)
Coeliac disease 84 (10·8) 27 (5·0) <0·001 2·18 1·35–3·54 0·002
Autoimmune type A gastritis 53 (6·8) 7 (1·3) <0·001 6·52 2·76–15·42 <0·001
Autoimmune hepatitis 3 (0·4) 9 (1·7) 0·016 0·21 0·05–0·80 0·023
Type 1 diabetes 55 (7·1) 74 (13·8) <0·001 0·49 0·33–0·72 <0·001
Addison's disease 2 (0·3) 23 (4·3) <0·001 0·06 0·01–0·26 <0·001
Primary hypogonadism 11 (1·4) 25 (4·7) <0·001 0·64 0·28–1·48 0·298
Primary hypopara-thyroidism 1 (0·1) 3 (0·6) 0·164 0·31 0·03–3·25 0·333
Alopecia areata 11 (1·4) 29 (5·4) <0·001 0·25 0·12–0·53 <0·001
Vitiligo 27 (3·5) 30 (5·6) 0·064 0·75 0·42–1·36 0·344
Rheumatoid arthritis 12 (1·5) 18 (3·4) 0·031 0·50 0·23–1·11 0·090
Sjögren's syndrome 13 (1·7) 26 (4·9) 0·001 0·32 0·15–0·68 0·003
Systemic lupus erythematosus 5 (0·6) 10 (1·9) 0·041 0·38 0·13–1·14 0·085
Sarcoidosis 3 (0·4) 1 (0·2) 0·519 1·51 0·15–14·86 0·724
Scleroderma 1 (0·1) 2 (0·4) 0·362 0·34 0·30–3·88 0·386
Myasthenia gravis 4 (0·5) 0 0·096 Not applicable (n = 0 in one group)
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CI = confidence interval; n = number of patients; OR = odds ratio.

Comparison of co-morbidities in patients with and without thyroid-associated orbitopathy

Of 1310 patients with AITD, 610 (46·6%) had symptoms and signs of overt TAO and 700 (53·4%) did not have any orbital involvement. Median (range) age of patients with and without TAO was 50 years (4–85·5 years) and 43 years (4–83), respectively. Of patients with TAO, 491 of 610 (80·5%) were females versus 576 of 700 (82·3%) in non-TAO. The rate of smokers was 30 and 29·3% of patients with versus without TAO.

TAO was far more prevalent in patients with GD than in those with HT: 584 (95·7%) and 26 (4·3%) of the patients with GD and HT had TAO (P < 0·001), respectively. The same holds true for autoimmune diseases of the gastrointestinal tract, namely coeliac disease and autoimmune type A gastritis (Fig. 1). TSH receptor-blocking autoantibodies (TBAb) were positive in 133 of 533 (25%) patients with HT. Of these TBAb-positive patients, nine (6·8%) had coeliac disease versus 18 of 400 (4·5%) TBAb-negative HT patients (P = 0·302). Smoking was not associated with the presence of coeliac disease in TAO, as 59 of 72 (81·9%) patients with TAO and coeliac disease were non-smokers (P = 0·019).

Fig 1.

Fig 1

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Prevalence of autoimmune gastrointestinal diseases in patients with versus without thyroid-associated orbitopathy (TAO). The prevalence of coeliac disease, autoimmune type A gastritis and autoimmune hepatitis in patients with versus without TAO was 81 (13·3%) versus 30 (4·3%), P < 0·001; 45 (7·4%) versus 15 (2·1%), P < 0·001; and 2 (0·3) versus 10 (1·4%), P = 0·043 (univariate analysis), respectively.

Complete and detailed ophthalmic findings were available in a large subgroup of patients. Almost all patients with coeliac disease and TAO (23 of 24, 96%) had diplopia, of whom five (42%) showed constant diplopia. In 18 (75%) of these patients, a moderate-to-severe TAO was present. In contrast, in 10 of 15 cases (67%), patients with type 1 diabetes had a mild TAO and constant diplopia in one (7%) patient only. However, there were no statistically significant differences pertaining to ophthalmic findings between the various groups.

Table 3 illustrates the frequencies of the different co-morbidities in AITD patients with and without TAO. A higher rate of TAO was found, especially in GD patients with coeliac disease and with Sjögren's syndrome. In contrast, the presence of type 1 diabetes, Addison's disease and primary hypogonadism was protective for the presence of TAO.

Table 3.

Univariate analysis. Associated autoimmune diseases in patients with autoimmune thyroid diseases with and without thyroid-associated orbitopathy (TAO). Univariate analysis with P-values according to χ2 test. The P-values refer to the association between the presence of ‘no TAO’ versus ‘TAO’ and the autoimmune co-morbidities

All patients (n = 1310)
 Patients with Graves' disease (n = 777)
 Patients with Hashimoto's thyroiditis (n = 533)
n (%)
 n (%)
 n (%)
No TAO TAO P-value No TAO TAO P-value No TAO TAO P-value
Coeliac disease 30 (27·0) 81 (73·0) <0·001 5 (6·0) 79 (94·0) <0·001 25 (92·6) 2 (7·4) 0·528
Autoimmune gastritis 15 (25·0) 45 (75·0) <0·001 10 (18·9) 43 (81·1) 0·312 5 (71·4) 2 (28·6) 0·003
Autoimmune hepatitis 10 (83·3) 2 (16·7) 0·037 1 (33·3) 2 (66·7) 0·726 9 (100) 0 0·494
Type 1 diabetes 103 (79·8) 26 (20·2) <0·001 30 (54·5) 25 (45·5) <0·001 73 (98·6) 1 (1·4) 0·131
Addison's disease 24 (96·0) 1 (4·0) <0·001 1 (50·0) 1 (50·0) 0·405 23 (100) 0 0·268
Primary hypogonadism 28 (78) 8 (22) 0·003 3 (27) 8 (73) 0·839 25 (100) 0 0·247
Primary hypo-parathyroidism 4 (100) 0 0·062 1 (100) 0 0·080 3 (100) 0 0·695
Alopecia areata 36 (90·0) 4 (10·0) <0·001 8 (72·7) 3 (27·3) <0·001 28 (96·6) 1 (3·4) 0·716
Vitiligo 39 (68·4) 18 (31·6) 0·020 10 (37·0) 17 (63·0) 0·128 29 (96·7) 1 (3·3) 0·689
Rheumatoid arthritis 24 (80·0) 6 (20·0) 0·003 6 (50·0) 6 (50·0) 0·040 18 (100) 0 0·392
Sjögren's syndrome 26 (66·7) 13 (33·3) 0·093 0 13 (100) 0·038 26 (100) 0 0·237
Systemic lupus erythematosus 11 (73·3) 4 (26·7) 0·120 1 (20·0) 4 (80·0) 0·809 10 (100) 0 0·471
Sarcoidosis 1 (25·0) 3 (75·0) 0·254 0 3 (100) 0·321 1 (100) 0 0·821
Scleroderma 3 (100) 0 0·106 1 (100) 0 0·080 2 (100) 0 0·749
Myasthenia gravis 0 4 (100) 0·032 0 4 (100) 0·251 0 0 –
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Multivariate analysis

Multivariate analysis (Table 4) showed that in the total collective of 1310 AITD patients, coeliac disease and autoimmune gastritis were associated positively with the presence of TAO. In contrast, the risks for developing TAO was lower in patients with type I diabetes, Addison's disease, alopecia areata and rheumatoid arthritis. In the subgroup of GD patients, coeliac disease was still associated positively with TAO, whereas there was a negative association between type I diabetes and TAO. In patients with HT, the positive association between autoimmune gastritis and TAO was high (OR 8·2).

Table 4.

Multivariate analysis. Autoimmune co-morbidity in patients with autoimmune thyroid diseases (Graves' disease and Hashimoto's thyroiditis). Odds ratios (ORs) refer to the association with thyroid-associated orbitopathy. Binary logistic regression with OR, 95% confidence interval (CI) and P-value

All patients
 Patients with Graves' disease
 Patients with Hashimoto's thyroiditis
OR 95% CI P-value OR 95% CI P-value OR 95% CI P-value
Coeliac disease 3·40 2·12–5·44 <0·001 1·87 2·43–17·35 <0·001 2·16 0·46–10·25 0·331
Autoimmune gastritis 4·03 2·08–7·80 <0·001 1·28 0·58–2·84 0·540 8·20 1·41–47·62 0·019
Autoimmune hepatitis 0·19 0·38–0·94 0·042 0·40 0·03–5·14 0·480 Not applicable (n = 0 in one group)
Type 1 diabetes 0·25 0·16–0·40 <0·001 −1·47 0·13–0·42 <0·001 0·18 0·022–1·49 0·112
Addison's disease 0·05 0·01–0·39 0·004 0·19 0·01–3·98 0·282 Not applicable (n = 0 in one group)
Primary hypogonadism 0·68 0·26–1·79 0·437 0·23 0·13–0·42 0·413 Not applicable (n = 0 in one group)
Primary hypo-parathyroid Not applicable (n = 0 in one group) Not applicable (n = 0 in one group) Not applicable (n = 0 in one group)
Alopecia areata 0·13 0·04–0·94 <0·001 0·11 0·29–0·50 0·004 0·82 1·41–47·62 0·858
Vitiligo 0·62 0·33–1·12 0·153 0·73 0·28–1·86 0·505 1·02 0·13–8·09 0·989
Rheumatoid arthritis 0·29 0·11–0·74 0·010 0·36 0·11–1 16 0·086 Not applicable (n = 0 in one group)
Sjögren's syndrome 0·56 0·26–1·22 0·146 Not applicable (n = 0 in one group) Not applicable (n = 0 in one group)
Systemic lupus erythematosus 0·41 0·13–1·31 0·133 0·64 0·06–7·09 0·714 Not applicable (n = 0 in one group)
Sarcoidosis 2·39 0·24–24·04 0·459 Not applicable (n = 0 in one group) Not applicable (n = 0 in one group)
Scleroderma Not applicable (n = 0 in one group) Not applicable (n = 0 in one group) Not applicable (n = 0 in one group)
Myasthenia gravis Not applicable (n = 0 in one group) Not applicable (n = 0 in one group) Not applicable (n = 0 in one group)
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Discussion

Prevalence of autoimmune diseases in patients with and without thyroid-associated orbitopathy

This study of a very large collective of unselected and consecutive patients with AITD has shown several relevant findings. First, as expected, the overwhelming majority of subjects with TAO have concomitant GD and only a small minority is associated with HT.

Secondly, gastrointestinal autoimmune diseases, e.g. coeliac disease and autoimmune-type gastritis, are more prevalent in patients with TAO versus those without. The association of TAO with gastrointestinal autoimmune diseases is clinically relevant, as both coeliac disease as well as chronic type A autoimmune gastritis may strongly influence the resorption of tablets, vitamins and minerals in those subjects 18–21. In line with this, iron and vitamin B12 deficiency leading to pernicious anaemia are prevalent in patients with autoimmune gastritis and may therefore be observed frequently in subjects with TAO. Furthermore, coeliac disease-induced malabsorption may interfere in the medical treatment of subjects with AITD delaying or reducing the resorption of important medications such as levothyroxine and/or anti-thyroid drugs.

Thirdly, the concomitant presence of type 1 diabetes and/or further autoimmune skin and rheumatic diseases seems to significantly lower the risk of developing TAO, as shown clearly by multivariate regression analysis. After adjustment for age, gender, smoking and the type of AITD (GD versus HT), the presence of type 1 diabetes was somewhat ‘protective’ for the development of TAO, whereas there was a three- to fourfold increased risk for TAO in patients with coeliac disease.

Fourthly, the link between AITD and type 1 diabetes as part of the autoimmune polyglandular syndrome is well described 22. In comparison, in a previous study on the rates of associated autoimmune diseases in a markedly smaller number of patients with and without TAO, non-thyroid autoimmune diseases were detected in fewer than 10% and, as in the present study, type 1 diabetes was the most prevalent non-thyroid autoimmune disease in patients without TAO (6·7 versus 14·7% in our collective) 23.

In the present cohort, no cases of multiple sclerosis were documented. Recent reports have shown that treatment of multiple sclerosis with alemtuzumab results in increased rates of AITD, predominantly GD 24. Thus, in the present study we were not able to test whether the risk of GD was lower in patients with multiple sclerosis not subject to alemtuzumab therapy.

Thyroid-associated orbitopathy and gastrointestinal autoimmune diseases – is there a link?

In patients with TAO, coeliac disease was the most prevalent co-morbid autoimmune condition and rates were increased compared to GD patients without TAO. This association may be relevant to understanding the common aetiopathology between these two diseases. In contrast, the fact that type 1 diabetes is not increased in TAO argues that there is a specific shared mechanism here, not just ‘generally more autoimmunity’.

The association of AITD with coeliac disease has been shown for patients with hyper- and hypothyroidism 23,25–27. For example, in a collective of 83 patients with AITD the frequency of coeliac disease was 4·8%, with three of four patients being asymptomatic 28. The exact pathogenesis of co-existent AITD and other autoimmune diseases is not known, while the close association of coeliac disease with AITD and other autoimmune diseases, such as type 1 diabetes, is well studied 29–32. In one study, the prevalence of coeliac disease among 100 patients with AITD was 2% 33. This study identified patients on a gluten-free diet who achieved complete reversal of villous abnormalities within 6 months of diet initiation. This emphasizes the role of early disease detection and a strict gluten-free diet for disease remission and long-term prognosis.

However, our study is the first to show that coeliac disease was significantly more prevalent in patients with TAO than in those without orbital involvement. The observed link between the orbital manifestation of AITD and coeliac disease may be due to a common (auto-) antigen, as similar morphological changes are present in both autoimmune disorders with lymphocytic infiltration leading to tissue remodelling and subsequent fibrosis in TAO or to villous atrophy of the duodenal mucosa in coeliac disease 34–38. Furthermore, local release of proinflammatory cytokines (e.g. interferon-γ, tumour necrosis factor-α, interleukin 6) has been reported in both TAO and coeliac disease 39–42. Also in these diseases, clinical activity and severity as well as villous morphology correlate closely with the levels of disease-specific autoantibodies 43,44. As there is evidence that anti-tissue transglutaminase antibodies are involved in the pathogenesis of coeliac disease 45, it might also be that there is a shared immune defect, e.g. a tendency towards an antibody-mediated T helper type 2 (Th2)-like autoimmunity. Hence, TAO and coeliac disease would be two of a very small number of ‘common’ antibody-mediated organ-specific autoimmune diseases. Finally, common genetic links, e.g. common major histocompatibility complex (MHC) class II antigens have been described 38,46–48.

Limitations of the study and clinically relevant recommendations

We have studied a large cohort of sequential unselected AITD patients seen at the specialized out-patient clinic for autoimmune (endocrine) diseases of a single academic institution, which is recognized as a multi-disciplinary thyroid–orbital centre. Patients with TAO are usually referred to a specialized centre due to their severe disease phenotype. This could have led to a selection bias, including more patients with severe TAO and more autoimmune co-morbidities. Another limitation is that there is a potential risk of misclassification of ‘non-TAO’ in the present study, as it is possible to have radiological evidence of TAO without clinical evidence. Because orbital imaging was not performed in all subjects, the ascertainment of TAO versus non-TAO pertains to clinically apparent disease, and most probably to the more advance manifestations of the disease. Another selection bias pertains to the inclusion of more patients with GD than with HT. This is due probably to the referral of patients with (suspected) TAO. Furthermore, smoking was assessed as a binary variable only. To further investigate the influence of smoking, more detailed information should be collected in future studies, especially regarding ex-smokers, amount of smoking, pack years, etc. Also, in the present study the overall rate of ocular myasthenia gravis was lower than reported previously 8. A possible explanation is that subtle ocular symptoms and signs might have been overlooked, as patients were recruited primarily from an endocrine out-patient clinic. Thus, mainly patients with seropositive myasthenia gravis and elevated acetylcholine-receptor antibodies, but no overt neurological symptoms, were detected. This may have led to either an under- or an over-estimation, as (i) patients with severe symptoms of myasthenia probably report primarily to a neurological clinic, and (ii) 20–25% of patients with myasthenia gravis are seronegative for these antibodies 46. As an association between seronegative myasthenia gravis and GD has been reported, TAO patients should be both clinically carefully assessed, as well as via novel tests such as the newly introduced muscle-specific kinase autoantibodies 47.

In conclusion, based on our large cross-sectional study, we recommend that every patient with TAO should be investigated not only for symptoms and chemistries of autoimmune thyrotoxicosis, but also for gastrointestinal complaints and clinical chemical parameters related to type A autoimmune gastritis, subsequent pernicious anaemia, and especially coeliac disease. Coeliac disease is the only (partly) autoimmune disease where all complaints and pathognomonic autoantibodies to the autoantigen tissue transglutaminase usually resolve once patients adhere to a gluten-free diet.

Acknowledgments

Thyroid-blocking autoantibodies were measured at the JGU Thyroid Research laboratory by M. Kanitz, laboratory technician; his excellent work is greatly appreciated. No financial support was obtained for this study.

Disclosure

The authors have nothing to disclose.

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