Epidemiology and Natural History

About 5% to 10% of solitary thyroid nodules are toxic. This figure varies from country to country and is higher in Europe.2,3 In nodules with a diameter of less than 2.5 cm, the proportion that are toxic is only 1.9%, whereas in nodules of 2.5 cm or greater, this figure is 42.6%. In a study of patients 60 years and older with AFTNs, 57% were thyrotoxic. In patients younger than 60 years, thyrotoxicity was noted in only 13%. In patients younger than 40 years, only 19.5% had AFTNs with a diameter of 3 cm or larger, but in older patients, this figure was 45.9%.² The proportion of AFTNs that are responsible for the hyperthyroidism of referred patients varies geographically between 1.5% and 44.5% (Table 11-1). About five times more women than men suffer from this disorder.⁴ The natural history of the growth of AFTNs varies. They may stay the same over the years, grow, or shrink. In a group of 159 patients who were observed for 1 to 15 years, an increase in size was seen in 10% and a decrease in 4%.² Changes in function of the nodule over the years also occur. In an observation period of 6 years, 10% of patients with AFTNs became toxic, and loss of function due to degeneration was observed in 4%.² Development of hyperthyroidism occurred predominantly in nodules greater than 3 cm in diameter,³ with a minimal volume of 16 mL by ultrasound.⁵

Pathogenesis

From a histologic point of view, two types of nodules (Figs. 11-1 and 11-2) may be discerned: a monoclonal and a polyclonal type. Studer and his group developed the concept that even if monoclonal at the molecular level, nodules may become polyclonal from a functional and histologic aspect during evolution. They suggest that individual follicular cells may acquire new qualities that were not present in the mother cells but become inheritable during further replication. Obviously this change supposes some sort of genetic event. This sequence of events may lead to loss of anatomic and functional integrity of the follicular cells. The process might be accelerated by stimulatory factors such as TSH (e.g., in iodine deficiency, by goitrogens) and by local stimulatory and growth factors.⁶

At the genetic level, two types of monoclonal autonomously functioning nodules have been reported. Both are somatic mutations. One involves the TSH receptor (TSHR) gene and the other involves the G_sα protein gene. Both mutations lead to constitutive activation of the adenylate cyclase system, probably also activation of the inositol phosphates pathways⁷ in the follicular cell, and to autonomy of the follicle. Mutations of the TSHR gene, and with a much lower prevalence, the G_sα gene, play a major (principal) role in the pathogenesis of AFTN.⁸ For those monoclonal toxic adenomas (TA) in which no mutations are found in the TSHR or G_sα unit, probably other somatic mutations are involved.⁹ In a recent study of 75 hot thyroid nodules, somatic TSH receptor mutations were detected in 57% and G_sα mutations in 3% of the nodules.¹⁰ The same group studied females with AFTN, but without mutations in the TSH-R or G_sα unit, and detected a monoclonal origin in 10 out of 20 of cases when tested for X-chromosome inactivation. This strongly suggests a mutation at other location(s).¹⁰ Although some believe that iodine deficiency can increase mutation rate and functional expression of autonomy¹¹ in AFTN, others¹² consider the fundamental process of goitrogenesis in (multi)nodular goiter as independent from iodine deficiency but operating through mechanisms that are innate to the hereditary and acquired heterogeneity among the thyrocytes themselves. However, superimposed iodine deficiency may shift clinical expression to younger ages. Van Sande and co-workers¹³ hypothesized that as 16 different activating mutations were identified in the TSHR gene, this receptor is in a constrained conformation in its wild-type form. They also report that AFTA have a high level of Na⁺/iodide symporter gene expression, a high thyroperoxidase mRNA and protein content, and a low H₂O₂ generation. Inositol uptake was also increased, but inositol phosphates were not increased. TA secreted more thyroid hormone than the quiescent surrounding tissue. Other characteristics of TA were increased cycling of thyrocytes as compared to normal surrounding tissue, little apoptosis, and low expression of early immediate genes.¹⁴ An important study by Fuhrer and co-workers¹⁵ showed that a panel of different activating TSHR mutations caused different functional and morphologic responses in vitro in rat and human primary thyrocytes. Their data suggest that different biologic properties of the TSHR mutants may result in different in vivo phenotypes. Finally, other mutated genes causing AFTN may be located in the AMP cascade.

Pathology

On macroscopic examination, a solitary toxic nodule is surrounded by normal thyroid tissue that is functionally suppressed. Rarely, a microscopically monotonous picture is seen that consists of uniform follicular cells without signs of malignancy. Usually the picture is heterogeneous with cells of different size, sometimes with signs of fresh and old hemorrhage and calcification. This picture, however, does not exclude a monoclonal origin of the nodule but may be the result of stimulatory local growth factors (see the section entitled “Pathogenesis”). No information is available at present on the exact ratio between primarily monoclonal and polyclonal AFTNs of the thyroid. Sometimes, autonomously functioning micronodules are present in the surrounding thyroid tissue. This finding is in agreement with the thesis of Studer and co-workers⁶ that the true adenoma is one end of a large spectrum of thyroid nodules growing from single thyrocytes or tiny cell families, each replicating with an individual growth rate, whereas the grossly abnormal multinodular goiter is at the other end of the scale.

Clinical Features

The signs and symptoms of patients with toxic adenoma are those of thyrotoxicosis, without the specific signs of Graves’ disease, such as eye signs, pretibial myxedema, and acropachy. On palpation of the thyroid region, a nodule is found in one of the lobes, usually with a diameter of 3 cm or larger.² The thyroid tissue surrounding the nodule and the thyroid lobe on the other side are not usually palpable because of TSH suppression.

Laboratory Diagnosis

When a single nodule is found in the thyroid and the patient is clinically thyrotoxic, estimation of serum TSH is sufficient for the diagnosis of toxic adenoma. To have an idea about the severity of the thyrotoxicosis, estimation of serum free thyroxine (T₄) is sufficient. If this parameter is normal, serum triiodothyronine (T₃) or free T₃ should be determined because it may be solely elevated in minimal thyrotoxicosis, that is, T₃ toxicosis. If findings on palpation are inconclusive, it is wise to perform a scintiscan of the thyroid. In the case of a toxic nodule, activity is seen in the nodule, with minimal or no activity anywhere else in the thyroid region (Fig. 11-3). The presence of a thyroid carcinoma in an AFTN is rare.¹⁶ Although some authors are of the opinion that the occurrence of carcinoma in an AFTN may be more than coincidental,¹⁷ most thyroidologists believe that such is not the case. The differential diagnosis of a toxic nodule includes relapse of hyperthyroid Graves’ disease in remnant thyroid tissue after thyroid surgery or in thyroid dysgenesis. The latter possibility is especially remote. Theoretically, a TSH stimulation test would distinguish between an AFTN and the two other possibilities, but this test is hardly ever necessary in clinical practice. It is of no value to perform fine-needle aspiration cytology of an AFTN, because differentiation between a follicular adenoma and carcinoma is difficult if not impossible with this technique. When a hot nodule is present, that is, prominent uptake in the nodule but less in the surrounding tissue while serum TSH is normal, autonomous function can be tested by performing a T₃ or T₄ suppression test. In the case of autonomous function, uptake in the nodule is still present after the administration of 25 µg T₃ three times daily for 10 days or 125 µg T₄ for 14 days, whereas uptake is suppressed in the surrounding tissue. Sometimes uptake in a single nodule is indistinguishable from uptake in the surrounding tissue, a situation described as a “warm” nodule. This picture may be generated either by normal affinity of the nodular tissue for the isotope or because a nonfunctioning nodule is surrounded by normal thyroid tissue. Thus the possibility of the presence of a carcinoma in a warm nodule is certainly not excluded, which means that it should be evaluated as though it were a cold nodule.

Treatment

No treatment of a hot nodule is necessary as long as the patient remains euthyroid. Regular TSH measurement at intervals of a half to 1 year suffices. Most patients remain euthyroid. Occasionally, a hemorrhage in the nodule leads to spontaneous resolution. Treatment of toxic nodules with antithyroid drugs is useless because after discontinuation of medication, relapse invariably occurs. Three modes of treatment of toxic nodules include nodulectomy, administration of radioactive iodine, and percutaneous injection of alcohol into the nodule. Nodulectomy is very effective in rendering the patient euthyroid and has a low surgical complication rate. Surprisingly, permanent hypothyroidism develops in about 5% of patients, perhaps because of coexistent thyroid disease.2,18 Obviously, the disadvantages of surgery are its operative risks, the residual scar, and its cost, which is high in relation to the other two forms of treatment.

Treatment with radioactive iodine is safe, cheap, and effective. Two reports indicate no risk of posttreatment hypothyroidism 6 months after treatment in a total of 93 patients.19,20 However, when a longer period of follow-up was taken into account in 23 patients, such as 4 to 16.5 years after treatment, hypothyroidism developed in up to 36%.²¹ In another study of 126 patients with autonomously functioning nodules, the percentage of hypothyroidism after a mean period of 10 years was 9.7% when the nodules were hot and 1.5% when toxic.²² In this and the previous study, no relationship was found between the total dose administered, the size of the nodule, and the development of hypothyroidism. However, if thyroid autoantibodies were present, hypothyroidism occurred in 18% of patients and, when absent, in 1.4%.²² It is important that when ¹³¹I is administered, uptake be present only in the nodule and not in the surrounding tissue or in the other lobe, which could occur after pretreatment with antithyroid drugs. To avoid this complication, pretreatment with T₃ or T₄ might be considered. In some patients, typical Graves’ disease has developed months after treatment of a toxic nodule with ¹³¹I. Possibly, antigens released by the ¹³¹I therapy induce or exacerbate an autoimmune response.

The third treatment modality is of rather recent date and involves percutaneous alcohol injection into the nodule. Euthyroidism is achieved in 65% to 85% of patients by 12 months after treatment. Injections are repeated 2 to 12 times at weekly intervals. The treatment is usually well tolerated, with few side effects. When nodule volume exceeds 30 mL, results are less favorable.23,24 All three treatment modalities are acceptable, the choice depending on local circumstances and the patient’s preference. Laser photocoagulation of AFTN is the most recent introduced therapy.²⁵ A recent study showed that its efficacy is comparable to that of ethanol injection, with possibly less ensuing hypothyroidism.²⁴

Incidence

The incidence varies geographically. In 1980, this syndrome accounted for 10% of cases of thyrotoxicosis in Japan but only 3% to 4% in New York City.22,26,27 A random poll showed that silent thyroiditis was uncommon in Argentina, Europe, and the east and west coasts of the United States but occurred more frequently around the Great Lakes and in Canada.²⁸ Patients are usually between 30 and 60 years old, and the female-to-male ratio is 1.5 to 1. Apart from its association with pregnancy, known then as postpartum thyroiditis, the condition is currently rarely diagnosed. Postpartum thyroiditis occurs in 5% to 9% of women in the first year after delivery, especially in those who have circulating autoantibodies against thyroperoxidase.²⁹

Etiology

Silent thyroiditis is an autoimmune lymphocytic thyroiditis, and many patients with this disease have a family history of thyroid disease. Postpartum thyroiditis has been significantly associated with HLA-D3 and HLA-D5.³⁰ Exposure to iodine, such as in the form of amiodarone or lithium, interleukin (IL)-2, interferon, and etanercept has been suggested as an initiating event.^31–33 Silent thyroiditis is associated with other autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, Graves’ disease, primary adrenal insufficiency, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, rubella, and seasonal allergies.^33–38

Pathology

Microscopically, follicles are disrupted, and infiltration of lymphocytes and plasma cells occurs. The infiltration may be focal or diffuse, and sometimes formation of lymphoid follicles is seen. Follicular cells may be cuboidal or, when stimulated by TSH in the hypothyroid phase, columnar. Sometimes Hürthle or Askanazy cells are present. These cells are large and oxyphilic and contain many mitochondria. Thyroid tissue obtained during hypothyroidism or the recovery phase shows regenerating follicles with little colloid. Occasionally, persistent lymphocytic infiltration is observed. Extensive fibrosis may ultimately develop. A few multinucleated giant cells are regularly present.³⁹

Clinical Features

The initial symptoms in 112 patients with 122 episodes of silent thyroiditis have been reviewed.⁴⁰ Characteristically, thyroid pain was absent in all cases. The female-to-male ratio was 1.3 : 1. The mean age (±SD) in females and males was 32 ± 8.5 and 24.9 ± 8.2 years, respectively. Recurrences were uncommon. The symptoms are similar to other causes of thyrotoxicosis and varied from mild to severe. Specific signs that are characteristic of Graves’ disease, such as eye signs, pretibial myxedema, and acropachy, were absent. The mean duration of the toxic phase in these patients was 3.6 ± 2.0 months. In most reports, the thyroid gland had a firm consistency. In about half the patients, a goiter was present. The course of the disease follows four sequential stages: thyrotoxicosis, euthyroidism, hypothyroidism, and euthyroidism. These stages need not be present in all patients. In one series, 57 of 112 patients became euthyroid, and hypothyroidism did not develop. Clinical hypothyroidism was present in only 32 patients. Hypothyroidism was transient in 24 patients but permanent in 8, who required thyroid hormone substitution. Ultimately, about half of the patients with silent thyroiditis become permanently hypothyroid.⁴¹

Laboratory Findings

The acute (first) phase of the disease is characterized by leakage of thyroid hormone and thyroglobulin from the damaged thyroid. This leakage results in elevated serum concentrations of thyroid hormones and thyroglobulin and suppression of serum TSH. Uptake of radioactive iodine by the thyroid is absent in this stage. The C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) are mostly, but not always, slightly elevated. The ESR was elevated in 34 of 53 episodes but higher than 40 mm only in 8.⁴⁰ This result contrasts with subacute thyroiditis, in which the ESR is invariably much more elevated. T₄ and T₃ start to decline in the first phase and reach normal levels in the second (euthyroid) phase, but TSH remains suppressed. In the third (hypothyroid) phase, thyroid hormone levels are subnormal, and serum TSH starts to rise at the end of this stage. Because of TSH stimulation, the fourth stage is characterized by normalization of serum T₄ and T₃. Serum TSH ultimately normalizes, but normalization can take several months, so temporary subclinical hypothyroidism intervenes. For the mean period of the different phases, see Fig. 11-4.