Characteristics of allergy in autoimmune thyroid diseases. Ildikó Molnár MD, PhD, EndoMed, Hungary

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1 Characteristics of allergy in autoimmune thyroid diseases Ildikó Molnár MD, PhD, EndoMed, Hungary

2 Relationship between allergic responses and thyroid autoimmunity IgE levels IgE deposits are present in Graves thyroid and orbital tissues (Werner SC et al., N Engl Med, 1972;287: ; Raikow RB et al., Ophthalmol. 199; 97: ) Elevated IgE levels associated with hyperthyroid Graves disease (Akira S et al., J Clin Endocrinol Metab 1999; 84: ; Takashi Y et al., J Clin Endocrinol Metab 2; 8: ) Evidence of immunglobulin E autoantibodies to thyrotropin receptor (TSH rec) and thyroid peroxidase (TPO) (Metcalfe R et al., J Clin Endocrinol Metab 22;87: ; Gou J et al., Clin Immunol Immunopathol 1997; 82: ) Th2-derived cytokine profils Elevated serum levels of IL- and IL-13 cytokines. (Hidaka Y et al., Thyroid 1998; 8: ; Ichiro K et al., J Clin Endocrinol Metab 21; 86: ) Allergic rhinitis associated frequently with Graves disease (Amino N et al., Thyroid 23; 13: ; Hidaka Y et al., Thyroid 1996; 6: ) Common key factors regulate the immune responses in both allergic and autoimmune conditions (Rottem M et al., Dev Immunology 22; 9: )

3 Previous results Graves ophthalmopathy associated with increased total IgE serum levels. Molnár I et al., Eur J Med Rev 1996; 1: Hyperthyroid Graves ophthalmopathy demonstrated elevated serum IL- levels compared to patients who had no eye signs. Molnár I, Abstract: ACT International Suppl., 2; 2: 22. Decreased serum levels of nerve growth factor (NGF) associated with hyperthyroid Graves ophthalmopathy compared to those who had no eye signs. Molnár I et al., Cytokine 26; 3: A difference in the balance shift of IL-12/IL- between Graves patients with and without ophthalmopathy was demonstrated. Molnár I, Autoimmunity 27; 4:31-37.

4 Patients and methods 324 patients were investigated, of whom 149 suffered from Graves disease (7 with ophthalmopathy), 11 had Hashimoto s thyroiditis, and 6 euthyroid goitre formed controls. Allergen-specific IgE detection was carried out with immunoblot method using commercial AllergyScreen TM test (MEDIWISS Analytic GmbH, Germany) and Kodak camera was used for evaluation. The levels of thyroid hormones and antibodies were measured using commercial kits in a fully automated way, except TSH receptor antibody,that was measured with radioimmunoassay (Brahms Diagnostics,Germany). Chi-squared with Yates correction and Mann-Whitney nonparametric comperative tests were used for statistical analysis. Parameters Graves disease n=149 Hashimoto s thyroiditis n=11 Controls n=6 Age (years) 49 ± 13 ± ± 13 Gender (male / women) Duration of thyroid disease (months) 28 / / 14 4 / ± ± 7 38 ± 4

5 Respiratory allergens

6 Prevalence of allergic symptoms in autoimmune thyroid diseases Allergic symptoms Graves disease (n=149) No 94 (63,1%) Rhinitis * Conjunctivitis 11 a (7,4%) 37 b (24,8 %) Urticaria 7 (4,7%) Hashimoto s thyroiditis (n=11) 63 (7,3%) 2 a (18,2%) 21 c (19,1%) (4,%) Asthma 1 (,9%) Controls (n=6) 4 (83,1%) 1 (1,4%) Total 211 (6,1%) 41 (12,7%) b, c 8 (17,9%) 1 (1,%) 13 (4%) 1 (,3%) Total a P <,14, b P<,1 and c P<,4 after Yates correction * P<,7 after Yates correction between Graves patients with (n=7) and without (n=92) eye signs:32 (9,9%) vs (1,%).

7 The month of the onset of autoimmune thyroid diseases was similar to those characterized by the seasonal allergic attack Month for thyroidal onset and seasonal allergic attack is common Graves disease (n=149) No 77 (81,9%) Common 17 a (18,1%) Hashimoto s thyroiditis (n=11) 9 (92,8%) 7 a,b (7,2%) Controls (n=6) 48 (78,7%) 13 b (21,3%) Total 21 (8,3%) 37 (14,7%) Total * a P <,4 and b P<,2 * No exact data were given in 72 cases

8 Prevalence of allergen-specific IgE in autoimmune thyroid diseases Allergen groups Graves disease (n=149) D (dust mite I-II) 33 (22,1%) T (alder, birch, hazel) W (mugwort, plantain, ragweed) 2 a (16,8%) 3 b (23, %) G (grass-mixture) 3 (2,1%) E (cat, dog and others epithelia, feather-mixture) 4 (26,8%) M (molds*) 1 (6,7%) Hashimoto s thyroiditis (n=11) 2 (22,7%) 7 a (6,4%) 12 b (1,9%) 14 (12,7%) 23 (2,9%) 4 (3,6%) Controls (n=6) 7 (1,8%) 6 (9,2%) 1 (16,4%) 7 (1,8%) 19 (29,2%) 4 (6,2%) Total 6 (2,1%) 38 (11,7%) 7 (17,6%) 1 (1,7%) 82 (2,3%) 18 (,6%) Total a P <,2 and b P<,1 * Alternaria,Aspergillus, Cladosporium, Penicillium

9 Prevalence of allergen-specific IgE (%) Prevalence of allergen-specific IgE (%) Prevalence of allergen-specific IgE (%) Graves disease (n=149) Controls (n=6) Graves disease (n=149) Hashimoto s thyroidiitis (n=11) Hashimoto s thyroidiitis (n=11) Controls (n=6) P<.2 P<. 12, 1, 8, 6, 4, 2,, P<.2 P<.4 P<.4 P<.1 P<.2 P<.2 Dust Alder Alder Birch Hazel Ragweed Grass- Hamster Dustmite II (T2) (T2) (T3) (T4) (W1) mixture epithelia mite II (D2) (Gx) (E84) (D2) P<.2

10 Allergen-specific IgE levels (IU/ml) Graves ophthalmopathy Hashimoto s thyroiditis Graves disease without eye signs 3 P<.4 2 * * D1 D2 T2 T3 T4 W1 Gx G12 W6 E1 (dust-mite) (alder) (birch) (hazel) (ragweed) (rye pollen) (cat) I II (grass-mixture) (mugwort) E2 (dog) E84 (hamster epithelia)

11 Allergen-specific IgE levels (IU/ml) P<,1 P<,12 Patient groups Graves'diseases without ophthalmopathy Graves' ophthalmopathy P<,46 1 P<,33 P<,21 1 T2 T3 T4 W1 Gx G12 E1 E M2 alder birch hazel ragweed grass- rye pollen cat dog cladosporium mixture epithelia

12 IU/ml Class Allergen-specific IgE content <,3 none,3,69 1 low,7 3,4 2 increased 3, 17,4 3 significantly increased 17, 49,9 4 high - 1 very high >1 6 extremely high

13 Allergen-specific IgE levels (IU/ml) Patient groups Hyperthyroid Euthyroid Hypothyroid Class D1 D2 T2 T3 T4 W1 Gx G12 E1 E dust-mite alder birch hazel ragweed grass- rye pollen cat dog I II mixture epithelia

14 Allergen-specific IgE levels (IU/ml) 3 2 Graves disease TSH receptor antibody negative TSH receptor antibody positive P<,32 D1 D2 T2 T3 T4 W1 Gx G12 W6 W9 E1 E M2 M3 dust-mite alder birch hazel ragweed rye pollen plantain cat dog cladosporium I II grass-mixture mugwort epithelia aspergillus

15 Allergen-specific IgE levels (IU/ml) 3 2 anti-tpo negative Graves disease (TPO: thyroid peroxidase) anti-tpo positive D1 D2 T2 T3 T4 W1 Gx G12 W6 W9 E1 E M1 M2 M3 dust-mite alder birch hazel ragweed rye pollen plantain cat dog penicillium aspergillus I II grass-mixture mugwort epithelia cladosporium

16 Allergen-specific IgE levels (IU/ml) Graves disease anti-htg negative anti-htg positive (Htg: human thyroglobulin) 1 1 * P<,46 D1 D2 T2 T3 T4 W1 Gx G12 W6 W9 E1 E dust-mite alder birch hazel ragweed grass- rye pollen plantain cat dog I II mixture mugwort epithelia *

17 Allergen-specific IgE levels (IU/ml) 4 Graves disease without ophthalmopathy * P<,44 ** P<,3 ** anti-htg negative anti-htg positive (Htg: human thyroglobulin) 1 * D1 D2 T2 T3 T4 W1 Gx G12 W6 W9 E1 E dust-mite alder birch hazel ragweed grass- rye pollen plantain cat dog I II mixture mugwort epithelia

18 Allergen-specific IgE levels (IU/ml) 6 4 Patient groups None anti-tpo + TSH rec antibody * P<,24 * * D1 T2 W1 Gx E1 Dust-mite I Alder Ragweed Grass-mixture Cat epithelia

19 Conclusions Allergic rhinitis and conjunctivitis was more frequent in autoimmune thyroid diseases However, the attack of allergic rhinitis was higher in Hashimoto s thyroiditis and allergic conjunctivitis in Graves disease. Seasonal allergic attack can play as an inducer or aggravator role in the development of Graves disease. The prevalence of allergen-specific IgE levels against trees and weeds were more frequent in Graves disease than in Hashimoto s thyroiditis. Allergen-specific IgE levels were lower in Graves ophthalmopathy compared to those without eye signs, as well as lower compared to Hashimoto s thyroiditis. Hyperthyroidism was associated with elevated allergen-specific IgE levels resulting in a higher class degree. (Except cat epithelia.) The presence of antithyroid antibodies influenced the allergen-specific IgE levels. TSH receptor antibody positive and sometimes anti-thyroid peroxidase positive patients showed higher IgE levels, but anti-thyroglobulin (Htg) positivity was associated lower IgE levels, particularly in Graves ophthalmopathy. The frequent presence of allergic conjunctivitis in Graves disease can lead to a difficulty in the diagnosis of ophthalmopathy.

20 Food allergens

21 Prevalence of food allergen-specific IgE in autoimmune thyroid diseases Allergen groups Graves disease (n=149) Hashimoto s thyroiditis (n=11) Controls (n=6) Total F17 (hazelnut) 13 a (8,7%) 1 a (,9%) 2 (3,1%) 16 (4,9%) F3 (potato) 16 b, c (1,7%) 3 b (2,7%) 1 c (1,%) 2 (6,2%) F8 (celery) 24 d (16,1%) d (4,%) 4 (6,2%) 33 (1,2%) F31 (carrot) 2 e (16,8 %) 6 e (,%) 4 (6,2%) 3 (1,8%) F2 (tomato) 1 f (6,7%) 1 f (,9%) 11 (3,4%) F33 (orange) 17 g,h (11,4%) 3 g (2,7%) 1 h (1,%) 21 (6,%) F4 (wheat flour) 22 i (14,8%) 4 i (3,6%) 3 (4,6%) 29 (9%) Total a P <.1, b P<.3, c P<.4, d P<.1, e P<.1, f P<.3, g P<.2, h P<.3 and i P<.1 with Yates corrections.

22 Allergen-specific IgE levels (IU/ml) Allergen-specific IgE levels (IU/ml) Allergen-specific IgE levels (IU/ml) Graves disease (n=149) Controls (n=6) Graves disease without (n=92) Graves disease with ophthalmopathy (n=7) Hashimoto s thyroiditis (n=11) Controls (n=6) 7 6 P<.2 P<.2 1, 9, 8, 7, P<.4 P<.3,7,6, P< ,, 4,,4,3 2 3,,2 1 2, 1,,1, F8 F31 F3 F31 F16 celery carrot potato carrot walnuts

23 Allergen-specific IgE levels (IU/ml) 18 Patient groups Hyperthyroid Euthyroid Hypothyroid * P<, * * F16 F3 F8 F31 F33 F4 F F14 walnuts potato celery carrot orange wheat flour rye meal soybeans

24 hazelnuts paelnuts walnuts milk casein potato celery carrot tomato creb orange apple wheat flour rye meal Soybeans Allergen-specific IgE levels (IU/ml) TSH receptor antibody negative TSH receptor antibody positive Graves disease F17 F13 F16 F2 F78 F3 F8 F31 F2 F23 F33 F49 F4 F F14

25 hazelnuts milk potato celery carrot tomato orange apple wheat flour Soybeans Allergen-specific IgE levels (IU/ml) 2, 2 Graves ophthalmopathy TSH receptor antibody negative TSH receptor antibody positive 1, 1, * P<,4 * F17 F2 F3 F8 F31 F2 F33 F49 F4 F14

26 hazelnuts paelnuts walnuts milk casein potato celery carrot tomato orange apple wheat flour rye meal Soybeans Allergen-specific IgE levels (IU/ml) 9 8 anti-tpo negative (TPO: thyroid peroxidase) Graves disease anti-tpo positive F17 F13 F16 F2 F78 F3 F8 F31 F2 F33 F49 F4 F F14

27 hazelnuts milk potato celery carrot tomato orange apple wheat flour rye meal Soybeans Allergen-specific IgE levels (IU/ml) Graves disease anti-htg negative anti-htg positive (Htg: human thyroglobulin) F17 F2 F3 F8 F31 F2 F33 F49 F4 F F14

28 TSH levels (µu/ml) P<.24 TSH FT4 FT3 TSH rec a-tpo a-htg antibody P<.3 P<.13 FT 4 levels (ng/dl) P<.1 P<.3 FT 3 l evels (pg/ml) P<.42 TSH ereceptor antibody levels (IU/l) P<.21 Anti-TPO antibofódy levels (IUl/l) P<.1 P<.4 Anti-Htg antibofódy levels (IUl/l) P< F78 M1 M2 M1 M2 M6 W6 F14 F16 F14 negative positive F78: casein M1: Penicillium M2: Cladosporium M6: Alternaria W6: mugwort F14: soybeans F16: walnuts

29 Conclusions Food allergen-sensitization was more frequent in Graves disease compared to that in Hashimoto s thyroiditis, and it can affect our daily meals. Allergen-specific IgE levels were higher in Graves disease, but lower in Hashimoto s thyroiditis than controls. Hyperthyroidism was associated with elevated allergen-specific IgE levels. Anti-thyroid antibodies influenced the degree of IgE levels: 1. TSH receptor and anti-tpo antibody levels were associated with higher IgE levels. (Except milk and casein allergens). 2. Anti-Htg antibody levels were connected to lower IgE levels.

30 Thank you for your attention! This study contains works of Erzsébet Kelemen MD, otolaryngologist Láng Antalné, medical laboratory assistant

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