Plummers Disease Toxic Multinodular Adenomatous Goiter

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Toxic multinodular goiter was first described in 1913 by Dr. Henry Plummer (see Fig. 7-2), who believed that practically all adenomatous goiters would eventually become toxic given enough time. He noted that the average interval from first detection of the goiter to subsequent development of symptoms was 15 years.45,46


Nodular goiters (Fig. 7-8A) occur when hyperplasia of a small subset of follicular cells with abnormal growth potential occurs at multiple sites in the thyroid gland.10 In contrast with Graves' disease, where the thyroid follicular cells are hyperfunctional due to an external factor, IgG, which binds to and stimulates the TSH receptor, autonomous thyroid nodules develop hyperfunction through alterations in the cell biology of the follicular cell, possibly via a somatic mutation constitutively activating cAMP.47 The development of toxic multinodular goiter is a gradual process, as Plummer noted that goiters were present an average of 17 years before becoming toxic.45,46 Plummer's disease occurs when one or more thyroid nodules become autonomous, trap and organify more iodine, and secrete more thyroid hormone independently of control by TSH stimulation.44 In the remainder of the gland, the normal feedback mechanism is operative.11 As the adenomatous areas grow, their contribution to thyroid secretion increases and TSH secretion, therefore, decreases. This decrease in TSH results in decreased activity of the extranodular tissue. One or more follicles in a diffuse goiter has greater intrinsic growth and functional capability than the others and continues to grow and function despite declining TSH secretion, causing initially a nontoxic multinodular goiter and, ultimately, a toxic multinodular goiter 48 There is a gradual evolution of a sporadic diffuse goiter to a toxic one.

A multinodular goiter occurs due to recurrent episodes of hyperplasia and involution and is considered toxic if it

Adenomatous Goiter With Cystic Change

FIGURE 7-8. Toxic multinodular goiter (Plummer's disease). A, Patient with a multilobulated, asymmetrically enlarged thyroid gland, fi, The gland is inhomogeneous and coarsely nodular with areas of fibrosis and cystic change. C, Focal regions of increased 99mTc uptake on radionuclide scan revealing multiple functioning thyroid nodules with suppressed uptake in surrounding tissue. (B from Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid. In: Manual of Endocrine Surgery, 2nd ed. New York, Springer-Verlag, 1984.)

FIGURE 7-8. Toxic multinodular goiter (Plummer's disease). A, Patient with a multilobulated, asymmetrically enlarged thyroid gland, fi, The gland is inhomogeneous and coarsely nodular with areas of fibrosis and cystic change. C, Focal regions of increased 99mTc uptake on radionuclide scan revealing multiple functioning thyroid nodules with suppressed uptake in surrounding tissue. (B from Edis AJ, Grant CS, Egdahl RH: Surgery of the thyroid. In: Manual of Endocrine Surgery, 2nd ed. New York, Springer-Verlag, 1984.)

induces thyrotoxicosis. These multinodular goiters produce the most extreme enlargement of the thyroid, up to 2 kg, and are multilobulated and asymmetrically enlarged.19 Most "hot" or "autonomous" nodules have either TSH receptor mutations (most often) or gsp (less common) mutations.44 There is no correlation between morphology and function of the nodules.10 In contrast to the thyroid in Graves' disease, which is soft and resembles muscle, the thyroid in Plummer's disease on cut section has irregular nodules containing brown, gelatinous colloid.19 It most commonly occurs in areas of endemic goiter.44

Clinical Manifestations

Plummer's disease is more common than Graves' disease in elderly patients. It accounts for 15% of cases of hyperthyroidism in nonendemic goiter regions.10 The hyperthyroidism may be caused by multiple hyperfunctioning nodules or, less frequently, a single hyperfunctioning nodule. It is differentiated from Graves' disease in that extrathyroidal manifestations and thyroid autoantibodies are not present.20'44 Approximately 80% of patients with multinodular goiter are chemically euthyroid at initial presentation.10 Patients are more likely to have a prolonged course with weight loss, depression, atrial fibrillation, and muscle wasting than with Graves' disease and thyrotoxicosis is often less obvious and easily missed.20 When it presents in the young, thyrotoxicosis is seen as weight loss, anxiety, tremor, insomnia, and heat intolerance, similar to Graves' disease.28 Atrial fibrillation in the setting of an enlarged goiter is often the only finding in the elderly.44 Symptoms of dysphagia, hoarseness, dyspnea, stridor, and cough may indicate a retrosternal or intrathoracic multinodular goiter.10 It is important to monitor T3 carefully because these patients are more likely to have T3 toxicosis, with high serum free T3 and normal free T4 concentrations. This may be due to limited ability of the nodules to oxidize iodide or may be due to their preponderance in areas of relatively low iodine intake. On examination, the goiter has one or more palpable nodules. Compressive symptoms such as dysphagia or dyspnea may be present. Thyrotoxicosis may be exacerbated following iodine-containing contrast media, leading to the Jodbasedow phenomenon.28 Toxic multinodular goiter accounts for less than 5% of cases of thyrotoxicosis in iodine-sufficient areas but nearly half of cases in relatively iodine-deficient areas. Many patients have subclinical thyrotoxicosis with few, if any, symptoms and signs of thyrotoxicosis and normal thyroid hormone levels, but others have overt thyrotoxicosis. The incidence of thyroid cancer coexisting with multinodular goiter approaches 10%, similar to that in patients with a solitary thyroid nodule. Coexistent cancer is more common with nonfunctioning nodules and in men.10


Patients with toxic multinodular goiter present with increased T3 but a normal T4 and free T4 index (T3 thyrotoxicosis). A thyroid scintiscan (Fig. 7-8B) classically reveals one or more areas of increased uptake and suppressed areas in between. The hot nodules are identified as areas concentrating radioactive iodine to a greater degree than the surrounding thyroid tissue. Technetium pertechnetate is preferred over radioiodide scanning and is useful in the differentiation of toxic nodular goiter from Graves' disease or to evaluate compressive symptoms.10 However, iodine is the preferred imaging agent for a toxic goiter with a substernal component due to its higher energy photons.47

Autonomous function of the nodules can be demonstrated by administering suppressive doses of T3, which does not affect the function of the nodule but decreases the uptake of the extranodular tissue. Administration of TSH increases or restores the radionuclide uptake in the quiescent tissue.48 In contrast with Graves' disease, administration of exogenous T3 or T4 does not suppress the function of autonomous nodules because their secretory activity is, by definition, independent of stimulation with pituitary TSH. In addition, the secretions of the autonomous nodules suppress pituitary TSH, causing variable reduction of the function of the extrathyroidal tissue.


Similar to treatment of Graves' disease, there are three major classes of therapy: antithyroid medications, radioactive iodine ablation, and subtotal or near-total thyroidectomy. Antithyroid medications have not been widely accepted in the treatment of Plummer's disease because they are less effective and lifetime therapy would be necessary since, unlike the usual spontaneous remission of Graves' disease, the hyperthyroidism of toxic multinodular goiter continues indefinitely.20-44 Their use is recommended only as adjunctive when needed for the initial control of hyperthyroidism.10 As with Graves' disease, prior to surgery, patients should be rendered euthyroid with (3 blockers and thionamides.28 Lugol's solution, in contrast with Graves' disease, should be avoided in pretreatment of Plummer's disease because it may significantly worsen thyrotoxicosis.47

Radioactive iodine therapy is inferior to its role in Graves' disease because the toxic multinodular goiter often persists after therapy.44 The goal of radiation therapy in Plummer's disease is destruction of autonomous tissue and restoration of euthyroidism.49 Erickson and associates evaluated medical records of 253 patients treated for toxic multinodular goiter between 1975 and 1993.50 Of those treated with radioactive iodine, 20% required a second treatment, compared to zero patients treated with surgery. A latency of several months occurs before treatment is effective. In the report by Erickson and associates, half of surgically treated patients had achieved success within 3 days for surgical treatment versus 3 months for radioactive iodine treatment.50 Similar results were found in a report by Jensen and colleagues, who evaluated the records of 446 patients treated between 1950 and 1974.51

The dose of radioactive iodine is variable, and several doses may be needed. Uptake is often relatively low, necessitating high doses to almost twice those given to Graves' patients for successful treatment. Uptake is localized to the autonomous toxic nodules and the remaining thyroid tissue is suppressed.44 The thyroid tissue adjacent to the thyroid nodule receives about 2000 rads, which is in the carcinogenic range for the surrounding normal tissue, enough to induce subsequent thyroid cancer. Radioactive iodine therapy in large multinodular goiters extending substernally puts patients at risk for radiation-induced thyroiditis that can, although rare, cause acute thyroid enlargement and airway compression.28

A follow-up study assessed solitary autonomous thyroid nodules treated with iodine.52 In this study of 23 patients, 54% of nodules were still palpable, 9% had increased in size, and 36% were hypothyroid. Goldstein and Hart concluded that iodine does not eradicate the nodule. The incidence of hypothyroidism in that study was not related to gland size, thyroid function, or total dose of radiation. Radioactive iodine is an effective therapy for hyperthyroidism caused by a single hot nodule, since the suppressed normal extranodular tissue should be protected via its inability to concentrate radioactive iodine. It is also suitable for patients with mild hyperthyroidism or those considered at high risk for surgical management.50

A recent study suggests that patients treated with high doses of 13II, such as those needed for Plummer's disease, may have xerostomia and xerophthalmia that persist for several years after therapy.53 Seventy-nine patients were treated between 1990 and 1995 with a dose ranging from 25 to 100 mCi. The numbers of patients who reported xerostomia 1, 2, and 3 years after therapy were 33%, 20%, and 15%, respectively. The most common symptoms were dry mouth and abnormal taste; oral ulcers and sialadenitis were also reported. One explanation is that salivary glands and lacrimal tissue have sodium-iodide transporters. Induction of an autoimmune lacrimal gland dysfunction, similar to that in Sjogren's syndrome, may also occur.

For these reasons, surgery is the treatment of choice in Plummer's disease, particularly if patients have obstructive symptoms or if there is concern of carcinoma in the goiter. Surgery is immediate and certain, there is a low recurrence rate, and the patient is freed from the large goiter volume and its associated cardiac manifestations. The surgical approach varies depending on the type of nodule.28 For solitary nodules, nodulectomy or thyroid lobectomy is the treatment of choice because cancer is rare. For toxic multinodular goiter, lobectomy on one side and subtotal lobectomy on the other side is recommended in most cases to prevent the need for bilateral reoperation in cases of recurrence.54 The approach and precautions are similar to the surgical management of Graves' disease.

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