Toxic Nodular Goiter

TNG is the most frequent cause of thyrotoxicosis in the elderly. It accounts for about 5% to 15% of patients with endogenous hyperthyroidism, but the proportion is higher in iodine-deficient geographic regions.^2,3 Changes in the iodine content of salt and in the iodine supplementation of water have been linked to changes in the incidence of TNG. In Switzerland in 1980 and in Spain in 1994, the iodine content of salt was increased, and this was associated with a transient increased incidence of thyrotoxicosis followed by decreased incidence, mainly the result of reduced TNG incidence.^4,5

Graves’ Disease

Being the most common cause of thyrotoxicosis in all age groups, Graves’ disease accounts for 70% to 80% of endogenous hyperthyroidism. The incidence of Graves’ disease is five times higher in females than in males, occurring generally during women’s reproductive years, although it may occur at any age.²

Toxic Nodular Goiter

The natural history of a nontoxic MNG involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of thyrotropin or thyroid-stimulating hormone receptor (TSHR) in 20% to 80% of toxic adenomas and some nodules of MNGs.⁶ Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism predominantly occurs when single autonomous nodules are larger than 2.5 cm in diameter. However, in geographic areas with iodine deficiency, smaller autonomous nodules may produce systemic, clinical manifestations of hyperthyroidism.⁷

The development of hyperthyroidism in MNG takes many years. The process evolves from a small gland with one small nodule or more to nodules increasing progressively in number, size, and function. Initially, most patients are euthyroid, but with enlarging goiters, autonomy develops, illustrated by low or suppressed serum thyroid-stimulating hormone (TSH) with normal serum levels of thyroid hormones. As shown in Figure 5-1, a state of subclinical hyperthyroidism with low TSH but normal free T4 and free T3 levels may exist for years before progression to clinical hyperthyroidism.

Figure 5-1 The evolution of hyperthyroidism in multinodular goiter, a process that often takes years, associated with an increase in the number, size, and function of nodules. Transition from a euthyroid (Eu) state (normal thyroid-stimulating hormone [TSH], free thyroxine [FT4], and free triiodothyronine [FT3]) to subclinical hyperthyroidism (SCH) (low TSH, normal FT4 and FT3) to clinical hyperthyroidism (Hyp) (low TSH, elevated FT4 and FT3). NL indicates the normal range.

(Adapted from Studer H, Peter HJ, Gerber H: Toxic nodular goitre. Clin Endocrinol Metab 14:351-372, 1985.)

Graves’ Disease

Graves’ disease is a syndrome that consists of hyperthyroidism, goiter, ophthalmopathy (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. Hyperthyroidism is the most common feature of Graves’ disease, affecting nearly all patients, and is caused by autoantibodies to the TSHR (TSHR-Ab) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter).

The histology of the thyroid gland in patients with Graves’ hyperthyroidism is characterized by follicular hyperplasia, a patchy (multifocal) lymphocytic infiltration, and rare lymphoid germinal centers. The majority of intrathyroidal lymphocytes are T cells, and germinal centers (B cells) are much less common than in chronic autoimmune thyroiditis (Hashimoto’s disease). Thyroid epithelial cell size correlates with the intensity of the lymphocytic infiltrate, suggesting thyroid cell stimulation by local B cells secreting TSHR-Ab.⁸ The presence of these antibodies is positively correlated with active disease and with relapse of the disease. There is an underlying genetic predisposition, because of an increased frequency of haplotypes human leukocyte antigen (HLA)-B8 and HLA-DRw3 in white patients, HLA-Bw36 in Japanese patients, and HLA-Bw46 in Chinese patients with the disease. However, it is not clear what triggers the acute episodes. Some factors that may incite the immune response are pregnancy, particularly the postpartum period; iodine excess, particularly in geographic areas of iodine deficiency; lithium therapy; viral or bacterial infections; and glucocorticoid withdrawal.

The etiology and pathogenesis of Graves’ ophthalmopathy are not known. It may involve cytotoxic lymphocytes and cytotoxic antibodies sensitized to a common antigen in orbital fibroblasts, orbital muscle, and thyroid tissue, which may cause inflammation, resulting in proptosis of the globes. It has been suggested recently that TSHR-bearing circulating fibroblasts and fibrocytes may be activated directly by the TSHR-Ab.⁹ The pathogenesis of dermopathy may also involve this mechanism. Patients with exophthalmos and particularly those with dermopathy almost always have high titers of circulating TSHR autoantibodies, suggesting that these two clinical manifestations represent the most severe form of this disease.

History and Physical Examination

The clinical presentation ranges from no symptoms and a suppressed sensitive serum TSH level to overt or obvious clinical hyperthyroidism. The latter includes symptoms associated with increased adrenergic tone and resting energy expenditure and other hormonal effects. Features related to increased adrenergic tone include nervousness, tremor, increased frequency of defecation, palpitations, diaphoresis, irritability, insomnia, headaches, lid retraction and lid lag, muscle weakness, tachycardia, hyperreflexia, and widened pulse pressure. Those related to increased energy expenditure include heat intolerance, unintentional weight loss without anorexia, and warm, moist skin. In elderly subjects, the presentation may be subtle, with atrial fibrillation, weight loss, weakness, and depression.¹⁰

Goiter may be detected in patients with either TNG or Graves’ disease. Nodular irregularity is characteristic of TNG, whereas Graves’ disease is more typically diffuse, soft, and rubbery and may have an overlying thyroid region bruit. Patients with Graves’ disease often have a goiter, may present with hyperthyroidism alone, or may have one or more extrathyroidal manifestations. Clinically apparent eye disease may occur in up to a third of patients with Graves’ disease, but orbital CT may detect changes in a majority of patients. Signs of eye disease include proptosis or exophthalmos, lid lag and retraction, and impaired extraocular muscle function. Eye symptoms and signs generally begin about 6 months before or after the diagnosis of Graves’ disease. It is generally uncommon for eye involvement to develop after the thyroid disease has been successfully treated. There is great variability, however, and in some patients with eye involvement, hyperthyroidism may never develop. The severity of eye involvement is not related to the severity of hyperthyroidism. Early signs of eye involvement may be red or inflamed eyes. Ultimately, proptosis may develop from the inflammation of retro-orbital tissues. Diminished or double vision is a rare problem that usually occurs later. It is not well known why, but problems with the eyes occur much more often in people with Graves’ disease who smoke cigarettes than in those who do not smoke.

Other features of Graves’ disease include onycholysis, acropachy, and pretibial myxedema (Figure 5-2). Pretibial myxedema is a rare, reddish lumpy thickening of the skin of the shins. This skin condition is usually painless and is not serious. Like the eye disorders of Graves’ disease, the skin manifestation does not necessarily begin precisely when hyperthyroidism starts. Its severity is not related to the level of thyroid hormones. It is not known why this problem is usually limited to the lower leg or why so few people have it. Occasionally symptoms related to the mass effect of a large goiter may occur. Very large goiter may extend retrosternally or substernally, resulting in symptoms and signs of tracheoesophageal pressure. These may include dysphagia, cough, and choking sensation or stridor, particularly if severe tracheal narrowing exists. The development of facial plethora, cyanosis, and distention of neck veins with raising both arms simultaneously may result from deep goiter compression of the structures located within the bony confines of the thoracic inlet (Pemberton sign).

Figure 5-2 Extrathyroidal manifestations of Graves’ disease: ophthalmopathy (A), pretibial myxedema or Graves’ dermopathy (B), and acropachy (C).

Common and important clinical differences between Graves’ disease and TNG are summarized in Table 5-1.

Table 5-1 Clinical Differences between Graves’ Disease and Toxic Nodular Goiter

Laboratory Evaluation

Diagnosis is always established by the measurement of sensitive TSH and thyroid hormone levels (free T3 and free T4). Thyrotoxicosis caused by TNG or Graves’ disease is usually characterized by a suppressed TSH level with either normal (subclinical) or elevated (overt) free thyroid hormone levels. It is insufficient to rely on the measurement of TSH or free thyroid hormones alone to diagnose TNG or Graves’ disease, because suppression of TSH or elevation of thyroid hormones can be associated with clinical conditions other than TNG and Graves’ disease (Table 5-2). Other serologic findings, such as antithyroid antibodies (antithyroid peroxidase and antithyroglobulin), that support the diagnosis of autoimmune thyroid disease may be detected in patients with Graves’ disease. However, serum TSHR-Ab is occasionally helpful in the diagnosis of Graves’ disease, though there is no consensus regarding its routine measurement in Graves’ disease.

Table 5-2 Clinical Conditions Associated with Abnormal TSH and High Free Thyroid Hormone without Toxic Nodular Goiter or Graves’ Disease

Imaging

Radionuclide Imaging

Radionuclide scanning and radioactive iodine uptake (RAIU) are useful tests to elucidate the cause of hyperthyroidism. In TNG, the radioactive iodine (RAI) concentration is in the nodule(s), and uptake is inhibited in the surrounding tissue, giving the appearance of “patchy uptake” (Figure 5-3). Consequently, the total RAIU may be either slightly raised or at the upper limit of normal. In Graves’ disease, because of diffuse thyroid involvement, the RAIU is always intense and increased (Figure 5-4). Thyroid radionuclide imaging may not be necessary in every case when the diagnosis is obvious, but it is helpful in the differentiation of other clinical conditions associated with hyperthyroidism but with low RAIU (Table 5-3).

Figure 5-3 Radionuclide scan of toxic nodular goiter demonstrating intense focal uptake of several hot nodules with different degrees of suppression of adjacent thyroid tissue (A) compared with the scan from a patient with nontoxic multinodular goiter, showing less intense patchy radioactive iodine uptake (B).

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