Chapter 30Thyroid disease and autoimmune diseases

Introduction

Autoimmune thyroid diseases (AITD) are the most prevalent organ-specific autoimmune diseases (ADs) and affect 2 - 5% of the population (1) with great variability between genders (i.e., women 5–15% and men 1–5%) (2). AITD include Graves’ Disease (GD) and Hashimoto Thyroiditis (HT), among others. HT and GD are the major causes of hypothyroidism and hyperthyroidism, respectively (3). They reflect the loss of immunological tolerance and share the presence of cell and humoral immune response against antigens from the thyroid gland with reactive infiltration of T cells and B cells, autoantibody generation and, subsequently, the development of clinical manifestations (4, 5).

The lymphocytic infiltration causes tissue damage and alters the function of the thyroid gland. The injury is caused when the autoantibodies and/or sensitized T cells react with the thyroid cells causing the inflammatory reaction and, in some cases, cell lysis (6). Generally, while T lymphocytes are the main cell type infiltrating the gland in HT, a B cell response predominates and determines the presence of GD (7).

As with other ADs, there is a multifactorial etiology with a complex interaction of environmental factors in genetically susceptible individuals (8) (Figure 1). Some of these genes are specific for GD and HT while others are mutual for both diseases, which indicates a genetic predisposition shared in these processes together. Candidate genes include immunoregulators [e.g., human leukocyte antigen (HLA), cytotoxic T lymphocyte antigen-4 (CTLA-4)] and others specific to the thyroid (e.g., TSH receptors, thyroglobulin, etc.). The main environmental factors are smoking, stress, and iodine consumption (6).

Figure 1

Risk factors for AITD: multifactorial disease. The etiology of AITD is multifactorial, in which a mosaic of predisposing and stochastic factors play in concert for the induction of loss tolerance and subsequent organ damage. The pre-clinical stage is (more...)

AITD is the most hierarchical AD coexisting in the same individual [e.g., polyautoimmunity and multiple autoimmune syndromes (MAS)] (5,9). In fact, rheumatologists may be consulted for clinical manifestations of AITD that mimic several symptoms of other ADs (3).

Genetics

Genetics play a key role in the pathogenesis of AITD. In fact, a number of immune-related genes have been implicated in genetic susceptibility to AITD. For instance, it is calculated that up to 80% of the susceptibility for the development of GD is secondary to the presence of determined genes (10). These genes include both immunological-synapse genes [e.g., HLA-DR, CTLA-4, CD40, and the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) gene] and regulatory T–cell genes (e.g., FOXP3, CD25) (3).

The association between HLA alleles and AITD is well known, but the primary etiological variant in this region is still uncertain (1). Thus, the pathological findings for both GD and HT are similar, and are associated with particular HLA-B and HLA-DR, suggesting that inherited risk factors are important in the development of these entities (11,12). HLA-DR locus plays an important role since HLA-DR3 is present in up to 55% of the patients with GD compared to the 30% prevalence in the general population (4). In fact, it has been discovered that HLA-DR3 and HLA-DR5 are linked to HT and provide a greater risk for the disease (4). Moreover, Ban et al. (11) identified arginine at position 74 of the HLA-DRβ1 (DRβ-Arg74) as the critical DR amino acid (a.a) conferring susceptibility to GD, and glutamine at position 74 as a protective a.a. Regarding HT, Menconi et al. (13,14) reported similar findings for this disease. They were able to identify the thyroglobulin peptides that could be presented by HLA-DR pockets containing arginine at position beta 74 to T cells and, therefore, initiate the autoimmune process (14). There are, in turn, studies that suggest alleles from HLA-DQ might be genetic markers that confer resistance to the development of AITD (15). Likewise, atrophic and subacute thyroiditis are strongly associated with HLA-B35 in many ethnic groups while painless thyroiditis is associated with HLA-DR3 (11,12,16).

There are associations with a number of immune-related genes, other than HLA genes, which have also been found in many other ADs and presumably underpin the inherited susceptibility to autoimmunity. Polymorphism in certain alleles of CTLA-4 predispose to GD and HT (17–21). For instance, in a study of 379 patients with GD in the United Kingdom, 42% had a particular allele (G allele) of the CTLA-4 gene compared to 32% of the controls (20). This genetic abnormality also stimulates higher levels of thyroid-specific autoantibodies and clinical thyroid disease when interacting with other loci (4,20–22). Currently, both HLA-DR3 and CTLA-4 are considered to be the main genes associated with the development of AITD.

CD40 is expressed on thyroid follicular cells and on B cells. Polymorphisms of this gene are associated with a 20–30% increase in translation of CD40 mRNA transcripts in patients with AITDs (23).

Polymorphisms of the PTPN22 gene, which encodes a negative regulator of T cell activation, have been associated with AITD and other ADs. A gain of function trait has been identified, but its role in autoimmunity is uncertain (24,25). Finally, abnormalities in the FOXP3 gene (differentiation of T cells into natural Treg cells) have been associated with juvenile GD (26). Changes in the CD25 gene region have also been associated with GD (27).

Epigenetics

Although the link between susceptibility genes and environmental triggers is clear, the mechanisms by which gene variants interact with environmental factors to cause autoimmunity are still unclear. Recent data suggest that epigenetic mechanisms might underlie genetics. Their effects on gene expression have been broadened to include non-DNA-sequence-encoded effects on gene expression that are mitotically stable (28). Epigenetic modulation of gene expression can occur through alterations in DNA methylation, histone modification patterns (e.g., acetylation, deacetylation, and methylation), and RNA interference through microRNAs. Recently, interferon-a (IFN-α) was shown to induce alterations in thyroglobulin (Tg) gene expression through epigenetic changes in histone modifications (29). Since IFN-α is secreted locally during viral infections, this could be an attractive mechanism by which infections can trigger AITD (30). Another epigenetic phenomenon described in the pathogenesis of AITD is the X chromosome inactivation. The degree of X chromosome inactivation is an important contributor to the increased risk females have of developing AITD, as demonstrated by Yin et al. (31).

Environmental factors

There are a number of environmental factors associated with the occurrence of AITD such as low birth weight, iodine excess, selenium deficiency, use of anovulatories, parity, stress, smoking, allergy, radiation exposure, viral or bacterial infections, and fetal microchimerism (32).

Autoantibodies

The TPOAb and TgAb are the most common thyroid autoantibodies present in patients with AITD and are associated with complement - mediated cytotoxicity against thyrocytes (49,50). In fact, the absence of these autoantibodies could exclude a diagnosis of AITD, which means that these tests have high negative predictive value (51). The TSHR antibody (TRAb) is identified in patients with GD (52). There are other less common autoantibodies such as those against the sodium/iodine symporter (NIS) and pendrin, but their clinical utility is limited (53,54) (Table 1 and Figure 2).

Table 1

Antibodies described in AITD, frequency of presentation and detection method.

Figure 2

Molecular target for thyroid autoantibodies. (1) Iodine is translocated to the thyrocyte lumen through the NIS located at the basal cell membrane and travel down its electrochemical gradient to the apical surface. (2) Synthesis of Tg in the endoplasmic (more...)

These autoantibodies may be present in individuals without clinical or laboratory evidence of thyroid dysfunction (55,56). Presence of antibodies in the absence of disease has been related to a greater risk of developing an AITD in the future, especially postpartum thyroiditis, as seen in women with recurrent abortion (57). These antibodies has also been linked to an increased probability of thyroid dysfunction secondary to the use of medication that can potentially alter the thyrocyte function (58). The aging process is, likewise, associated with a greater presence of these antibodies. Moreover, these antibodies have been detected in up to 50% of women with a first degree relative with AITD and in 30% of men in the same situation and thus, suggests a dominant inheritance pattern (19).

Even though the recognition of these antibodies does not generate a direct intervention against them, they allow us to predict a clinical outcome or therapeutic response. It is known that the complete ablation of the thyroid tissue results in complete disappearance of these antibodies, in accordance with the theory that the production of these antibodies is triggered by the presence of autoantigens (59). Another clinical utility of these antibodies is related to thyroid ophthalmopathy. Patients that present with this clinical manifestation have higher titers of TRAb and lower levels of TPOAb (60).

Autoimmune thyroid diseases

The clinical entities found in AITDs are diverse and vary depending on whether a state of hypothyroidism (HT), hyperthyroidism (GD), or both [Painless thyroiditis (PT), Postpartum thyroiditis (PPT), and Subacute thyroiditis (SAT)] predominate in the patient (7) (Table 2).

Table 2

Main characteristics of autoimmune thyroid diseases.

The term thyroiditis encompasses a varied group of disorders characterized by some form of thyroid inflammation. They include conditions that cause acute illness with severe thyroid pain and others in which there is no clinically evident inflammation, and the illness is manifested primarily by thyroid dysfunction or goiter. PT, PPT, HT, and GD all have an autoimmune basis (6).

Hashimoto thyroiditis

HT (chronic autoimmune thyroiditis or chronic lymphocytic thyroiditis) is the prototypic example of organ-specific AD and the most common cause of hypothyroidism in iodine sufficient areas of the world (3,80,81). It was first defined in 1912 by surgeon Hakaru Hashimoto who described four women with a condition he initially denominated struma lymphomatosa (82).

Epidemiology. Its prevalence is about 1 in 1,000 people and increases with age, affecting up to 40% of elderly women (80,81). Thyroid failure is seen in up to 10% of the population. The incidence of HT is higher in countries where there is excess iodine in the diet, approximately 1.3%, compared to 1% in countries that are iodine sufficient (83). It affects more women than men with a female to male ratio of 18:1 (82). The sibling recurrence risk is >20 (21). There is a peak frequency during the fourth decade, and the mean age of presentation is 35 years (82). The disease clusters in families, sometimes alone and sometimes in combination with GD (see below) (84). Although thyroid lymphoma is a rather rare condition, there is an increased risk for this disease in patients with HT with a RR of 67 (85).

Pathogenesis. HT is characterized by gradual loss of thyroid function, goiter, or both due to autoimmune–mediated destruction of the thyroid gland through apoptosis of the thyrocytes (82). Several mechanisms have been suggested to explain the pathogenesis of HT. These include first, molecular mimicry. Here HT is thought to be caused by an immune reaction against an antigen that shares structural similarities with endogenous proteins (86). Second, there is bystander activation. In this case, a virus reaching the gland or activation of non–specific lymphocytes within the thyroid by virus may cause the release of cytokines which, in turn, activate local thyroid–specific T cells and favor an inflammatory reaction (i.e., thyroiditis) (87). Third is thyroid cell expression of HLA antigens. As previously discussed, thyroid follicular cells in patients with HT express HLA-II. The expression of these molecules can be induced by IFN-γ and other products from activated T cells or by virus directly. Thyroid cells expressing HLA-II, in turn, become non-professional antigen presenting cells (88,89). Fourth is thyroid cell apoptosis. In autoimmune thyroiditis, cytokine (e.g., IL–1) production from antigen presenting cells (APC) and Th1 cells induces the expression of Fas and Fas ligand on thyrocytes, thereby causing self–apoptosis (90).

Clinical Manifestations. The two major clinical forms of HT are goitrous autoimmune thyroiditis and atrophic autoimmune thyroiditis (82). The decrease in circulating thyroid hormones causes a negative effect on the metabolic rate and on multiple organ systems (91). The deposit of glycosaminoglycans secondary to an increase in the synthesis of hyaluronic acid and the decrease in the metabolic rate explains most of the clinical manifestations of patients with hypothyroidism (91).

Clinically, the signs and symptoms of hypothyroidism that characterize HT are shown in the Figure 3. These symptoms are usually insidious and are unrecognized by the patient for a prolonged time (82). The most typical clinical manifestations include:

• Skin: findings on the skin depend on the degree of the hypothyroidism and the ethnicity of the patient (91). Usually there is xeroderma, thickening of the skin, cold intolerance, livedo reticularis, and loss of lateral eyebrows (Queen Anne sign) (82,91). The face is swollen, and the tongue is thickened. Patients complain of hair loss and the nails are frail (82).
• Cardiovascular System: the most common finding is bradycardia followed by reduced cardiac output and low voltage on electrocardiogram (82,91).
• Musculoskeletal: fatigue, carpal tunnel syndrome, myopathy, and arthritis may be present (91). Myopathic symptoms consist of proximal muscular weakness accompanied by an increase in serum creatine kinase (91,92). The association between arthritis and hypothyroidism is well-known (93,94). Bland et al. (95) had previously described the arthritis that accompanied patients with hypothyroidism as characterized by affected knees, metacarpophalangeal joints, proximal interphalangeal joints, and metatarsophalangeal joints without the presence of sinovitis. It is thought to be a TSH-dependent increase in hyaluronic acid and proteoglycan synthesis in this subgroup of hypothyroid patients. This observation is supported by the symptomatic response to thyroid hormone replacement with concomitant TSH suppression (93,95).
• Neuropsychiatric System: sleepiness and slow discourse are frequent, along with depression, anxiety, and psychomotor retardation (82,91). Patients may also complain of memory impairment. Functional imaging studies have shown a decrease in cerebral blood flow and glucose metabolism (96).
• GI Tract: constipation is the main gastroenterological symptom secondary to dysfunctional motility (82,91). Other symptoms caused by decreased motility include dyspepsia and gastroesophageal reflux. Coexisting ADs may cause a decrease in gastric acid production and malabsorption (97).
• Endocrine System: oligomenorrhea and menorrhagia are the most common menstrual disturbances seen in these women (98). Men have lower concentrations of sex hormone – binding globulin and free testosterone (99).
• Other findings: patients with hypothyroidism may present with hyponatremia secondary to plasma dilution due to decreased free water clearance. This finding together with accumulation of mucopolysaccharides, reduced glomerular filtration rate, and low cardiac output results in edema (100). Hypothyroidism is characterized by abnormal lipid values; more than 90% of patients present with increased low–densitiy lipoproteins (LDL) and apolipoprotein B because of reduced hepatic clearance secondary to a decrease in hepatic LDL receptors (101).

Figure 3

Clinical manifestations of hypothyroidism and hyperthyroidism. GI: gastrointestinal tract; CNS: central nervous system.

Some patients with HT, especially those with the goitrous form, might not present with the classic symptoms of overt hypothyroidism, but with symptoms secondary to the presence of a mass on the neck. The main compression symptoms are dyspnea, dysphagia, and dysphonia (82).

Laboratory Findings. Even though the clinical manifestations are very sensitive, their specificity is rather low (102). This is the reason the laboratory findings constitute the cornerstone for the diagnosis of thyroid dysfunction.

Secretion of the thyroid hormones, thyroxine (T4) and T3, is regulated by the TSH. In turn, TSH secretion is controlled by thyroid hormones. There is a negative relationship between free T4 (fT4) and TSH, where small changes in fT4 concentration induce very large reciprocal changes in TSH concentration (103). This means that serum levels of TSH are best for assessing the thyroid function. However, there is considerable controversy regarding the normal upper limit of serum TSH. Several authors have addressed this issue but, currently, there is no consensus (104–107). Even though most laboratories have used values of 5.0 IU/mL concurrent with the American Academy of Clinical Endocrinology (AACE) (106), an article published by the National Academy of Clinical Biochemistry argues that the upper limit should be reduced to 2.5 IU/mL based on their results where 95% of the euthyroid volunteers had serum values between 0.4 – 2.5 IU/mL (107). Jensen et al. and Hamilton et al. (104,105) found a normal upper TSH level of 4.1 IU/mL, which is more clinically acceptable for initiating therapy. Regarding T4 and T3, the free hormone hypothesis states that the unbound or free hormone is the one available for uptake into cells and interaction with nuclear receptors. The bound hormone, on the other hand, represents a circulating storage pool that is not immediately available for cell uptake. Free T3 (fT3) and fT4 are usually measured rather than serum total T3 and T4 concentrations.

The most common tests done in HT are TSH, fT4, TPOAb, and TgAb. The usual findings in patients with hypothyroidism include high TSH and low fT4 levels. Patients with high TSH but normal fT4 have a condition known as subclinical hypothyroidism (91). High serum TPOAb concentrations are present in 90% of the patients, and high serum TgAb are found in 50–90% of these patients. As discussed earlier, some patients with HT might have TRAb levels (i.e., up to 10%), but their role in the diagnosis is uncertain (91). The diagnosis of HT can be made in patients with high TSH levels, low fT4, and positive TPOAb.

Other tests that may be done include thyroid gland ultrasound (US) that will reveal an enlarged or shrunken gland depending on the clinical presentation of the HT (82). Radioiodine uptake (RaIU) over 24 hours does not provide useful information for diagnosis as it might be normal, reduced, or high depending on the functional phase of the disease (6,82). The fine needle aspiration (FNAB) should be done on every patient who presents with a dominant thyroid nodule and HT since, as discussed previously, lymphoma and thyroid carcinoma must be ruled out. A FNAB positive for HT will reveal the classical pathological findings that include a marked lymphocytic infiltration and the Hürthle cells (6,82).

Patients with hypothyroidism must be assessed on their cardiovascular risk as severe hypothyroidism leads to hypercholesterolemia and hypertriglyceridemia with a higher risk of atherosclerosis and acute coronary syndrome (101). Lipid profile tests should be done periodically on these patients. Patients with dyslipidemia, in turn, should always be screened for hypothyroidism (91).

Treatment. Thyroid hormone replacement therapy constitutes the main therapeutic strategy for patients with hypothyroidism (82,108). The treatment of choice is oral supplementation with synthetic thyroxine (levo–thyroxine, L-T4). L-T4 is a prohormone with very little intrinsic action. It is, in turn, peripherally deiodinated into T3, the active thyroid hormone. As the L-T4 has a prolonged half–life (i.e., approximately 7 days), once a day treatment ensures steady concentrations of T4 and T3 (109).

The goals of the treatment are improvement of the symptoms and normalization of TSH secretion. In addition, in patients with the goitrous form of presentation, a decrease in the size of the goiter is also considered a therapeutic objective (110). These goals are usually achieved with an average replacement dose of 1.6 mcg/kg/day (111). Elderly patients with coronary disease or multiple coronary risk factors should be treated conservatively since thyroid hormones increase myocardial oxygen demand which can induce angina, arrhythmias, or even myocardial infarction (82). The starting dose for these patients should be 50 mcg/day, and those with a prior history of coronary heart disease must be treated with 25 mcg/day (82).

Patients with replacement therapy must be monitored by assessing serum TSH levels. Although symptoms may begin to resolve a couple of weeks after initiating the treatment, steady–state TSH concentrations are not achieved for at least six weeks. Thus, these patients should be reevaluated with serum TSH in six weeks (112). If the TSH level persists at higher than the normal upper limit, the dose must be increased 12.5–25 mcg per day. Serum fT4 measurements are very insensitive for assessing the appropriateness of the dose (112). In the case of subclinical hypothyroidism, the decision to initiate replacement treatment depends on serum TSH levels. If the TSH level is >10 IU/mL, treatment with L–T4 is indicated to prevent progression to overt hypothyroidism. Patients with TSH levels that are between 4–10 IU/mL who also present with goiter, nonspecific symptoms of hypothyroidism, or high titers of TPOAb must be started on replacement therapy (113). Other therapeutic strategies such as the use of immunosuppressive agents [e.g., glucocorticoids (GCs)] are not required since the lifelong administration of L–T4 is enough for these patients (82).

Painless thyroiditis

PT, also called silent thyroiditis, is characterized by hyperthyroidism, followed by hypothyroidism, and finally, recovery to a euthyroid state (6,114). It is considered a variant form of HT, suggesting that it is part of the spectrum of AITD (114,115). There are many similarities with PPT and SAT (6,114,115).

The incidence of PT is not well-delineated and accounts for 1–5% of the cases of hyperthyroidism. It seems to be more prevalent in areas of higher iodine intake (117). Women are affected more commonly than men at a ratio of 4:1. The mean age of presentation is between 30–40 years (115). It is associated with a specific HLA, most often HLA–DR3, which suggests an inherited susceptibility. However, this association is weaker compared with HLA–B35 and SAT (16).

Factors postulated to initiate PT include excess iodine intake and various cytokines (115,116). It has been reported in patients following cessation of GCs and in external radiation of the neck for Hodgkin lymphoma (117–120). The resulting thyroid inflammation damages thyroid follicles and activates proteolysis of the Tg stored in the colloid. This causes an unregulated release of T4 and T3 into the circulation and results in hyperthyroidism. Once the Tg is exhausted, hormone synthesis ceases and a state of hypothyroidism may develop. As the inflammation subsides, the repaired thyroid follicles resume normal synthesis and secretion of thyroid hormone (6,115).

Approximately 5% to 20% of the patients with PT present with the triphasic course of hyperthyroidism, hypothyroidism, and restoration to normal thyroid function (Figure 4). This clinical course is also described for PPT and SAT (115). The signs and symptoms that characterize hyperthyroidism and hypothyroidism are shown in Figure 3. The hypothyroid phase is recognized and diagnosed more often compared to the hyperthyroid phase (121). The thyroid gland is not painful, non-tender, but it is usually minimally enlarged sometimes firm in texture upon palpation (115).

Figure 4

Naturla history of Painless, Postpartum and Subacute thyroiditis. These diseases share in common triphasic clinical course consisting in hyperthyroidism, hypothyroidism and return to normal thyroid function. During the hyperthyroidism phase, there is (more...)

As expected, thyroid function tests vary during the clinical course of the PT, and changes in serum TSH usually lag behind those in fT4 and fT3 (114,115) as explained in Figure 4. Thyroid function tests should be done every four to eight weeks to confirm resolution of hyperthyroidism and detect the development of hypothyroidism (115). Up to 50% of the patients with PT have increased titers of TPOAb but not to the same extent as those with HT (122). Other laboratory results as well as common imaging results are described in Table 2.

Most of the patients do not require any treatment at all since the thyroid dysfunction is not severe enough to make them symptomatic. However, patients who develop clinical manifestations do need treatment based on the phase of the clinical course they are in. During the hyperthyroid phase, the treatment of choice is beta-blockers (BB) (Table 3). In the hypothyroid phase, the replacement therapy is L-T4. Based on the results of the thyroid function tests, the course of the supplementation therapy must be defined (115). Although most patients recover full thyroid function, up to 20% will develop permanent hypothyroidism (123).

Table 3

Beta-blockers used for management of symptomatic hyperthyroidism.

Graves’ disease

Graves’ disease (GD), named after the physician Robert Graves who first described the association in 1835, is clinically characterized by the presence of hyperthyroidism, diffuse goiter, ophthalmopathy (GO), and dermopathy (142,143).

Epidemiology. GD is the most common cause of hyperthyroidism, representing up to 80% of the cases (144). The annual incidence of GD is 20–25/100,000 in Caucasian populations. It is lower among people with African ancestry (142). It affects ten times more women than men. A peak frequency between the ages of 40–60 years has been reported (143,144). The concordance rate for GD between monozygotic twins is 38% (10). A family history of thyroid disease, especially among maternal relatives, is associated with increased risk of GD and a younger age of onset (145).

Pathogenesis. GD is the result of the presence of circulating TRAb that bind and activate the TSH receptor, thus stimulating follicle hypertrophy and hyperplasia as well as increasing the synthesis of thyroid hormones and the fraction of T3 relative to T4 (74,142). In GD, as discussed previously, there is an environmental factor that triggers an autoimmune response to the thyroid either by molecular mimicry or by bystander activation (142). Thyroid cells expressing HLA-R molecules may act as APC activating local T cells through the expression of co-stimulating molecules. As a result, there is a production of cytokines which in turn, activates thyroid–specific T cells and B cells to produce TRAb (142).

Clinical Manifestations. The clinical manifestations can be classified into those secondary to the excess of circulating thyroid hormones (hyperthyroidism) and those specific to GD (142). Typical signs and symptoms of hyperthyroidism are shown in Figure 3 (143,145). Some signs and symptoms are highly specific to GD including the following:

• Goiter: diffuse enlargement of the thyroid gland that can vary in size (142).
• Ophthalmopathy: approximately 20–25% of patients with GD have clinically obvious GO (33). The estimated incidence of GO is 16/100,000 persons in women and 3/100,000 in men (146). It appears before the onset of hyperthyroidism in 20% of the patients, concurrently in 40%, and six months after diagnosis in about 20% (147). The characteristics signs are proptosis and periorbital edema. The major symptoms include sense of irritation in the eyes, excessive tearing, retroorbital discomfort or pain, blurring of vision, diplopia, and occasionally, loss of vision (148). Most of the patients have mild non–progressive ocular involvement, but in 5–10% of the cases, there is severe ophthalmopathy associated with significant visual impairment that can lead to visual loss (142). The pathogenesis of GO is a result of a cross-reaction between the TRAb and TSHR found on orbital fibroblasts, which induces the production of glycosaminoglycans, especially hyaluronic acid. (33).
• Dermopathy: present in 1–2% of the patients with GD, most commonly in those with severe ophthalmopathy (142). It is characterized by a non–pitting edema with occasional hyperpigmented papules, located on the pretibial area (142).
• Thyroid acropachy: clubbing caused by soft tissue swelling and periosteal bone changes in the fingers and toes. This sign represents a rare manifestation of GD (142).

Laboratory Findings. The laboratory findings in patients with GD are completely opposite to those found in hypothyroidism (Table 2). Monitoring of the patients with GD involves obtaining fT3 periodically to asses response to treatment when medical management is indicated (see below) (149). The main thyroid autoantibody present in patients with GD is the TRAb in >95% which, in contrast to HT, are stimulating antibodies (51,78,142,143). Other autoantibodies are also present. TPOAb is elevated in 40–70% of the patients and TgAb is found in 20–40% of GD (78,142). Thyroid gland US shows a diffusely enlarged thyroid (142). Color Doppler will show increased blood flow (143). RaIU in 24hrs reveals an increased uptake from the gland, which can be helpful to differentiate from the hyperthyroidism phase of thyroiditis (142). Diagnostic criteria are used based on clinical and laboratory findings (142) (Table 4).

Table 4

Diagnostic criteria for Graves’ disease.

Treatment. The treatment of GD is based upon one of three therapeutic strategies: medical management, using medication to suppress the hyperthyroid symptoms (i.e., BB), and blocking thyroid hormone synthesis with antithyroid medication (i.e., PTU, MMI); radioactive iodine therapy; or surgical approach with total thyroidectomy (149). The decision to choose one over the other depends on each individual and is based on the severity of the thyrotoxicosis, the presence of goiter and ophthalmopathy, and the patient’s preference (149) (Table 5).

Table 5

Treatment strategies for Graves’ Disease.

Polyautoimmunity

Several clinical signs and symptoms that are shared among ADs –physiopathological mechanism and risk factors– indicate that they have a common origin, which has been called the autoimmune tautology (5,8). The clinical evidence of the autoimmune tautology highlights the co-occurrence of more than one AD in a single patient, namely polyautoimmunity, or MAS, a form of polyautoimmunity which corresponds to the coexistence of two or more well-defined ADs (5,9). The importance of these terms is due to the fact that patients with polyautoimmunity or MAS may have a modified disease course (i.e., with a worse prognosis or a better one) and a modified clinical presentation (9).

AITD has been described as the most prevalent AD as well as being associated with other organ-specific and non-organ specific ADs (150). In a study in which we analyzed 1,083 patients, polyautoimmunity was observed in 34.4% of the cases, and AITD was the most frequent polyautoimmunity found (9). This finding was supported by systemic literature review where three basic, large clusters were found. According to the analysis, the most hierarchical (i.e., chaperon) AD in the MAS cases is represented by AITD. It was associated with sclerodema (SSc) in 23% of the cases, rheumatoid arthritis (RA) in 21%, SLE in 17.9%, and multiple sclerosis (MS) in 9.1%. Female gender was a shared factor that was significantly associated with polyautoimmunity in the four ADs (9). Possible explanations for the relationship of these AD include the immunomodulatory effects of antithyroid antibodies, molecular mimicry between thyroid and disease-specific epitopes, and a genetic link between thyroid autoimmunity and the susceptibility to AD. Other studies have demonstrated the association between AITD and non–organ specific AD, particularly with RA, SLE, and Sjögren’s syndrome (SS) (150-152) (Table 6).

Table 6

Polyautoimmunity and AITD.

Familial autoimmunity (FA) is defined as the presence of any AD in first-degree relatives (FDRs) of the proband, which are at increased risk of developing an AD (1,4–6). Recently, we found FA to be strongly associated with AITD (69). For instance, if the proband has AITD, the most common AD in the FDRs are: Addison’s disease (AdD), celiac disease (CD), inflammatory bowel disease (IBD), myasthenia gravis, MS, pernicious anemia (PA), RA, SLE, T1DM, vitiligo (VIT), localized SSc, and discoid lupus erythematosus. On the other hand, if AITD is the AD in FDRs, the probands are predisposed to T1DM, SLE, RA, MS, SS, SSc, IBD, VIT, juvenile rheumatoid arthritis, juvenile lupus erythematous, inflammatory idiopathic myositis, CD, and alopecia areata. These finding shows that there is familial clustering of AITD in FDRs, particularly in female relatives (7).

Boelaert et al. (153) described FA among probands with HT or GD. Both ADs were significantly associated with the presence of T1DM, RA, PA, SLE, CD, VIT, and MS. Only GD was associated with AdD and IBD. Compared to the general population, FA in GD probands disclosed PA as the strongest association (RR:14.1) followed by RA (RR:13.5). Hemminki et al. (154) assessed FA only in probands with GD from Sweden. To calculate familial risk within a large community based cohort, they calculated standardized incidence ratios (SIR) as the ratio between the observed and the expected frequency for each disease. A value over one indicates a higher frequency of what is expected whereas a value below one indicates a decreased frequency. The analysis was stratified based on the FDR involved. For a single parent affected, HT, PA, and RA were the only diseases significantly associated as they had a SIR of 2.04, 1.82, and 1.48 respectively and thus, showed a frequency that was higher than what was expected. Significant associations for singleton siblings were found for T1DM, discoid lupus, and localized SSc if a parent and a sibling were affected with the same AD. The significant association was between HT with a SIR of 37.41 and SLE with a SIR of 14.33 (154). In another study, FA was significantly associated with polyautoimmunity in SLE and SSc patients (9), while Walker et al. (155) found an excess risk for AITD in RA multicase families compared to the general population.

AITD and rheumatoid arthritis

For several decades, an increasing occurrence of thyroid disorders in patients suffering from RA has been documented, both autoimmune and non-autoimmune in nature (94,156–158). In addition, rheumatological and non-rheumatological manifestations of AITD have been described (55). Within these manifestations, it is noteworthy that the most common symptoms are polyarthralgia and unclassified arthritis, which are the main features of RA. Genetic background is an important aspect in autoimmunity. Genetic risk factors shared among diseases have been described in AITD and RA (55,159,160).

The prevalence of AITD in RA cases has ranged from 0.5% in Morocco (161) to 27% in Slovakia (78). It varies between regions and ethnicities [i.e., 1% in Germany (162), 2.1–9.8% in North America (163-166)]. For more details, see Figure 5. In Latin America, the prevalence of polyautoimmunity was reported to be 9.8% in a cross sectional analytical study of Colombian RA patients. This association, adjusted by gender and RA duration, was related to the presence of diabetes, thrombosis, and abnormal body mass index. Furthermore, a lower AITD frequency was demonstrated for the lowest educational level than for the highest one. This is also true when antimalarials are used (150).

Figure 5

Prevalence of AITD and thyroid antibodies worldwide. Tg: thyroglobulin; TPO: thyroperoxidase.

It is widely accepted that, among the thyroid antibodies, the most frequent is TPOAb compared to TgAb (80). The prevalence for TgAb ranged from 5% in men from the UK (167) and 6% regardless of gender in Egypt (168), to 31% in RA patients from Japan (169). The prevalence for TPOAb was within the range of 5% in Egypt (170) to 37% in Italy (151). Cárdenas-Roldán et al. (150) in a recent cross-sectional analysis of 800 RA patients found that the presence of antibodies was 37.8% for TPOAb and 20.8% for TgAb. In contrast, Ruggeri et al. (171) show the assessment of thyroid antibodies at three points in time. There were more patients with TPOAb and TgAb than with a clinical diagnosis of AITD. Considering the idea that autoantibodies are predictors of disease (45,172), it is important to remain vigilant in following the clinical course of these patients. TPOAb and TgAb are known to predict AITD. This was demonstrated in the Wickham cohort (173). Patients within the accepted TSH reference range and who had the above mentioned autoantibodies had a greater risk of developing overt hypothyroidism. A careful assessment of those patients with a normal range of TSH but presenting specific antibodies should be done. For more details, see Figure 5.

The association between AITD and extra-articular manifestations (EAM) seems to be linked to CVD (174), and it is considered a major predictor of poor prognosis (175). In fact, Raterman et al. (156) agreed that the presence of hypothyroidism, including HT, is a risk factor for CVD in patients with RA. Moreover, McCoy et al. (165) found that L-T4 supplementation was significantly associated with CVD, which supports the fact that the administration of this medication does not decrease the occurrence of this outcome. Autoimmunity itself may be an independent risk factor for CVD. As both diseases increase inflammatory parameters and cytokines and cause endothelial dysfunction, a relationship between polyautoimmunity and the occurrence of CVD is not surprising.

With respect to RA severity, the literature is scarce. Charles et al. (176) did not find a relationship between the presence of thyroid antibodies and the occurrence of anti-cyclic citrullinated peptide antibody (anti-CCP), although they did the analysis with the PTPN22 R620W allele. Likewise, another cohort did not find a correlation between AITD and proxy variables for RA severity such as erosions, biological agent use, the presence of anti-CCP, and EAM (150). One cannot but hypothesize that many of these studies are cross-sectional in nature and because the importance of DAS28 and HAQ is along a timeline, it is not relevant to include these variables in the analysis.

Conclusions

AITD is a term used to bring together a group of pathologies that include thyroid dysfunction and an autoimmune response to the thyroid gland. Even though the prevalence of this disease in the general population varies between countries, AITD can be regarded as the most common autoimmune endocrine disease. It includes a group of AD clustered together with a diverse clinical presentation that depends on whether it causes hypothyroidism, hyperthyroidism, or both. An international consensus to accurately diagnose AITD is warranted.

AITD is frequently associated with other organ specific and non-organ specific AD, most commonly RA, SLE, and SS. AITD is clinically important in the context of autoimmunity, and it is mandatory to screen patients with hypothyroidism or hyperthyroidism symptoms for the autoimmune etiology when there is suspicion of the coexistence of AITD (i.e. polyautoimmunity).

Routine screening for CVD among these patients should be considered. These results may help to further the study of the common mechanisms of AD, to improve patient outcome, and to define public health policies, especially for RA patients.

Abbreviation list

AACE:

American Academy of Endocrinology

AD:

autoimmune diseases

AdD:

Addison Disease

AITD:

autoimmune thyroid disease

ANA:

antinuclear antibodies

ANCA:

anti-neutrophil cytoplasmic antibodies

APC:

antigen presenting cell

ATD:

anti-thyroid drugs

BB:

beta-blockers

BID:

two-times per day

CBC:

complete blood count

CRP:

C-reactive protein

CTLA-4:

cytotoxic T lymphocyte antigen-4

CVD:

cardiovascular disease

EAM:

extra-articular manifestations

ELISA:

enzyme-linked immunosorbent assay

ESR:

erythrocyte sedimentation rate

FA:

familial autoimmunity

fT3:

free-fraction triiodothyronine

fT4:

free-fraction thyroxine

FNAB:

fine-needle aspiration biopsy

GCs:

glucocorticoids

GD:

Graves’ disease

GO:

Graves’ ophthalmopathy

HLA:

human leukocyte antigen

HT:

Hashimoto thyroiditis

IBD:

inflammatory bowel disease

IFN:

interferon

L-T4:

levothyroxine.

MAS:

multiple autoimmune syndrome

MMI:

methimazole

MS:

multiple sclerosis

NIS:

sodium/iodine symporter

NSAIDs:

non-steroidal anti-inflammatory drugs

PA:

pernicious anemia

PPT:

postpartum thyroiditis

PTPN22:

protein tyrosine phosphatase, nonreceptor type 22

PT:

painless thyroiditis

PTU:

propylthiouracyl

QD:

once per day

QID:

four-times per day

RA:

rheumatoid arthritis

RaIU:

radioactive iodine uptake

SAT:

subacute thyroiditis

SLE:

systemic lupus erythematosus

SLEDAI:

systemic lupus erythematosus disease activity index

SS:

Sjögren syndrome.

SSc:

scleroderma

T1DM:

type 1 diabetes mellitus

T3:

triiodothyrosine

T4:

thryoxine

Tg:

thyroglobulin

TgAb:

thyroglobulin antibodies

TID:

three-times per day

TPO:

thyroperoxidase

TPOAb:

thyroperoxidase antibodies

TRAb:

thyroid stimulating hormone receptor antibodies

TSH:

thyroid stimulating hormone

TSHR:

thyroid stimulating hormone receptor

US:

ultrasonography

VIT:

vitiligo

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