Chronic urticaria and thyroid autoimmunity: a perplexing association

Chronic urticaria and thyroid autoimmunity: a perplexing association Chronic urticaria has long been thought to be associated with autoimmune conditions, in particular autoimmune thyroid disease (AITD). We detail an unusual case of a 49-year-old patient presenting with urticaria distributed on both shins and hands, with no known associated triggers, and subsequently diagnosed with AITD. The urticaria resolved upon treatment of the AITD. We also summarize the currently postulated pathophysiological links between the two diseases. This case highlights that physicians should have a low threshold for investigating autoimmune conditions in cases of chronic urticaria, with particular attention given to AITD. INTRODUCTION lesions appeared suddenly and lasted from between 8 and 12 h, The term urticaria is commonly used to describe a skin condition with no association to the time of day. The size varied from characterized by recurrent attacks of itchy hives that may vary in between 3 and 15 mm in diameter. The patient was unaware of size, number and distribution [1]. Urticaria is defined as chronic any triggering factors such as specific foods, cold or hot tem- when patients experience daily manifestations for more than 6 peratures, water or emotional stress. However, the patient weeks [2]. In total, 40–50% of these patients have accompanied reported increased lethargy. Examination revealed urticarial angioedema [2]. There are several known causes of chronic urti- wheals but was otherwise completely unremarkable with vital caria (CU); some of the most important include contact, allergy signs within normal limits (Fig. 1). and stress [2]. Autoimmunity due to IgE and IgG autoantibodies Due to the patient’s associated symptom of lethargy and in are also thought to play a significant role in the aetiology of CU in accordance with the British Society for Allergy and Clinical a sub-population of patients [1]. In particular, the association of Immunology guidelines [3], a complete blood count, erythrocyte thyroid autoimmunity with CU has been described since 1907 sedimentation rate (ESR), liver function tests (LFTs) and thyroid though the extent of association and mechanistic links are not function tests were measured to rule out the possibility of any fully understood [1]. We report a patient presenting with persist- systemic disease. Investigations revealed normal haemoglobin, ent hives with no associated triggers, and eventually diagnosed white cell count, absence of eosonophillia, normal ESR and nor- with autoimmune thyroid disease (AITD). Additionally, we mal LFTs. However, the T4 and T3 was lower than the normal explore and summarize the postulated pathophysiological links range (8.6 and 3.2 pmol/L, respectively [normal T4 values: between CU and thyroid autoimmunity. 10–20pmol/L and normal T3 values: 3.5–7.8 pmol/L]) and the thyroid stimulating hormone (TSH) was raised (5.4 mU/L [nor- CASE REPORT mal range: 0.4–4 mU/L]). A diagnosis of hypothyroidism was A 49-year-old woman presented with a 6-week history of prur- made. Given the association described in the literature and to itic raised wheals on her shins and dorsum of both hands. The help elucidate the possible trigger of the urticaria, a further Joint first authors. Received: October 19, 2017. Revised: November 17, 2017. Accepted: November 24, 2017 © The Author(s) 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx099/4898990 by Ed 'DeepDyve' Gillespie user on 16 March 2018 62 S.S. Selvendran and N. Aggarwal patient was reviewed 4 weeks later. By this time the urticaria had resolved and the patient was managed on long-term thy- roxine replacement. There have been no relapses of urticaria after 14 months of successful management of AITD, further demonstrating this association (Fig. 2). DISCUSSION Approximately 5–34% of patients with CU have anti-thyroid antibodies and another 5–10% have clinically or biochemically apparent thyroid disease [4]. The connection between AITD and CU is an unresolved mystery but there are a number of plaus- ible explanations. CU is initiated by inappropriate activation and degranula- tion of mast cells, a key pathophysiological event [5]. A possible mechanistic link between CU and thyroid autoimmunity is thought to involve elevated IgG anti-thyroid autoantibodies (IgG-anti-TPO, IgG-anti-TG) [4]. It has been postulated that IgG anti-thyroid autoantibodies are not directly involved in the degranulation of mast cells but may intensify mast cell suscep- tibility to other activating signals [4]. Rumbyrt et al. [6] theorized that an inflammatory response in the thyroid gland leads to a generalized inflammatory state and decreases the activation threshold of mast cells to other stimuli. Products of the thyroid autoimmune response such as thyroid protein immune com- plexes stimulate the classical complement pathway, leading to Figure 1: Urticaria after 1 week of treatment. the C3a and C5a generation. This activates mast cells and baso- phils in CU patients [4]. Recently, studies have demonstrated high levels of IgE anti-thyroid autoantibodies (IgE anti-TPO and IgE anti-dsDNA) in some CU patients [2]. It is thought that IgE anti-TPO auto- antibodies, when bound to the surface of mast cells and baso- phils, directly increase their sensitivity to specific circulating antigens found in autoimmune thyroid damage such as thy- roid peroxidase [2]. This is further reinforced by the efficacy of omalizumab, an anti IgE therapy, in CU patients who are IgE anti-TPO-positive [7]. Infectious agents are thought to be involved in the patho- genesis of both CU and thyroid autoimmunity [4]. For example, Staphylococcus aureus protein A has shown to cause the release of pro-inflammatory cytokines that induce attacks of CU [4]. Moreover, Wan et al. [8] illustrated that staphylococcal entero- toxin A superantigen stimulation of thyroglobulin primed cells caused the adoptive transfer of experimental autoimmune thyroiditis in mice. In addition to this, Hepatitis C virus has been proposed to play a role in the aetiology and pathogenesis of urticaria and AITD [4]. Marone et al. [9] demonstrated that protein Fv, produced by viral hepatitis, stimulates urticaria reactions by binding to a component of IgE. Additionally, Hepatitis C envelope glycoproteins, E1 and E2, are thought to activate intracellular signalling pathways triggering the release of pro-inflammatory mediators such as interleukin-8. This could possibly induce thyroid autoimmunity through bystander activation [10]. Finally, recent studies have highlighted the overlap of immunological mechanisms that play a role in the pathogen- Figure 2: Absence of urticaria after 4 weeks of treatment. esis of both CU and thyroid autoimmunity [11]. Interleukin-6 (IL-6) has been linked with the development or exacerbation of CU [11]. It has also been discovered in high levels in trials investigation was conducted which revealed raised anti- studying AITD. Interestingly, a correlation between IL-6 and thyroid peroxidase antibodies (48 IU/mL [normal values: <38 IU/ severity of CU as well as anti-TPO levels has been demon- mL]) confirming AITD. Treatment was commenced with 25 µg strated [11]. Additionally, lower serum levels and functional- once daily thyroxine replacement and Cetirizine 10 mg once ity of T-CD4+CD25+Foxp3+ cells are associated with the daily for 4 weeks was started to manage the urticaria. The Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx099/4898990 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Chronic urticaria and thyroid autoimmunity 63 pathogenesis of these two diseases [11]. Further studies are REFERENCES needed to confirm these hypothetical observations. 1. Zauli D, Grassi A, Ballardini G, Contestabile S, Zucchini S, In conclusion, there is a wide array of potential processes by Bianchi FB. Thyroid autoimmunity in chronic idiopathic which the two conditions are interlinked. Therefore, physicians urticaria. Am J Clin Dermatol 2002;3:525–8. and other healthcare workers should have a low threshold for 2. Bagnasco M, Minciullo PL, Schiavo M, Saraceno G, Gangemi investigating autoimmune conditions, in particular AITD, with S, Benvenga S. Urticaria and thyroid autoimmunity. Thyroid a patient presenting with CU. 2011;21:401–10. 3. Powell R, Leech S, Till S, Huber P, Nasser S, Clark A. BSACI guideline for the management of chronic urticaria and ACKNOWLEDGEMENTS angioedema. Clin Exp Allergy 2015;45:547–65. None. 4. Kolkhir P, Metz M, Altrichter S, Maurer M. Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: a systematic review. Allergy 2017;72:1440–60. CONFLICT OF INTEREST STATEMENT 5. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol 2004;114:465–74. All authors disclose no conflicts of interest with work involved 6. Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urti- in this article. caria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995;96:901–5. 7. Maurer M, Altrichter S, Bieber T, Biedermann T, Bräutigam FUNDING M, Seyfried S, et al.Efficacy and safety of omalizumab in No funding was received for the work involved in this article. patients with chronic urticaria who exhibit IgE against thyr- operoxidase. J Allergy Clin Immunol 2011;128:202–9.e5. 8. Wan Q, Kita M, Flynn JC, Panos JC, Motte RW, Davies TF, ETHICAL APPROVAL et al. Participation of Vβ13 and Vβ1 T cells in transfer thyroi- ditis after activation of mouse thyroglobulin-primed T cells Not applicable as this article does not involve direct human by superantigen staphylococcal enterotoxin A. Cell Immunol subject involvement. No approval was required. 2001;213:149–57. 9. Marone G, SpadaroG,Liccardo B,Rossi F, D’Orio C, Detoraki A. Superallergens: a new mechanism of immunologic activation CONSENT of human basophils and mast cells. Inflamm Res 2006;55:S25–7. Patient consent was obtained for the publication of this case 10. Akeno N, Blackard JT, Tomer Y. HCV E2 protein binds directly report. to thyroid cells and induces IL-8 production: a new mechan- ism for HCV induced thyroid autoimmunity. J Autoimmun 2008;31:339–44. GUARANTOR 11. Berghi NO. Immunological mechanisms implicated in the All authors nominated S. Selvendran as the guarantor for the pathogenesis of chronic urticaria and hashimoto thyroidi- article. tis. Iran J Allergy Asthma Immunol 2017;16:358–66. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx099/4898990 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

Chronic urticaria and thyroid autoimmunity: a perplexing association

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Abstract

Chronic urticaria has long been thought to be associated with autoimmune conditions, in particular autoimmune thyroid disease (AITD). We detail an unusual case of a 49-year-old patient presenting with urticaria distributed on both shins and hands, with no known associated triggers, and subsequently diagnosed with AITD. The urticaria resolved upon treatment of the AITD. We also summarize the currently postulated pathophysiological links between the two diseases. This case highlights that physicians should have a low threshold for investigating autoimmune conditions in cases of chronic urticaria, with particular attention given to AITD. INTRODUCTION lesions appeared suddenly and lasted from between 8 and 12 h, The term urticaria is commonly used to describe a skin condition with no association to the time of day. The size varied from characterized by recurrent attacks of itchy hives that may vary in between 3 and 15 mm in diameter. The patient was unaware of size, number and distribution [1]. Urticaria is defined as chronic any triggering factors such as specific foods, cold or hot tem- when patients experience daily manifestations for more than 6 peratures, water or emotional stress. However, the patient weeks [2]. In total, 40–50% of these patients have accompanied reported increased lethargy. Examination revealed urticarial angioedema [2]. There are several known causes of chronic urti- wheals but was otherwise completely unremarkable with vital caria (CU); some of the most important include contact, allergy signs within normal limits (Fig. 1). and stress [2]. Autoimmunity due to IgE and IgG autoantibodies Due to the patient’s associated symptom of lethargy and in are also thought to play a significant role in the aetiology of CU in accordance with the British Society for Allergy and Clinical a sub-population of patients [1]. In particular, the association of Immunology guidelines [3], a complete blood count, erythrocyte thyroid autoimmunity with CU has been described since 1907 sedimentation rate (ESR), liver function tests (LFTs) and thyroid though the extent of association and mechanistic links are not function tests were measured to rule out the possibility of any fully understood [1]. We report a patient presenting with persist- systemic disease. Investigations revealed normal haemoglobin, ent hives with no associated triggers, and eventually diagnosed white cell count, absence of eosonophillia, normal ESR and nor- with autoimmune thyroid disease (AITD). Additionally, we mal LFTs. However, the T4 and T3 was lower than the normal explore and summarize the postulated pathophysiological links range (8.6 and 3.2 pmol/L, respectively [normal T4 values: between CU and thyroid autoimmunity. 10–20pmol/L and normal T3 values: 3.5–7.8 pmol/L]) and the thyroid stimulating hormone (TSH) was raised (5.4 mU/L [nor- CASE REPORT mal range: 0.4–4 mU/L]). A diagnosis of hypothyroidism was A 49-year-old woman presented with a 6-week history of prur- made. Given the association described in the literature and to itic raised wheals on her shins and dorsum of both hands. The help elucidate the possible trigger of the urticaria, a further Joint first authors. Received: October 19, 2017. Revised: November 17, 2017. Accepted: November 24, 2017 © The Author(s) 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx099/4898990 by Ed 'DeepDyve' Gillespie user on 16 March 2018 62 S.S. Selvendran and N. Aggarwal patient was reviewed 4 weeks later. By this time the urticaria had resolved and the patient was managed on long-term thy- roxine replacement. There have been no relapses of urticaria after 14 months of successful management of AITD, further demonstrating this association (Fig. 2). DISCUSSION Approximately 5–34% of patients with CU have anti-thyroid antibodies and another 5–10% have clinically or biochemically apparent thyroid disease [4]. The connection between AITD and CU is an unresolved mystery but there are a number of plaus- ible explanations. CU is initiated by inappropriate activation and degranula- tion of mast cells, a key pathophysiological event [5]. A possible mechanistic link between CU and thyroid autoimmunity is thought to involve elevated IgG anti-thyroid autoantibodies (IgG-anti-TPO, IgG-anti-TG) [4]. It has been postulated that IgG anti-thyroid autoantibodies are not directly involved in the degranulation of mast cells but may intensify mast cell suscep- tibility to other activating signals [4]. Rumbyrt et al. [6] theorized that an inflammatory response in the thyroid gland leads to a generalized inflammatory state and decreases the activation threshold of mast cells to other stimuli. Products of the thyroid autoimmune response such as thyroid protein immune com- plexes stimulate the classical complement pathway, leading to Figure 1: Urticaria after 1 week of treatment. the C3a and C5a generation. This activates mast cells and baso- phils in CU patients [4]. Recently, studies have demonstrated high levels of IgE anti-thyroid autoantibodies (IgE anti-TPO and IgE anti-dsDNA) in some CU patients [2]. It is thought that IgE anti-TPO auto- antibodies, when bound to the surface of mast cells and baso- phils, directly increase their sensitivity to specific circulating antigens found in autoimmune thyroid damage such as thy- roid peroxidase [2]. This is further reinforced by the efficacy of omalizumab, an anti IgE therapy, in CU patients who are IgE anti-TPO-positive [7]. Infectious agents are thought to be involved in the patho- genesis of both CU and thyroid autoimmunity [4]. For example, Staphylococcus aureus protein A has shown to cause the release of pro-inflammatory cytokines that induce attacks of CU [4]. Moreover, Wan et al. [8] illustrated that staphylococcal entero- toxin A superantigen stimulation of thyroglobulin primed cells caused the adoptive transfer of experimental autoimmune thyroiditis in mice. In addition to this, Hepatitis C virus has been proposed to play a role in the aetiology and pathogenesis of urticaria and AITD [4]. Marone et al. [9] demonstrated that protein Fv, produced by viral hepatitis, stimulates urticaria reactions by binding to a component of IgE. Additionally, Hepatitis C envelope glycoproteins, E1 and E2, are thought to activate intracellular signalling pathways triggering the release of pro-inflammatory mediators such as interleukin-8. This could possibly induce thyroid autoimmunity through bystander activation [10]. Finally, recent studies have highlighted the overlap of immunological mechanisms that play a role in the pathogen- Figure 2: Absence of urticaria after 4 weeks of treatment. esis of both CU and thyroid autoimmunity [11]. Interleukin-6 (IL-6) has been linked with the development or exacerbation of CU [11]. It has also been discovered in high levels in trials investigation was conducted which revealed raised anti- studying AITD. Interestingly, a correlation between IL-6 and thyroid peroxidase antibodies (48 IU/mL [normal values: <38 IU/ severity of CU as well as anti-TPO levels has been demon- mL]) confirming AITD. Treatment was commenced with 25 µg strated [11]. Additionally, lower serum levels and functional- once daily thyroxine replacement and Cetirizine 10 mg once ity of T-CD4+CD25+Foxp3+ cells are associated with the daily for 4 weeks was started to manage the urticaria. The Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx099/4898990 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Chronic urticaria and thyroid autoimmunity 63 pathogenesis of these two diseases [11]. Further studies are REFERENCES needed to confirm these hypothetical observations. 1. Zauli D, Grassi A, Ballardini G, Contestabile S, Zucchini S, In conclusion, there is a wide array of potential processes by Bianchi FB. Thyroid autoimmunity in chronic idiopathic which the two conditions are interlinked. Therefore, physicians urticaria. Am J Clin Dermatol 2002;3:525–8. and other healthcare workers should have a low threshold for 2. Bagnasco M, Minciullo PL, Schiavo M, Saraceno G, Gangemi investigating autoimmune conditions, in particular AITD, with S, Benvenga S. Urticaria and thyroid autoimmunity. Thyroid a patient presenting with CU. 2011;21:401–10. 3. Powell R, Leech S, Till S, Huber P, Nasser S, Clark A. BSACI guideline for the management of chronic urticaria and ACKNOWLEDGEMENTS angioedema. Clin Exp Allergy 2015;45:547–65. None. 4. Kolkhir P, Metz M, Altrichter S, Maurer M. Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: a systematic review. Allergy 2017;72:1440–60. CONFLICT OF INTEREST STATEMENT 5. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol 2004;114:465–74. All authors disclose no conflicts of interest with work involved 6. Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urti- in this article. caria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995;96:901–5. 7. Maurer M, Altrichter S, Bieber T, Biedermann T, Bräutigam FUNDING M, Seyfried S, et al.Efficacy and safety of omalizumab in No funding was received for the work involved in this article. patients with chronic urticaria who exhibit IgE against thyr- operoxidase. J Allergy Clin Immunol 2011;128:202–9.e5. 8. Wan Q, Kita M, Flynn JC, Panos JC, Motte RW, Davies TF, ETHICAL APPROVAL et al. Participation of Vβ13 and Vβ1 T cells in transfer thyroi- ditis after activation of mouse thyroglobulin-primed T cells Not applicable as this article does not involve direct human by superantigen staphylococcal enterotoxin A. Cell Immunol subject involvement. No approval was required. 2001;213:149–57. 9. Marone G, SpadaroG,Liccardo B,Rossi F, D’Orio C, Detoraki A. Superallergens: a new mechanism of immunologic activation CONSENT of human basophils and mast cells. Inflamm Res 2006;55:S25–7. Patient consent was obtained for the publication of this case 10. Akeno N, Blackard JT, Tomer Y. HCV E2 protein binds directly report. to thyroid cells and induces IL-8 production: a new mechan- ism for HCV induced thyroid autoimmunity. J Autoimmun 2008;31:339–44. GUARANTOR 11. Berghi NO. Immunological mechanisms implicated in the All authors nominated S. Selvendran as the guarantor for the pathogenesis of chronic urticaria and hashimoto thyroidi- article. tis. Iran J Allergy Asthma Immunol 2017;16:358–66. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx099/4898990 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Oxford Medical Case ReportsOxford University Press

Published: Feb 1, 2018

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