|Year : 2015 | Volume
| Issue : 2 | Page : 84-89
Association between thyroid autoimmunity and chronic urticaria in patients versus healthy controls
Ashraf M Okba1, Dina S Sheha1, Asmaa S Moustafa1, Alyaa A El-Sherbeny MD 2, Nesrine A Mohamed3, Manar F Aglan4
1 Department of Internal Medicine, Allergy and Clinical Immunology, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine and Endocrinology, Ain Shams University, Cairo, Egypt
3 Department of Clinical Pathology and Immunology, Ain Shams University, Cairo, Egypt
4 Post Graduate, Ain Shams University, Cairo, Egypt
|Date of Submission||23-Apr-2015|
|Date of Acceptance||02-Aug-2015|
|Date of Web Publication||23-Nov-2015|
Alyaa A El-Sherbeny
Department of Internal Medicine, Ain Shams University, 1234, Cairo
Source of Support: None, Conflict of Interest: None
There is growing evidence that some cases of chronic idiopathic urticaria are associated with various autoimmune diseases such as thyroid autoimmunity. The association between chronic urticaria (CU) and thyroid disorders has been a subject of controversy. Some reports link CU with hyperthyroidism or hypothyroidism. The frequency of thyroid antibodies in patients with chronic idiopathic urticaria reported in 2009 was 30%, which is higher than that previously reported.
This is a case-control study that aimed to detect the presence of markers of thyroid autoimmunity (thyroid autoantibodies with or without underlying abnormal thyroid functions) among a cohort of autologous serum skin test (ASST)-positive patients with CU in comparison with ASST-negative CU patients as well as with healthy controls, and correlating it to the severity of urticaria symptoms.
Patients and methods
This study was carried out on 80 CU patients attending the Allergy and Immunology Clinic of Ain Shams University Hospitals. CU was diagnosed on the basis of the appearance of continuous recurrent hives for more than 6 weeks. The patients were subdivided into the following groups: group A - 40 CU patients with positive ASST; group B - 40 CU patients with negative ASST. In addition, 40 healthy individuals were included in this study as healthy controls. History and general examination were conducted to all study grouos. Assessment of the Urticaria Activity Score-7 and laboratory investigations including those for complete blood count, erythrocyte sedimentation rate, thyroid function, thyroid Abs, namelyantimicrosomal antibody and antithyroglobulin antibody and total immunoglobulin E (IgE), were done.
Comparison between the three groups showed that antithyroglobulin antibody was highly statistically significant in group A than in both group B and healthy controls. Moreover, antimicrosomal antibody was also found to be of higher statistical significance in group A than in both group B and healthy controls. Although total IgE had no statistical significance between groups A and B, total IgE was found to be statistically significantly higher in group B than in healthy controls. Level of thyroid stimulating hormone was higher in group A than in controls, and free T3 was lower in group A than in group B.
We suggest that thyroid diseases have a role in CU, which was confirmed by a higher level of thyroid antibodies in the ASST-positive group than in ASST-negative patients and healthy controls.
Keywords: Antimicrosomal antibody, antithyroglobulin antibody, chronic urticaria
|How to cite this article:|
Okba AM, Sheha DS, Moustafa AS, El-Sherbeny AA, Mohamed NA, Aglan MF. Association between thyroid autoimmunity and chronic urticaria in patients versus healthy controls. Egypt J Obes Diabetes Endocrinol 2015;1:84-9
|How to cite this URL:|
Okba AM, Sheha DS, Moustafa AS, El-Sherbeny AA, Mohamed NA, Aglan MF. Association between thyroid autoimmunity and chronic urticaria in patients versus healthy controls. Egypt J Obes Diabetes Endocrinol [serial online] 2015 [cited 2018 May 24];1:84-9. Available from: http://www.ejode.eg.net/text.asp?2015/1/2/84/170206
| Introduction|| |
There is growing evidence that some cases of chronic idiopathic urticaria (CIU) are associated with various autoimmune diseases such as thyroid autoimmunity. The association between chronic urticaria (CU) and thyroid disorders has been a subject of controversy. Some reports link CU with hyperthyroidism or hypothyroidism . The frequency of thyroid antibodies in patients with CIU reported in 2009 was 30%, which is higher than that previously reported . More recently, some studies have suggested that there may be a link between CU and thyroid autoimmunity . It is also documented that some patients may respond to the administration of thyroid hormones .
CU is a common skin disorder affecting 0.11% of the general population. It is characterized by recurrent and transitory (<24 h) pruritic erythematous wheals that present at least twice weekly for at least 6 weeks .
CIU is the most common type of CU, making up to 90% of all cases of CU . It has been estimated that CIU affects between 0.6%  and 5%  of the population during their lifetime. Over 50% of cases of CIU are thought to be caused by an autoimmune mechanism . This is supported by the observation that 60% of patients with CIU elicit a wheal and flare reaction to intradermal autologous serum injections in the autologous serum skin test (ASST) . Approximately 50% of patients with CIU have immunoglobulin G antibodies that are specific for the high-affinity immunoglobulin E (IgE) receptor (FceRI) ,. These autoantibodies activate mast cells in the skin, circulating basophils, and the complement system . Furthermore, sera from some patients with CU and Hashimoto's thyroiditis exhibited degranulation of normal basophils in the absence of anti-FceRI antibodies. The factor causing basophil degranulation was not determined. These results showed that Hashimoto's thyroiditis likely represents a marker of autoimmunity, rather than being a direct cause for CU .
As early as 1983, Leznoff et al.  suggested an association between thyroid autoimmunity and CIU. The term autoimmune thyroid disease includes all autoimmune thyroid conditions, including Hashimoto's thyroiditis, Graves' disease, most cases of silent thyroiditis, and postpartum thyroiditis.
The frequency of thyroid antibodies in patients with CIU reported in 2009 was 30%, which is higher than that previously reported . Although the association of CU and thyroid autoimmunity is not well understood , patients with a positive ASST are more likely to be associated with HLADR4, to have autoimmune thyroid disease and a more prolonged disease course, and may be less responsive to H1-antihistamine treatment than those with a negative ASST .
| Patients and methods|| |
Our study is a case-control investigation that included 40 ASST-positive CU patients who constituted group A and 40 ASST-negative CU patients who constituted group B, recruited from the Allergy and Immunology Clinic of Ain Shams University Hospitals from January until December 2013 after obtaining their informed consent. CU was diagnosed according to EAACI/GA2LEN/EDF/WAO guidelines . The study also included 40 apparently healthy individuals as a control group. None of the controls had a history of urticaria or other allergic diseases. Exclusion criteria included secondary urticaria as in associated renal or liver disease, drug-induced urticaria, presence of associated allergic disorders such as asthma, atopic dermatitis, allergic rhinitis, positive skin prick test, reaction to common environmental allergens including mites, animal epithelia, pollens and moulds, pregnant and lactating women, patients on steroids or other immunosuppressive therapy within 6 weeks before enrolment and patients on long-acting antihistamines within 7 days before enrolment.
The primary outcome measure was detecting the number and percentage of patients with positive antithyroid antibodies - namely, antimicrosomal antibody (AMA) and antithyroglobulin antibody (TgAb) - with or without thyroid dysfunction in the three groups. Secondary outcome measure was linking positivity of ASST and antithyroid antibodies to the total IgE level and urticarial severity.
A volume of 8 ml venous blood was withdrawn from each patient; 5 ml was placed in an EDTA tube for performing a complete blood count and for determining the erythrocyte sedimentation rate and 3 ml of blood was collected in plain vacutainers for analysis of antinuclear antibodies (ANA), antithyroid antibodies, total IgE, free T3, T4, thyroid stimulating hormone (TSH), HBsAg, HCVAb and biochemical markers including aspartate aminotransferase, alanine aminotransferase, creatinine and blood urea nitrogen. Serum samples were stored at -20°C until the time of assay. They were measured in the clinical laboratory of Ain Shams University Hospitals.
(1) Complete blood picture using a CBC was done using Coulter counter (T660) (Beckman, Coulter, California, USA).
(2) Erythrocyte sedimentation rate (mm/h) was assessed using the Westergren method.
(3) ANA was performed by indirect immunofluorescence assay on HEp-2 cell substrate (IMMCO Diagnostics, Inc; Buffalo, New York, USA).
(4) Antithyroid antibodies (TgAb and AMA) were tested with an indirect immunofluorescence assay (Inova Diagnostics, USA).
(5) Total serum IgE levels were measured using IgE Accubind ELISA (Monobind Inc., Lake Forest, California, USA) according to the manufacturer's instructions. This procedure has a sensitivity of 1 IU/ml. The normal level of total IgE in adults is less than 100 IU/ml.
(6) Free T3, T4 and TSH were measured using the Cobas e-411 (Roche, California, USA) analyser by the electrochemiluminescence immunoassay method.
(7) Aspartate aminotransferase, alanine aminotransferase, creatinine and blood urea nitrogen were measured on a Synchron CX-9 Autoanalyser (Beckman Instruments Inc., Fullerton, California, USA).
(8) Stool analysis was carried out to exclude parasitic infestation.
Assessment of urticarial activity
Urticaria Activity Score-7 (UAS-7) is a simple scoring system that records the intensity of pruritus and the number of hives. Daily intensity of pruritus [range: 0 (none) to 3 (severe)] and number of hives ratings [range: 0 (none) to 3 (>12 hives)] are summed to create a daily UAS (range: 0-6 points/day); daily UAS are summed over a week to create the UAS-7 (range: 0-42) .
Autologous serum skin test
The ASST was performed by drawing 2 ml of venous blood in a nonheparinized test tube and leaving it to clot at room temperature; the serum was then separated by placing the blood in a centrifuge for 10 min at a velocity of 2000 rpm. A volume of 0.05 ml of the patient's serum was then injected intradermally into the volar aspect of the patient's forearm at the site not affected by a wheal in the last 24 h; at the same time the same volume of histamine and normal saline was injected separately intradermally over the volar aspect of the forearm at least 5 cm away from the serum injection site; we then waited for 30 min (15 min for the histamine) to see the response. The test was considered positive if there was a wheal and flare at the serum injection site of a diameter (measured by taking the mean of the largest two diameters) at least 1.5 mm more than the wheal and flare induced at the control site (if any) .
Values were reported as mean ± SD. Mean values were compared using Student's t-test and differences in positive results between groups were tested using the c2 test. The association of both AMA and TgAb with TSH and free T4 was assessed using Pearson's correlation test. A P value less than 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS (version 20; IBM, Chicago, USA).
| Results|| |
This case-control study included 40 ASST-positive CU patients who constituted group A and 40 ASST-negative CU patients who constituted group B, as well as 40 apparently healthy controls. Characteristics of the study groups are shown in [Table 1]. Group A included 33 (82.5%) women and seven (17.5%) men, whereas group B included 29 (72.5%) women and 11 (29.5%) men. The healthy control group included 23 (57.5%) women and 17 (42.5%) men. The study groups showed female predilection consistent with that reported in CU patients ,.
|Table 1: Demographic distribution of age, sex, duration and Urticaria Activity Score-7 in the study groups|
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Details of labarotory results of the studied group are shown in [Table 2]. As regards antithyroid antibodies, AMA and TgAb were significantly higher in group A than in the other two groups. Fifteen out of 40 (37.5%) patients in group A were AMA-positive, in contrast to only five out of 40 (12.5%) patients in group B and four out of 40 (10%) healthy controls. Regarding TgAb, 13 out of 40 (32.5%) patients in group A were TgAb-positive, but only one patient out of 40 (2.5%) in group B and one (2.5%) person out of 40 healthy controls had positive TgAb with high statistical significance [Table 2] and [Table 3]. While regard to the positivity of both AMA and TgAb in group A, 12 out of 40 (30%) patients tested positive to both AMA and TgAb with high statistical significance, whereas in group B only one out of 40 (2.5%) patients had both AMA and TgAb positivity.
|Table 3: Comparison between group A, group B and controls regarding laboratory findings|
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Regarding thyroid dysfunction, TSH was higher in group A than in group B and in healthy controls, whereas both free T3 and free T4 showed no statistically significant difference among the three studied groups. Among all CU patients in our study we found that of the 40 patients in group A (ASST-positive) 12 (30%) were hypothyroid, eight (20%) were hyperthyroid and 20 (50%) were euthyroid; in contrast, of the 40 patients in group B, three (7.5%) were hypothyroid, three (7.5%) were hyperthyroid and 34 (85%) were euthyroid. All patients in the control group were euthyroid. This suggests that thyroid dysfunction was detected among ASST-positive patients only.
As regards the characteristics of AMA-positive versus AMA-negative patients in group A, we did not detect statistically significant difference as regards urticarial severity or duration (P>0.05). Moreover, TgAb-positive patients had neither more severe urticaria nor longer duration of disease compared with TgAb-negative patients in group A. In addition, total IgE level showed no difference between positive and negative patients in group A.
| Discussion|| |
Autoimmune thyroid diseases are the most common organ-specific autoimmune disorders usually resulting in dysfunction (hyperfunction, hypofunction, or both) of the thyroid gland . The role of thyroid autoantibodies in physiological derangements of CU is highly debatable. . Although the pathophysiology of the association is not well understood, it seems that antithyroid antibodies may not be directly responsible for the lesions seen in CU patients but they are probably an indicator of autoimmunity . This autoimmune subgroup of CU patients frequently referred to as chronic autoimmune urticaria (CAU) patients were found to have autoantibodies directed at the FceR1a receptor located on mast cells and basophils or less commonly against IgE . ASST is generally considered a reasonably accurate and cheap predictive in-vivo clinical test to indicate the presence of functional circulating autoantibodies in this subset of patients .
Our study showed particular female predilection in CAU patients consistent with previous studies ,,. In one of the early studies by Leznoff et al. , 12% of patients with urticaria had elevated titres of thyroid antibodies, out of which 88.2% were female. Later on, a larger scale study also by Leznoff and Sussman  reported the results of a survey of 624 CIU and angio-oedema patients, among whom 90 (12.1%) had high titres of thyroid microsomal antibodies and 44 presented other clinical and laboratory findings suggestive of autoimmune thyroiditis. Our results detected a higher prevalence of thyroid antibodies among CU patients with ASST-positive in contrast to ASST-negative CU patients and healthy controls. This is consistent with many studies, and was first reported by Leznoff et al. , who reported thyroid microsomal antibody in 12% of their study population. Palma-Carlos et al.  performed a case-control study to evaluate thyroid antibodies in CIU patients, and detected TgAb positivity in 22.2% and AMA positivity in 26.8%. However, 93% of the CIU patients had normal thyroid functions. The authors concluded that thyroid antibody and function must be evaluated in all cases of CU. Moreover, Aamir et al.  reported elevated titres of TgAb and AMA in patients with CU. They were found to be positive in 42.6 and 57.4% of 47 patients, respectively, with CU. They found that the prevalence of thyroid antibodies was significantly higher in their patients with CU than in controls (22 vs. 6.5%), which agrees with our findings. In contrast, Sabroe and Greaves  found that thyroid autoimmunity prevalence in CIU patients is not greater than that in the general population.
As regards the type of thyroid antibody that was more prevalent, our study showed a higher prevalence of AMA than TgAb in group A. This is consistent with the results of Aamir et al.  who demonstrated that AMA had higher prevalence than TgAb in his study group.
Concerning the thyroid profile in our study groups, we found that among ASST-positive patients, 30% were hypothyroid, 20% were hyperthyroid and 50% were euthyroid, which is higher than that previously reported. Turktas et al.  and Kandeel et al.  also reported that the incidence of thyroid dysfunction had a statistical significance in chronic autoimmune urticaria patients. Sugiyama et al.  also noted that Hashimoto disease (HD) was an exacerbating factor in CU patients, and speculated that thyroid therapy in CU patients with HD may lead to remission of urticaria symptoms, and suggested that HD might possibly be involved in the aetiology of CU, or is at least a potential exacerbating factor for CU. However, thyroid autoimmunity may appear several years after the onset of CU, emphasizing the importance of follow-up and periodic blood tests for thyroxine/TSH and antithyroid antibodies in CU patients .
Our secondary outcome was to assess urticarial severity according to the UAS-7 activity score in the studied population. We found no statistically significant difference in the disease activity score between groups A and B, indicating that there is no correlation between the positivity of ASST and the severity of urticaria. We also reported no correlation between thyroid antibody positivity and severity of urticaria. This is consistent with the results of Nettis et al. , Kulthanan et al.  and Al-Hamamy et al. ; all of them agreed that there was no link between urticarial severity and positivity of autoantibodies .
In contrast, Caproni et al.  found that patients with a positive ASST had more severe clinical features than those with a negative test. Abdel Azim et al.  also demonstrated that the severity of urticaria was greater if the ASST result was positive. As regards total IgE, we found statistically significantly higher level of total IgE in group B when compared with healthy controls, whereas there was no statistically significant difference in total IgE between groups A and B, from which we assume that ASST-positive results were not accompanied by a higher total IgE level. While Kessel et al.  and Abdel Azim et al.  showed significantly higher serum IgE level in ASST-positive patients , this is in contrast to the results of Huilan et al.  and Abd El-Azim and Abd El-Azim  who stated that a positive ASST result was more likely to be associated with significantly lower IgE levels than a negative ASST result, attributing it to IgE-anti-IgE immune complex formation reducing the amount of detectable free IgE in patients with anti-IgE autoantibodies.
| Conclusion|| |
In our study we found the levels of thyroid antibodies (TgAb and AMA) to be higher in ASST-positive CU patients than in ASST-negative CU patients, and 50% of patients with ASST also had thyroid dysfunction (30% were hypothyroid and 20% were hyperthyroid), which suggests a role of thyroid diseases in CAU patients. However, we could not correlate antibody positivity to severity of urticarial symptoms (UAS-7) or to the level of total IgE.
We recommend routine screening of all ASST-positive CU patients for thyroid autoimmunity and possible thyroid dysfunction. Further larger scale, prospective clinical trials should be performed for long-term follow-up of all CAU patients to detect whether or not they might later develop autoimmune thyroid diseases, and whether treatment of thyroid disorders would improve symptom scores in CAU patients.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]