What does a high thyroid stimulating immunoglobulin mean

Thyroid-Stimulating Antibody in the Pathogenesis and Natural History of Graves’ Disease

Historically, the identification of TSAbs as the cause of hyperthyroidism and goiter in Graves’ disease came from the demonstration of a stimulating factor in the sera of hyperthyroid patients with a half-life much longer than that of TSH (LATS).11 Subsequently, this factor was shown to be an autoantibody.135-137 TSAbs were shown to interact with the TSH-R in that they act as a potent agonist and thus cause hyperfunction of the thyroid gland.109 Definitive proof that TRAbs interact with the TSH-R eventually came from studies with the cloned protein. A clear-cut demonstration of the role of TSAb in the pathogenesis of hyperthyroidism is provided by the observation that the transplacental transfer of antibodies from a TSAb-positive pregnant mother to her fetus may cause transient neonatal thyrotoxicosis that vanishes upon the disappearance of TSAb from the serum of the newborn.138

TSAbs are oligo- or pauciclonal, and this observation has suggested a primary defect at the B cell level.109 TSAbs appear to be produced mainly by thyroid-infiltrating lymphocytes and lymphocytes in the draining lymph nodes.139 Synthesis by peripheral blood lymphocytes has been documented as well.140-142 As mentioned above, TSAbs can be detected in more than 90% of patients with untreated Graves’ hyperthyroidism. The observation that a small proportion of hyperthyroid Graves’ patients have undetectable TBIIs or TSAbs has been attributed to the occurrence of these autoantibodies at a serum level too low to be detected by current methods. Alternatively, restricted intrathyroidal production of TRAbs has been hypothesized.143 A positive correlation between TSAb levels and serum triiodothyronine (T3) levels, serum Tg levels, and goiter size has been observed.109

TRAb levels usually fall during long-term treatment with antithyroid drugs.144-146 This phenomenon has been attributed to an immunosuppressive effect of the drugs,147 but it could also result from the correction of thyrotoxicosis or even reflect the natural history of the disease.109,148

Graves’ disease and hashitoxicosis

In Graves’ disease, thyroid stimulating immunoglobulins (TSI) bind to the TSH receptor on the thyroid gland resulting in unregulated production and release of thyroid hormone. Elevated levels of T3 and T4 feedback on the hypothalamus and pituitary resulting in low TSH. The incidence of pediatric Graves’ disease is approximately 0.1–3 per 100,000 (Hanley et al., 2016). While most common among adolescent females, it can occur at any age (Leger et al., 2018).

Children with Graves’ disease are typically symptomatic with one or more of the following features: tachycardia, hypertension, goiter, diarrhea, heat intolerance, emotional lability, anxiety, tremors, hyperactivity, linear growth acceleration, increased appetite, sleep disturbance, weight loss, and worsening school performance (Leger et al., 2018). Interestingly, fatigue is equally common in children with hyperthyroidism and hypothyroidism (Crocker and Kaplowitz, 2010). While approximately 30% of children may have Graves’ related eye disease including eyelid retraction, palpebral edema, and mild inflammation, it is typically less severe than that seen in adults (Leger et al., 2018; Hanley et al., 2016).

Lab findings in Graves’ disease include low TSH, high fT4, high fT3, and positive TRAb or TSI. T3 levels are useful in hyperthyroidism as 13% of children will have relatively normal levels of fT4 with markedly elevated fT3 and total T3 (Leger et al., 2018). Initial treatment is with the antithyroid medication methimazole, as propylthiouracil carries an increased risk of liver failure. The exception to this is during the first trimester of pregnancy, during which propylthiouracil is used due to lower teratogenicity. A beta-blocker may be used in the acute phase for symptom control while waiting for methimazole effect. Graves’ disease remission often requires long courses of methimazole, with approximately 30% of children able to discontinue therapy after 2 years (Leger et al., 2018). Younger age at diagnosis, higher disease severity based on labs, large goiter, poor medication compliance, and shorter duration of initial therapy are associated with decreased remission rates in children (Leger et al., 2018). Definitive therapy with radioactive iodine ablation or total thyroidectomy may be pursued in children who fail to enter remission or have adverse effects related to medical treatment.

While the majority of pediatric hyperthyroidism is due to Graves’ disease, Hashimoto's thyroiditis can also cause hyperthyroidism. Hashitoxicosis occurs when the destruction of thyroid follicles causes increased release of preformed T4 and T3 (Hanley et al., 2016), leading to a hyperthyroidism that is typically milder than Graves’ disease. Hashitoxicosis is transient, lasting 1–6 months (Leger et al., 2018), and affected individuals may require no treatment or simply beta-blockers for symptomatic relief. At resolution, children may be euthyroid or hypothyroid (Wasniewska et al., 2012). While Hashitoxicosis and Graves’ disease are typically considered separate entities, there can be overlap or mixed cases with features of both diseases (Nabhan et al., 2005).

Neonatal Thyrotoxicosis

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Most commonly secondary to transfer of thyroid stimulating immunoglobulins (TSIs) – (also known as thyrotropin receptor stimulating antibodies) from mother with Graves’ disease.

TSIs may continue to be produced even years after thyroidectomy/radioiodine ablation. It is especially important to identify these women in pregnancy as a predictor of possible neonatal problems.

When TSI related, thyrotoxicosis is transient, limited by clearance of maternal Ab.

Pathogenic Mechanisms

Graves’ disease clearly results from the action of TSAbs, primarily via the cAMP pathway, although other signaling pathways may be used by TSHR antibodies in some patients, which suggests a subdivision based on the effector function of these antibodies.109 TSAbs also increase the vascularity of the Graves’ thyroid by enhancing local expression of vascular endothelial growth factor and its receptor.110 In around 15% of patients with Graves’ disease who are treated with antithyroid drugs, hypothyroidism supervenes years later, thus indicating that similar destructive mechanisms operate in Graves’ disease and autoimmune hypothyroidism. These shared pathogenic mechanisms are detailed after consideration of the role of thyroid follicular cells as APCs.

The discovery that thyroid cells express MHC class II molecules in autoimmune thyroid disease, but not under normal circumstances, led to the suggestion that such expression could permit thyroid autoantigen presentation, which in turn could initiate or exacerbate disease.111 It is now clear that thyroid cells generally express class II molecules only after stimulation with IFN-γ, which implies that a T cell infiltrate must precede such expression, so class II expression is a secondary event, and transgenic expression of class II molecules on thyroid cells in mice alone does not induce EAT.112 Furthermore, thyroid cells do not express B7-1 or B7-2 costimulatory molecules and therefore can act as APCs only for T cells that no longer require such co-stimulation, in general those that have been activated previously. In vitro experiments confirm that thyroid cells can act as APCs under such circumstances, but they also are able to induce anergy in naïve T cells that require costimulation113 (see Fig. 81-3). Teleologically, MHC class II expression is likely to be an important means of ensuring peripheral T cell tolerance under normal circumstances, but such expression is damaging under conditions of thyroid autoimmunity (Fig. 81-9). Class II expression is more readily induced by IFN-γ in Graves’ thyroid cells than in those from multinodular goiter, thus suggesting a genetically regulated component to this response.114

Cytokines have a large number of other effects on thyroid cells that might be of pathogenic relevance. As well as adversely affecting thyroid growth and function, a number of immunologically important molecules are expressed by thyroid cells in response to cytokines that are known to be produced locally by the infiltrating leukocytes in Graves’ disease and autoimmune hypothyroidism94 (Fig. 81-10). Expression of ICAM-1, LFA-3, CD40, and MHC class I molecules is enhanced by IL-1, TNF, and IFN-γ, and this response increases the ability of cytotoxic T cells to mediate lysis.94 A complex series of interactions, including secretion of chemokines, is important in allowing lymphocytes to enter the thyroid gland and in some cases to develop tertiary lymphoid structures within the gland.115 Thyroid cell destruction is mediated both by perforin-containing T cells, which accumulate in the thyroid gland,116 and by Fas-dependent mechanisms.117 A unique type of suicide has been suggested by reports that IL-1 β–stimulated thyroid cells in Hashimoto’s thyroiditis express FasL, which could lead to self-ligation with Fas and thus cell death,117 but these findings have not been reproduced consistently, and the final outcome of Fas ligation depends on a complex regulatory pathway that might also involve the death ligand TRAIL.118 Cytokines and other toxic molecules such as nitric oxide and reactive oxygen metabolites probably also contribute directly to cell-mediated tissue injury.

Humoral immunity most likely exacerbates cell-mediated damage in a secondary fashion, both by direct complement fixation (for TPO antibodies) and by ADCC.98,119 These effects occur in addition to the inhibitory effects of TSHR-blocking antibodies on thyroid cell function. Thyroid cells increase their expression of a number of regulatory proteins (CD46, CD55, CD59) in response to cytokines, and these proteins prevent cell death in the face of widespread complement damage in autoimmune thyroid disease.87,120 Nonetheless, a sublethal complement attack, initiated via the classic or alternative pathway, impairs the metabolic function of thyroid cells and induces them to secrete IL-1, IL-6, reactive oxygen metabolites, and prostaglandins, all of which could enhance the autoimmune response.121 As well as T and B cells, dendritic cells and monocytes/macrophages accumulate in the thyroid gland, where they presumably play a major role as APCs that are capable of providing costimulatory signals. Phenotypic abnormalities in the plasmacytoid dendritic cell population have been detected in patients with thyroid autoimmunity, suggesting that these cells may also contribute to the underlying pathogenic immunoregulatory defect.122 An additional group of inflammatory cells, namely, NK-like T cells, has been identified in the thyroid infiltrate, in turn suggesting a role for lipid-containing molecules in thyroid autoimmunity.123

Activation by Autoantibodies

Autoantibodies found in Graves’ disease and some types of idiopathic myxedema can stimulate (TSAb) or block (TSBAb) TSH receptor, respectively (see Chapters 81 and 82Chapter 81Chapter 82). Epitopes recognized by TSAbs are being identified from precise mapping of binding site of murine or human monoclonal antibodies endowed with TSAb activity on the partial crystal structure of the ectodomain92 or models thereof.131 However, the actual mechanisms implicated in activation of the receptor by TSAbs (and by TSH) are still unknown. Although most TSAbs do compete with TSH for binding to the receptor,132,133 and despite similarity in interaction surfaces,92 the precise targets of the hormone and autoantibodies are likely to be different, at least in part. It has indeed been shown that sulfated tyrosine residues, which are important for TSH binding, are not implicated in recognition of TSH receptor by TSAbs.134 Also, contrary to TSH, most TSAbs from Graves’ patients display a delay in their ability to stimulate cAMP accumulation in transfected cells.44,135 The availability of TSAb preparations purified from individual patients should allow to explore these issues in a direct fashion.

Graves' Disease

Graves' hyperthyroidism is caused by autoantibodies to the receptor for TSH (TSI). These autoantibodies cause continuous production of thyroid hormone, and the thyroid is unresponsive to normal inhibitory feedback mechanisms (i.e., it is nonsuppressible). Imaging of the thyroid in Graves' disease reveals a diffusely enlarged gland with uniformly increased accumulation of tracer throughout both lobes (Fig. 2). The 24-h uptake value is elevated, often in the range of 60–80%. Visualization of the pyramidal lobe is more common in cases of autoimmune thyroid disease, perhaps due to increased stimulation of otherwise minimally functioning remnant tissue, and it is seen in more than 50% of patients.

Pathobiology

The proximate cause of hyperthyroidism in Graves’ disease is the production of thyroid-stimulating immunoglobulins (autoantibodies) that bind to and activate the TSH receptor, promoting thyroid hormone secretion and growth of the thyroid gland. Thyrotropin (TSH) receptor antibodies of the stimulating variety are the hallmark of hyperthyroidism in Graves’ disease. Other thyroid autoantibodies commonly identified in the setting of Graves’ disease include antithyroid peroxidase antibodies, antithyroglobulin antibodies, and anti-TSH receptor antibodies that block TSH binding. The fundamental pathogenesis of Graves’ disease remains unknown. A genetic predisposition is implicated by a higher incidence in monozygotic twins and first-degree relatives of affected individuals. Environmental factors implicated in triggering the onset of Graves’ disease include exposure to cigarette smoke, high dietary iodine intake, stressful life events, and certain antecedent infections.

Thyroid Stimulation and Regulation

The histologic picture of the thyroid gland during pregnancy is one of active stimulation. Columnar epithelium can be seen lining hyperplastic follicles.97 The increase in maternal production that occurs during normal gestation is most evident from clinical observations of thyroxine-replaced hypothyroid women who require a 25% to 40% dosage increase to maintain normal serum TSH levels in pregnancy.79,98 Furthermore, findings of relative hypothyroxinemia and slightly increased serum TSH levels during pregnancy in women from areas of borderline iodine sufficiency (<100 mcg/day) support the view that pregnancy constitutes a stress for the maternal thyroid gland by stimulating thyroid hormone production.99

Several factors are known to tax gravid thyroid economy, and each may have relative importance at a different time in gestation. In early pregnancy, the serum concentration of TBG increases rapidly, and more thyroid hormone is needed to saturate binding sites. Glomerular filtration rate increases, resulting in increased iodide clearance. Later, with placental growth, metabolism of T4 to its inactive metabolite rT3 is increased by the high levels of placental type III deiodinase.100 In addition, transplacental passage of maternal T4 occurs.101 Finally, alterations in the volume of distribution of thyroid hormone may occur because of both gravid physiology and the fetal/placental unit.

International Brand Names

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Based (Taiwan); Danantizol (Argentina); Metimazol (Finland); Strumazol (Belgium, Netherlands); Tapazol (Brazil, Venezuela); Tapazole (Canada, Philippines); Thacapzol (Sweden); Thiamazol (Austria, Germany, Russia); Thycapzol (Denmark); Thyrozol (Bulgaria, Germany, Russia); Tirodril (Germany); Unimazole (Greece)

Etiology

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Graves disease is an autoimmune condition caused by production of immunoglobulin G (IgG) thyroid‐stimulating immunoglobulins (TSIs).

The antibodies bind to the thyroid‐stimulating hormone (TSH) receptors on the thyroid gland and stimulate production of thyroid hormones and stimulate thyroid growth.

Hyperthyroidism occasionally is caused by a hyperfunctioning thyroid nodule (i.e., adenoma), McCune‐Albright syndrome, exogenous thyroid ingestion, or a TSH‐secreting adenoma (rare).

“Hashitoxicosis” is transient hyperthyroidism associated with Hashimoto's thyroiditis, presumably caused by release of preformed thyroxine during autoimmune thyroid destruction.