Hyperthyroidism: Toxic Nodular Goiter and Graves’ Disease

Chapter 5 Hyperthyroidism

Toxic Nodular Goiter and Graves’ Disease


Hyperthyroidism refers to thyrotoxicosis caused by the overproduction of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The most common type of thyrotoxicosis encountered in the United States and worldwide is Graves’ disease; toxic nodular goiter (TNG) is the second most common type of thyrotoxicosis.

Goiter is enlargement of the thyroid gland, commonly encountered in clinical endocrine practice. It may be classified as diffuse or nodular and may be either nontoxic or toxic. Nodular goiter may include multiple nodules (i.e., multinodular goiter [MNG]) or a single nodule. Regardless of different possible mechanisms of development, diffuse thyroid enlargement eventually evolves into a nodular stage.1

A TNG is a thyroid gland that contains autonomously functioning thyroid nodule(s), with resulting hyperthyroidism. Also called Plummer’s disease, TNG was first described by Henry Plummer at Mayo Clinic in 1913. In elderly individuals and in geographic areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.

Graves’ disease is the most common type of thyrotoxicosis encountered in the industrialized world. Graves’, disease owes its name to an Irish doctor, Robert James Graves’ who described the first case of goiter with exophthalmos in 1835.2 Patients with Graves’ disease usually have diffuse, nontender, symmetric enlargement of the thyroid gland. Other features of Graves’ disease affecting the eyes and skin will be described in ensuing sections in this chapter.


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.

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.

Diagnostic Evaluation

Thyrotoxicosis is the common feature of both TNG and Graves’ disease. It may be clinical or subclinical. Subclinical hyperthyroidism presents few, if any, mild symptoms in the presence of a suppressed TSH with normal free thyroid hormones (T3 and T4). Early in Graves’ disease, hyperthyroidism may be from preferential T3 secretion, so-called T3 toxicosis.

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).

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

Characteristic Graves’ Disease Toxic Nodular Goiter
Goiter Diffuse Multinodular
—Size Small Large
—Growth Rapid Slow
Patient age, y < 45 > 50
Hyperthyroid onset Rapid Slow
Histologic features Follicles similar, intense iodine metabolism Variable follicular size, shape, and intensity of iodine metabolism

Adapted from Hurley DL, Gharib H: Thyroid nodular disease: is it toxic or nontoxic, malignant or benign? Geriatrics 50:24-26, 29-31, 1995.

Jul 23, 2016 | Posted by in OTOLARYNGOLOGY | Comments Off on Hyperthyroidism: Toxic Nodular Goiter and Graves’ Disease
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