Graves’ disease (GD) is an autoimmune disorder that is characterized by the presence of anti-thyroid stimulating hormone (TSH) receptor antibodies causing thyrotoxicosis [1]. It is well recognized as the most common cause of hyperthyroidism in the world [2]. The signs and symptoms of GD vary widely but one of the least common and less understood of these symptoms is urticaria. The first association between thyroid disease and urticaria was made all the way back in 1907 by Ravitch at the 5th International Dermatological Congress. At the same congress, Ravitch also discussed the effects of treating thyroid disease on urticaria[1].
The earliest reports of urticarial manifestations in patients with hyperthyroidism actually predate those of autoimmune thyroiditis. In subsequent years, the link between thyroid disease and urticaria was analyzed by multiple studies [3]. The relationship between Graves’ and urticaria is complex to say the least and its nature is not yet well understood. However, a common autoimmune etiology has been suggested all the way back in 1972 in which Issacs described four patients suffering from thyrotoxicosis and chronic urticaria that was resolved by normalizing the thyroid function [1]. In this paper, we discuss a case of GD that presents as chronic urticaria and we review the literature about the relationship between these two pathological conditions.
A previously medically free 48-year-old female was referred from the dermatology clinic with a complaint of generalized pruritic urticaria refractory to conventional treatment of non-sedating antihistamines (allerfin 4 mg + XYZAL 5 mg) and topical corticosteroids (mometasone 0.1% QD). The pruritic urticaria started three days prior to presentation; however, she has been having similar episodes over the past few months but never as severe as her current presentation.General laboratory investigations were performed and the results were significant for undetectableTSH levels. Given these results, the patient was referred to Internal Medicine where further history and examinations were performed. The patient revealed to have been suffering from moderate cardiac palpitations, weight loss, heat intolerance, polyphagia, oligomenorrhea and diarrhea over the past four months. The patient had originally dismissed these symptoms as perimenopausal symptoms. On physical examination, the patient was found to have urticarial rash, staring look, fine tremors and a stage 3 goiter. However, all these thyrotoxic signs and symptoms were mild in this patient and she was notably negative for eye symptoms, lid lag and lid retraction.
The patient was started on propranolol 20 mg BID and complete thyroid function tests with thyroid antibodies were performed alongside an ultrasound of her thyroid and cervical lymph nodes. The ultrasound showed a mildly enlarged thyroid, measuring about 12 cc in size, with heterogeneous hypoechoic pattern and decreased vascularity that is suggestive of post-inflammatory thyroiditis. There were no suspicious focal thyroid lesions and cervical lymph nodes looked benign bilaterally (Figure 1).
Figure1:Duplex Doppler ultrasound of left and right lobes, showing a bilateral decrease in vascularity.
Lab results came back typical for primary hyperthyroidism with high free T3 and T4 but low TSH. Also, TSH receptor antibodies and anti-thyroglobulin antibodies came back positive which confirmed the diagnosis of GD. Notably, the patient IgE titer was also elevated.
After confirming the diagnosis, the patient was started on carbimazole 10 mg BID and was booked for follow-up in six weeks. During the first week of treatment, the patient developed a shortness of breath and a severe pruritic rash. She discontinued the medication by herself and her symptoms improved over the following week. Once the patient returned to baseline, she restarted carbimazole 10 mg QD, yet again she developed a shortness of breath and a severe pruritic rash. She discontinued the medication and presented to the clinic the following day. In the clinic, her hyperthyroidism was found to have gotten worse. The patient has also developed lid lag and lid retraction which were absent on the original presentation. Blood was sent for thyroid function tests (TFTs) which came back even higher than her original lab results. Hergamma-glutamyl transferase (GGT) was also elevated suggesting some hepatotoxicity from carbimazole. The patient was switched to propylthiouracil (PTU) 50 mg TID and was evaluated for possible radioactive iodine therapy.
After six weeks on PTU, the patient was reevaluated and she showed a marked improvement in her symptoms. Even her initial complaint of pruritic urticaria is now completely controlled on a low dose of antihistamines; however, she still had some lid lag and fine tremors. Laboratory studies also showed a marked improvementin TFT and GGT which normalised after discontinuing Carbimazole. The patient was followed up every six weeks and showed continuous improvements; by her sixth month of treatment, she was found to be clinically euthyroid with normal free T3 and T4 levels.
GDis an autoimmune disease that is triggered by a mixture of polygenetic and environmental factors. It is the most common cause of hyperthyroidism worldwide accounting for 60% to 80% of hyperthyroid cases and is more common in females than males with a reported lifetime risk in women and men of 3% and 0.5%, respectively [2,4]. The reported numbers are not that different in Saudi Arabia with a female:male ratio of 2.9:1 and a mean age of 32 +/-0.9 years [5].
The hallmark of GD is the presence of thyroid-stimulating auto-immunoglobulins that bind to and activate TSH receptors, causing hyperstimulation of the thyroid gland, and symptoms of hyperthyroidism. Given the systemic nature of GD, these symptoms may affect any system and usually they include heat intolerance, sweating, fatigue, weight loss, palpitation, hyper defecation, and tremors. On physical examination for GD, clinicians should examine for ophthalmopathy, including eyelid retraction, proptosis, and periorbital edema. Another sign of GD is thyroid dermopathy which causes thickening of the skin mainly over the tibia; however, it is a rare finding [4,6].
To diagnose GD, a thorough clinical evaluation is indicated to uncover any signs or symptoms of the disease. Once GD is suspected, laboratory tests should be carried out for definitive diagnosis. Initially, a thyroid function test must be performed to establish hyperthyroidism. If the TSHis suppressed, we need to establish the levels of free T4 and free T3 as well. To distinguish GD from other causes of hyperthyroidism we measure the level of TSH receptor antibody (TRAb). The measurement of TRAb with third-generation assay has a sensitivity of 97% and specificity of 99% for GD [4,7].
Treatment of GD relies on normalising thyroid hormone levels and controlling the symptoms of hyperthyroidism. Symptomatic control is usually accomplished by beta blockers while thyroid hormone levels are treated with antithyroid medications, radioactive iodine therapy or surgical thyroidectomy. All of these options for hyperthyroidism are established to be effective and treatment plans that only differ in their use according to patients' presentation. The main antithyroid medications used in hyperthyroidism are thionamides which include Propylthiouracil and Methimazole. They work by inhibiting thyroid peroxidase which mediates iodination of thyroglobulin. Side effect profile of these medications include: hepatotoxicity, neutropenia, and hypersensitivity reactions. A reported incidence of 3%-6 % of the patients had hypersensitivity reactions, which included pruritus, and rash [4].
Urticaria, specifically chronic idiopathic urticaria (CIU) as in our case, is a relatively common presentation with an estimated population prevalence that ranges from 0.5% to 5%. It is defined as the development of wheals, angioedema or both for more than a six-weekperiod [8]. The pathophysiology of CIU is not fully understood, but the main factor is triggering an immune response and thereby releasing histamine and cytokines. The findings of autoantibodies against the alpha subunit of the high-affinity IgE receptor and against IgE itself in about one-third of patients with CIUhave suggested an autoimmune etiology to the disease [9]
The diagnosis of CIU is somewhat difficult. Initially, the presence of wheals and angioedema alone would point towards CIU; however, If the patient presents with respiratory, gastrointestinal or constitutional signs or symptoms, other diagnoses such as allergic reactions should be ruled out first. Once CIU is diagnosed, its treatment relies on targeting the H1 receptors, using a nonsedating antihistamines. Also, exposure to any triggers that exacerbate the urticaria must be avoided [10]. Furthermore, medications other than antihistamines, namely Leukotriene antagonists, systemic steroidsand monoclonal antibodies, are now more commonly used but they still remain inferior to antihistamines as a first-line therapy.
There is an association between CIU and multiple autoimmune diseases, of which thyroid autoimmune disease is the most common [11]. Autoimmune thyroiditis and the presence of anti-thyroid antibodies have been reported in patients suffering CIU with a frequency of 6.5% to 57% [12]. In a 2017 systematic review by Kolkhir et al. [1], the assessment of 68 studies found an increase in IgG antithyroid peroxidase (IgG-anti-TPO) and IgG anti-thyroglobulin (IgG-anti-TG) in patients with CIU. The same review also looked at six independent studies and found levels of IgG anti-TSH receptor (IgG anti-TSHr) to be elevated in patients with CIU. Although most of these studies suggested that the findings of such antibodies were part of an independent, parallel disease process, a recent study proposed a different idea [13]. Altrichter et al. showed that a sizable subgroup of patients with CIU had increased IgE antibodies against thyroid peroxidase (TPO) [14]. These anti-TPO IgE antibodies, when bound to the surface of mast cells, could cause activation and degranulation of mast cells, thus playing an active role in the pathogenesis of CIU [13,14]. In the end, while suspected, a common pathogenesis between CIU and autoimmune thyroid disease is difficult to prove. Largely, this is due to the multitude of reports of associations between autoimmune diseases, making an overall susceptibility of a patient with an autoimmune disease, such as GD or CIU, to other autoimmune diseases much more likely [13].
In their assessment of 154 patients with CIU, Small and Lerman found six patients with autoimmune hyperthyroidism [1]. Another study by Collet et al. [13] found eight among 45 patients with CIU suffering from autoimmune thyroid disease; of those only one was suffering from GD. Gaig et al. [13] measured serum Ab-Tg and Ab-TPO in 170 patients with CIU, and found that 45 of them (14.7%) had at least one antithyroid antibody; of the 45, only 2 had GD. In a more recent study by Confino-Cohen et al. The prevalence of autoimmune thyroid disease was evaluated in 12, 778 patients with CIU, compared to a control group of10, 714 [15]. Antithyroid antibodies (TPO-Ab and TG-Ab) were found to be significantly higher in patients with CIU than in control groups, and 10% of patients with CIU had hypothyroidism compared with 0.6% of controls. The prevalence of hyperthyroidism, although less common than hypothyroidism, was also significantly higher in patients with CIU than in the control group (2.6% and 0.09% respectively). Overall, these studies concluded that the association between CIU with GD is present but to a lesser extent than that of CIU and autoimmune thyroiditis [1].
Another well-documented association is that of GD and allergic diseases. This has been supported by the elevation in serum levels of IgE in one-third of patients with GD, but not in patients with Hashimoto thyroiditis [16]. GD patients with elevated IgE also showed low rate of remission when treated with antithyroid drugs and high rate relapse [17]. Furthermore, there have been reports suggesting an improvement in CIU after therapeutic correction of hyperthyroidism [13]. Recently, Bansal and Hayman [18] described two patients with CIU that were poorly responsive to antihistamines and corticosteroids, who then developed symptoms of hyperthyroidism within 6 months of the onset of urticaria. In both patients, treatment of the hyperthyroidism with carbimazole and normalization of their thyroid function quickly improved their urticaria [1]. A possible mechanism might be because antithyroid drugs improve hyperthyroidism not only by decreasing the synthesis of thyroid hormones, but also by decreasing anti-thyroid antibodies probably due to immunosuppressive effects. In the same manner, this immunosuppressive effect may influence CIU of autoimmune origin [19].However, due to the scarcity of these reports, it is difficult to ascertain whether the improvement in urticarial symptoms is due to the antithyroid drugs or whether it is a natural improvement of the disease itself [1].
The association between GD and urticaria is well established and it is recommended to evaluate patients with urticaria for thyroid disease even when asymptomatic. However,there is a need for more research to better understand the nature of the relationship between GD and urticaria. Also, more research is needed to establish the time course for developing thyroid symptoms in urticarial patients. Finally, the relationship between Graves’ associated with urticaria and hypersensitivity reactions should be better studied for its important implications on clinical practice and patient education.
FAQs
Does Graves disease cause urticaria? ›
Graves' disease (GD) is an autoimmune disease that is characterized by the presence of antibodies targeting the thyroid gland. Commonly, the disease presents with symptoms of thyrotoxicosis such as sweating, tremors, and weight loss; less frequently, patients with GD might also have urticaria.
What is a hallmark of Graves disease? ›Graves disease is an autoimmune disorder that involves overactivity of the thyroid (hyperthyroidism). Hallmarks of the condition are bulging eyes (exophthalmos), heat intolerance, increased energy, difficulty sleeping, diarrhea and anxiety.
Can thyroid problems cause urticaria? ›These chemicals lead to inflammation of the skin. [6] One of the causes of chronic urticaria is hyperthyroidism. Hyperthyroidism triggers the activation of kinins and then chronic urticaria.
Is urticaria related to hyperthyroidism? ›Overall, urticaria is a complication of both autoimmune hyperthyroid disease and the medications used to treat hyperthyroidism. Differentiating between the two is both vital and challenging.
What autoimmune disease causes urticaria? ›Numerous autoimmune conditions including systemic lupus erythematosus, polymyositis, dermatomyositis, and rheumatoid arthritis have been associated with chronic urticaria (2).
How do you confirm Graves disease? ›Blood tests can help your doctor determine your levels of thyroid-stimulating hormone (TSH) — the pituitary hormone that normally stimulates the thyroid gland — and your levels of thyroid hormones. People with Graves' disease usually have lower than normal levels of TSH and higher levels of thyroid hormones.
Which symptom is a clinical indicator of Graves disease? ›Graves' disease is the only kind of hyperthyroidism that can be associated with inflammation of the eyes, swelling of the tissues around the eyes and bulging of the eyes (called Graves' ophthalmopathy or orbitopathy).
Which clinical manifestation is a classic finding in Graves disease? ›Ophthalmopathy is a hallmark of Graves disease. Approximately 25-30% of patients with Graves disease have clinical evidence of Graves ophthalmopathy. Progression from mild to moderate/severe ophthalmopathy occurs in about 3% of cases.
What can be mistaken for urticaria? ›Angioedema – swelling of tissue beneath the surface of the skin – can be mistaken for, or associated with hives. It can be caused by allergic reactions, medications or a hereditary deficiency of some enzymes.
How is thyroid urticaria treated? ›Hives can be treated with topical anti-itch creams or oral antihistamines. If autoimmune thyroid disease is involved, a synthetic thyroid hormone called levothyroxine may help prevent or treat a hives outbreak.
Can low TSH cause urticaria? ›
Can underactive thyroid cause hives? The exact link between chronic hives and the thyroid isn't fully understood, but one condition doesn't seem to cause the other. If an autoimmune disorder, such as Hashimoto's disease, is the cause of your hypothyroidism, you may be more likely to have or develop chronic hives.
Can hormones cause chronic urticaria? ›Chronic urticaria is approximately twice more frequent in women than in men. In addition, urticaria may be associated with some diseases and conditions characterized by hormonal changes, including endocrinopathy, menstrual cycle, pregnancy, menopause and hormonal contraceptives or hormone replacement therapy.
Can Graves disease cause allergic reaction? ›Results: Allergic sensitization was found in 88 cases (58%) for Graves' disease, 51 cases (46%) for Hashimoto's thyroiditis and 31 cases (55%) for euthyroid goitre.
Why wont my urticaria go away? ›If you have hives that keep coming and going for weeks on end, and you don't know what's causing them, see a doctor. You could have what is called chronic idiopathic urticaria (CIU) or chronic spontaneous urticaria (CSU). CIU is when a person has these breakouts almost daily for at least 6 weeks, with no known cause.
How can you tell if urticaria is autoimmune? ›The autologous serum skin test is used as a screening test for chronic autoimmune urticaria and has a sensitivity and specificity of about 70 and 80%, respectively. The current gold standard diagnostic test is the basophil histamine release assay.
What cancers cause urticaria? ›A thorough literature search, however, yielded findings of several other cases that suggest a causal relationship between urticaria and other malignancies including lung cancer, papillary thyroid cancers, lymphoma, ovarian cancer, brain tumours and carcinoid syndrome.
What is the root cause of urticaria? ›What causes urticaria? Urticaria occurs when a trigger causes high levels of histamine and other chemical messengers to be released in the skin. These substances cause the blood vessels in the affected area of skin to open up (often resulting in redness or pinkness) and become leaky.
What is the most common cause of Graves disease? ›Graves' disease is an autoimmune disease in which your immune system attacks healthy tissue in your thyroid gland for unknown reasons. It's the most common cause of hyperthyroidism, a condition in which your thyroid gland makes too much thyroid hormone.
Is it hard to diagnose Graves disease? ›It can be a challenge to detect Graves' disease early on. In fact, Graves' disease is sometimes confused with other conditions, which can make it very difficult to diagnose. That's why it's important to pay attention to your symptoms to help your doctor make an accurate diagnosis.
What hormone causes Graves disease? ›Thyroid hormones control the way your body uses energy, so they affect nearly every organ in your body, even the way your heart beats. With Graves' disease, your immune system attacks your thyroid gland, causing it to make more thyroid hormones than your body needs. As a result, many of your body's functions speed up.
How can you tell the difference between Graves disease and thyroiditis? ›
The ratio of total triiodothyronine (T3) to total thyroxine (T4) is a simple and helpful index for the differential diagnosis between Graves' disease and subacute thyroiditis [1], [2].
How can you tell the difference between Graves and Hashimoto's? ›Like Hashimoto's disease, Graves' is also an autoimmune disorder affecting the thyroid. The difference between the two is the type of antibodies your immune system attacks the thyroid with and how the attack impacts the thyroid. Hashimoto's disease causes hypothyroidism, whereas Graves' disease causes hyperthyroidism.
Can you have Graves disease with normal TSH? ›Some patients with Graves' disease may have subclinical (mild) hyperthyroidism without symptoms but with a goiter, suppressed TSH, TSH receptor antibodies, but with normal T4 and T3.
What has similar symptoms to Graves disease? ›Hashimoto's disease, also known as Hashimoto's thyroiditis or lymphoid thyroiditis, is an autoimmune disorder like Graves' disease.
What organ is affected in Graves disease? ›Graves' disease is an autoimmune disease which primarily affects the thyroid gland. It may also affect multiple other organs including eyes and skin. It is the most common cause of hyperthyroidism.
Which part of the body is affected by Graves disease? ›Graves' disease is an autoimmune condition where your immune system mistakenly attacks your thyroid which causes it to become overactive.
What other autoimmune diseases are associated with Graves disease? ›Graves disease is associated with pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic sclerosis, myasthenia gravis, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.
What are 4 major clinical symptoms of hyperthyroidism? ›Most patients with overt hyperthyroidism have a dramatic constellation of symptoms. The classic symptoms of hyperthyroidism include heat intolerance, tremor, palpitations, anxiety, weight loss despite a normal or increased appetite, increased frequency of bowel movements, and shortness of breath.
What is the difference between Graves disease and thyrotoxicosis? ›Hyperthyroidism: Hyperthyroidism, which happens when your thyroid makes and releases too much thyroid hormone, is the most common cause of thyrotoxicosis. Graves' disease, an autoimmune disease, is the most common cause of hyperthyroidism. It represents 80% of hyperthyroidism cases.
Can a blood test detect urticaria? ›Blood tests may also be used to help determine a diagnosis of Urticaria. The majority of testing for Urticaria is done through blood tests.
What is the hallmark of urticaria? ›
Urticaria (also called hives, wheals, or nettle rash) is characterized by pruritic, erythematous, and edematous wheals [1-10]. The hallmark of urticaria is that individual lesions wax and wane rapidly, usually lasting less than 4 hours [8, 9].
Does urticaria show up in blood test? ›Complete blood count, Erythrocyte sedimentation rate and C reactive protein are important investigations for diagnosis of infections in urticaria. Autologous serum skin test is a simple office procedure for diagnosis of auto reactive urticaria.
What is the first line treatment for urticaria? ›Antihistamines are first-line therapy for urticaria. The older sedating antihistamines (first-generation antihistamines) that block the H1 receptors were previously first-line therapy for urticaria. Diphenhydramine and hydroxyzine are the most commonly used in this class.
Does autoimmune urticaria go away? ›Most of the time, providers can't pinpoint the cause of chronic hives. However, treatments like antihistamines, steroids and even immunosuppressants can help. You can also take steps at home to ease itching and swelling. For many people, chronic hives eventually go away, although it may take a year or longer.
How do I know if my urticaria is serious? ›Seek emergency medical care. Chronic hives do not put you at sudden risk of a serious allergic reaction (anaphylaxis). If you get hives as part of a severe allergic reaction, seek emergency care. Symptoms of anaphylaxis include dizziness, trouble breathing, and swelling of the tongue, lips, mouth or throat.
Can Hashimoto's cause urticaria? ›Hashimoto thyroiditis may come with bouts of hives (urticaria). In fact, in one study, 30% of people² who experienced chronic hives were found to have Hashimoto's disease. The characteristics of chronic hives caused by Hashimoto's disease are similar to hives caused by other factors.
Can low estrogen cause urticaria? ›A lack of estrogen can also make your skin itch or cause it to be more sensitive than usual. This sensitivity makes you more likely to get a rash or hives when you're exposed to irritating substances like itchy fabrics, perfumes, and dyes.
Where does thyroid rash appear? ›Some people with hyperthyroidism develop a rare skin rash called pretibial myxedema (thyroid dermopathy). The rash is characterized by red, swollen skin and commonly appears on the shins and tops of feet.
Does Graves disease cause skin problems? ›Skin problems
Rarely, people with Graves' disease develop a condition that causes the skin to become reddish and thick, with a rough texture. Called Graves' dermopathy or pretibial myxedema, the condition usually affects your shins but can also develop on the top of your feet and other parts of your body.
Chronic hives are especially common in people with Hashimoto's thyroiditis , an autoimmune disease that causes hypothyroidism (an underactive thyroid gland).
Can Graves disease cause allergies? ›
Another study shows that people with autoimmune hyperthyroidism, or Graves' disease, are also more likely to have chronic allergies than the general population. The numbers are even higher for people with Graves' disease, where 42.9% of people with Graves' have allergic rhinitis.
What autoimmune diseases are associated with Graves disease? ›Graves disease is associated with pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic sclerosis, myasthenia gravis, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.
What causes Graves disease to flare up? ›Researchers don't know what causes autoimmune diseases like Graves' disease. Something triggers your immune system to overproduce an antibody called thyroid-stimulating immunoglobulin (TSI). TSI attaches to healthy thyroid cells, causing your thyroid to overproduce thyroid hormones.
What do thyroid hives look like? ›Symptoms of chronic urticaria in thyroid disease
The main symptom of idiopathic urticaria is round, swollen pink welts that appear anywhere on your skin. The hives are often very itchy. Hives generally go away within 24 hours, but sometimes new hives pop up as the old ones disappear.
Hashimoto thyroiditis may come with bouts of hives (urticaria). In fact, in one study, 30% of people² who experienced chronic hives were found to have Hashimoto's disease. The characteristics of chronic hives caused by Hashimoto's disease are similar to hives caused by other factors.
Is urticaria and autoimmune disease? ›Over half of all cases of chronic idiopathic urticaria are thought to occur by an autoimmune mechanism, primarily autoantibodies against the high affinity immunoglobulin E (IgE) receptor (FcεRI). Chronic urticaria is hypothesized to occur because of a predilection in the patient to develop reactions to self.
What part of the body itches with thyroid problems? ›Thyroid hormones also influence the quality of your skin in a variety of ways. With hyperthyroidism, you may notice itchy and dry patches of skin. Your face may feel softer and swollen. You may even notice swelling around your fingertips.
How do I know if I've got Graves disease? ›Blood tests can help your doctor determine your levels of thyroid-stimulating hormone (TSH) — the pituitary hormone that normally stimulates the thyroid gland — and your levels of thyroid hormones. People with Graves' disease usually have lower than normal levels of TSH and higher levels of thyroid hormones.
Can you take Benadryl with Graves disease? ›No interactions were found between Benadryl and thyroid desiccated. However, this does not necessarily mean no interactions exist. Always consult your healthcare provider.
What viruses cause Graves disease? ›Abstract. Introduction: Autoimmune thyroid diseases, including Graves' and Hashimoto's thyroiditis, are the most frequent autoimmune disorders. Viral infection, including Epstein-Barr virus (EBV), is one of the most frequently considered environmental factors involved in autoimmunity.