D

Figure 1-16. Graves' disease can usually be differentiated from other causes of thyrotoxicosis by the presence of extrathyroidal manifestations. A, Early pretibial myxedema. (Note the confluency of the violacious pigmented lesions often mistaken for insect bites.) B, Advanced pretibial myxedema. (Note the chronicity evident by the appearance of raised indurated plaques.) C, Acute red eye as part of Graves' ophthalmopathy. (Note the scleral injection and periorbital edema that is partly caused by the inflammation and partly by the proptosis of the eyeball.) D, Thyroid acropachy is a rare extrathy-roidal manifestation of Graves' disease that results from subperi-osteal bone formation and swelling. Reproduced with permission from Clark OH. Endocrine surgery of the thyroid and parathyroid glands. St. Louis: Mosby; 1985.

about 3% of patients to a potentially fatal agranulocytosis in about 0.5% of the patients. A white blood cell count must be obtained in any patient who develops fever or sore throat while taking thionamides. Iodides inhibit organic binding and block hormone release. They are valuable in preparing patients for surgery and for patients with thyroid storm. Propranolol suppresses the exaggerated sympathetic response in patients with hyperthyroidism and reduces the peripheral conversion of T4 to T3. When used preoperatively, it is reported to reduce the vascularity of the thyroid gland. Glucocorticoids can also be used to decrease the peripheral conversion of T4 to T3.

Figure 1-17. A radionuclide scan shows diffusely increased uptake in Graves' disease.

are stopped. Medical treatment is therefore usually recommended for patients with small goiters and for preparing patients for definitive thyroablative therapy by surgery or RAI.

Thionamide derivatives such as propylthiouracil or methimazole (Tapazole) medications inhibit the thy-roperoxidase enzyme and decrease thyroid hormone formation. They become effective 1 to 2 weeks after initiating therapy. Side effects of these antithyroid medications may occur soon after initiating treatment and range from mild hypersensitivity with skin rash in

Surgical Treatment

Prior to any surgical operation, patients must be rendered euthyroid, preferably using a thionamide medication. An iodide preparation should be administered beginning 10 days prior to thyroidectomy to decrease the vascularity of the gland (Figure 1-19). Some surgeons recommend only iodide or propranolol to prepare patients for thyroidec-tomy. This treatment should be done for 10 to 14 days preoperatively. We recommend thyroidectomy for the following:

• Patients with local compressive symptoms

• Patients with coexistent malignancy or suspicious thyroid nodules

Figure 1-18. Toxic adenoma (Plummer's disease) is suspected in thyrotoxic patients who have prominent thyroid nodules and no extrathyroidal manifestations. A, Classic appearance of a toxic adenoma on nuclear scanning as a hot nodule with a suppressed contralateral lobe. B, Gross appearance of a bivalved toxic adenoma in the center of the thyroid gland. Note the very vascular and well-demarcated nodule.

Figure 1-18. Toxic adenoma (Plummer's disease) is suspected in thyrotoxic patients who have prominent thyroid nodules and no extrathyroidal manifestations. A, Classic appearance of a toxic adenoma on nuclear scanning as a hot nodule with a suppressed contralateral lobe. B, Gross appearance of a bivalved toxic adenoma in the center of the thyroid gland. Note the very vascular and well-demarcated nodule.

Figure 1-19. Graves' disease glands are usually very vascular. This vascularity decreases when patients are treated with antithyroid medications, p-blockers, and iodide preparations.

• Pregnant women not easily controlled on low doses of antithyroid medications

• Patients with large goiters or low uptake

• Patients who need rapid remission

• Patients who are noncompliant or who developed serious side effects from medical treatment

For pregnant patients, thyroidectomy should be done during the second trimester and RAI must be avoided. Women who wish to get pregnant within a year of treatment are also best treated by surgery.

Many, but not all, experts recommend total thy-roidectomy for patients with severe ophthalmopathy

Figure 1-20. The thyroid gland from a 13-year-old adolescent girl suffering from Graves' disease reveals diffuse symmetric enlargement. The dark appearance is secondary to increased vascularity within the substance of the thyroid gland. This patient failed medical therapy and underwent a successful near-total thyroidectomy.

Figure 1-20. The thyroid gland from a 13-year-old adolescent girl suffering from Graves' disease reveals diffuse symmetric enlargement. The dark appearance is secondary to increased vascularity within the substance of the thyroid gland. This patient failed medical therapy and underwent a successful near-total thyroidectomy.

or associated malignancy (Figure 1-21) and for patients who have had a life-threatening complication from medications or their Graves' disease. For most patients, we prefer the Hartley-Dunhill operation, in which a total lobectomy is performed on one side and a subtotal lobectomy is performed on the contralateral side. The size of the remnant is around 4 to 5 g in adults and 2 to 3 g in children to avoid recurrence. A euthyroid state is achieved in 50% of adult patients. The incidence of hypothy-roidism depends on the size of the thyroid remnant, the length of follow-up, and the definition of hypothyroidism. Unfortunately, there are no other reliable predictors of recurrent hyperthyroidism or progression to hypothyroidism. The complication rate of total or subtotal thyroidectomy should not exceed 2%, including hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, and the less significant complications such as wound infection and keloid formation.

Radioactive Iodine Ablation

RAI is the most frequently used treatment in the United States for adult patients with Graves' disease.

Figure 1-21. Photomicrograph shows a focus of malignancy (arrows) in a patient with Graves' disease. Hyperplastic tall columnar epithelial cells with basal nuclei line the follicles with some papillary infoldings. Although not very prominent in this case owing to preop-erative treatment, the scalloped pattern at the edge of the colloid is the result of active reabsorption of colloid. A focus of papillary thyroid carcinoma is seen in the left upper corner. These occult tumors are thought to be of little clinical significance. However, patients who present with thyroid cancer and Graves' disease may have more aggressive tumors (hematoxylin and eosin; x40 original magnification).

Figure 1-21. Photomicrograph shows a focus of malignancy (arrows) in a patient with Graves' disease. Hyperplastic tall columnar epithelial cells with basal nuclei line the follicles with some papillary infoldings. Although not very prominent in this case owing to preop-erative treatment, the scalloped pattern at the edge of the colloid is the result of active reabsorption of colloid. A focus of papillary thyroid carcinoma is seen in the left upper corner. These occult tumors are thought to be of little clinical significance. However, patients who present with thyroid cancer and Graves' disease may have more aggressive tumors (hematoxylin and eosin; x40 original magnification).

It is preferred in older patients with moderate hyperthyroidism and small or moderate-size (< 50 g) goiters. As mentioned, RAI is contraindicated in pregnant or lactating women, in children, and in patients with large retrosternal goiters. About 20% of patients require a second dose to control their disease depending on the initial dose administered. For most patients with Graves' disease, the choice between surgery and RAI depends on the advantages and disadvantages of each treatment. Several issues need to be considered in making this choice. RAI has a 6-week to 3-month latency before the patient becomes euthyroid; during this time, patients must continue to receive medical therapy. It is important to prevent hypo- or hyperthyroidism post-RIA in patients suffering from Graves' eye disease because both of these states lead to worsening of the Graves' oph-thalmopathy. In patients with clinically apparent eye disease, glucocorticoid administration should be used prior to treatment with RAI or surgery. Initially, the percentage of patients who develop hypothyroidism after RAI treatment depends primarily on the dose used. Some patients may develop transient hypothyroidism 2 months post-RAI. In most reports, about 50% will develop permanent hypothyroidism within 1 year. The remaining patients develop hypothyroidism at a rate of 2 to 3% per year over the following years, with a 70% incidence at 10 years. Eventually, almost all patients develop hypothyroidism after treatment with RAI.

Treatment of Ophthalmopathy

Clinically detectable ophthalmopathy is seen in a third of patients with Graves' disease, but, luckily, only about 1 to 5% develop severe ophthalmopathy. When questioning the patient, it is important to determine whether the eyes are worse in the morning on awakening or at night. For the former, one should elevate the head of the bed, tape the eyes shut while sleeping, and apply methylcellulose eye drops. For the latter, one should avoid irritants such as smoking, wind, and sunshine. Eye drops are again useful. In some patients, a diuretic may be used to decrease the swelling. Lateral tarsorrhaphy is helpful in some patients with Graves' ophthalmopathy who have exophthalmos. Protecting the cornea from dryness and relieving eye discomfort is essential. In patients with severe inflammation, prednisone may be used alone or in combination with cyclosporine. Retrobulbar external irradiation (2,000 rad) over a period of 2 to 3 weeks may help during the acute phase. Patients who develop signs of optic nerve compression or strabismus may require retrobulbar corrective surgery.

Thyrotoxic Storm

Thyrotoxic storm is an uncommon but life-threatening complication of Graves' disease in which there is an exaggerated autonomic and systemic response. Patients present with high fever, hypotension, marked weakness, altered mentation, cardiovascular collapse, and shock as a result of failure to regulate vital functions in a state of extreme hypermetabolism. Precipitating factors include diabetic ketoacidosis, infection, and trauma, including surgery in untreated patients with Graves' disease. Thyroid hormone levels are elevated, and a radioiodine scan is likely to show very high tracer uptake. Management includes

• treatment with intravenous fluids, oxygen, and rapid cooling with a cooling blanket in an intensive care unit. Aspirin should not be used because it decreases binding of proteins to thyroid hormone.

• treatment with an iodide preparation such as ipo-date sodium that decreases thyroid hormone secretion.

• propylthiouracil, which is superior to methima-zole because it prevents the peripheral conversion of T4 to T3.

• intravenous or oral propranolol, which can block the sympathetic response and prevent peripheral conversion of T4 to T3.

• glucocorticoids, which should be used to prevent adrenal exhaustion and block the conversion of T4 to T3.10

Multinodular Toxic Goiter (Plummer's Disease)

Hyperthyroidism may be attributable to one or more autonomous functioning thyroid nodules. If the nodules are of sufficient size to secrete excessive levels of T3 and T4, the remaining gland will be suppressed and the patient will become thyrotoxic.11 Plummer's disease generally affects elderly patients. Patients with Plummer's disease often have milder symptoms than patients with Graves' disease, and there may be a longer history. Plummer's disease patients are more likely to have a greater weight loss, mood depression, cardiac disease with atrial fibrillation, and muscle wasting. Extrathyroidal manifestations of Graves' disease rarely or never occur in patients with Plummer's disease.

The recognition of hyperthyroid symptoms is rather difficult because the manifestations of Plum-mer's disease are usually mild in a patient with a long-standing history of multinodular goiter and apathetic hyperthyroidism. The diagnosis is usually confirmed by documenting elevated levels of thyroid hormones or a suppressed TSH level. It is important to measure T3 in these patients owing to a higher incidence of T3 thyrotoxicosis. Antibodies against TSH and thyroperoxidase are usually absent. Scanning reveals one or more areas of increased uptake and suppressed areas between them. Surgery is the ideal treatment for Plummer's disease (Figure 1-22) because

• patients have nodules that may not resolve after radioactive iodine ablation;

• uptake is often relatively low, requiring high doses of radioiodine, almost twice that given to Graves' disease patients for successful treatment; and

• the thyroid tissue adjacent to the thyroid nodule receives about 2,000 rads, which is in the carcinogenic range.12-14

TSH-Secreting Pituitary Tumors

TSH-secreting pituitary adenoma is a rare but important cause of thyrotoxicosis (Figure 1-23). Excessive secretion of TSH by the pituitary stimulates the thyroid gland to grow and produce excess thyroid hormone. The goiter is usually relatively small. A TSH-secreting pituitary adenoma should be suspected in a patient with high TSH and elevated thyroid hormone levels. An MRI scan of the pituitary in a patient with an elevated alpha subunit of TSH and hyperthyroidism confirms the diagnosis. Such patients are treated by a transsphenoidal approach to remove the tumor. External irradiation is used when the tumor is invasive after excision or as definitive therapy. Finally, medical therapy with a somatostatin analogue can be effective to control TSH secretion or the thyroid hormone production can be controlled by antithyroid drugs. Rarely, a

Figure 1-22. Patients with Plummer's disease are about 10 years older than patients with Graves' disease. Plummer's disease is also relatively common in older patients with multinodular goiters. A, A T3 thyrotoxic multinodular goiter from one lobe in a patient with recurrent goiter. The gland weighed 180 g. (Normal thyroid glands weigh 20 g on average.) Note the increased vascularity of the gland. B, Photomicrograph of the specimen in A shows several small hyperplastic follicles in the background of a typical colloid goiter with multiple cystic spaces and large follicles with flat cuboidal epithelia (hematoxylin and eosin; x40 original magnification).

Figure 1-22. Patients with Plummer's disease are about 10 years older than patients with Graves' disease. Plummer's disease is also relatively common in older patients with multinodular goiters. A, A T3 thyrotoxic multinodular goiter from one lobe in a patient with recurrent goiter. The gland weighed 180 g. (Normal thyroid glands weigh 20 g on average.) Note the increased vascularity of the gland. B, Photomicrograph of the specimen in A shows several small hyperplastic follicles in the background of a typical colloid goiter with multiple cystic spaces and large follicles with flat cuboidal epithelia (hematoxylin and eosin; x40 original magnification).

Figure 1-23. Thyroid-stimulating hormone (thyrotroph) adenomas are among the rarest types of pituitary tumors. A, Coronal Trweighted image reveals a 5 mm centrally located adenoma associated with focal deformity in the floor of the sella turcica. Their appearance is similar to other adenomas except that they are more frequently centrally located. Reproduced with permission from Atlas SW. Magnetic resonance imaging of the brain and spine. New York: Raven Press; 1991. B, Photomicrograph of a thyrotroph adenoma reveals round to angular cells that contain abundant immunoreactive hormone (immunoperoxidase stain) (hematoxylin and eosin; x100 original magnification). Reproduced with permission from Damjanov I, Linder J. Anderson's pathology. 10th ed. St. Louis: Mosby-Yearbook; 1996.

Figure 1-23. Thyroid-stimulating hormone (thyrotroph) adenomas are among the rarest types of pituitary tumors. A, Coronal Trweighted image reveals a 5 mm centrally located adenoma associated with focal deformity in the floor of the sella turcica. Their appearance is similar to other adenomas except that they are more frequently centrally located. Reproduced with permission from Atlas SW. Magnetic resonance imaging of the brain and spine. New York: Raven Press; 1991. B, Photomicrograph of a thyrotroph adenoma reveals round to angular cells that contain abundant immunoreactive hormone (immunoperoxidase stain) (hematoxylin and eosin; x100 original magnification). Reproduced with permission from Damjanov I, Linder J. Anderson's pathology. 10th ed. St. Louis: Mosby-Yearbook; 1996.

patient may need a total thyroidectomy to treat the thyrotoxic manifestations.15

Functional Metastases of Follicular Thyroid Cancer

Sizable masses of metastatic follicular thyroid cancer may produce excessive quantities of thyroid hormones, resulting in hyperthyroidism. Treatment is usually palliative, with debulking surgery and RAI ablation to decrease thyroid hormone levels (Figure 1-24). Antithyroid medications may also be necessary.

Trophoblastic Disease

There is abundant evidence that the human chorionic gonadotropin hormone (HCG) is a weak TSH agonist. An increased HCG level in trophoblastic disease (choriocarcinoma or molar pregnancy) stim-

Figure 1-25. Photomicrograph of the jodbasedow effect following Figure 1-24. Disseminated metastases of follicular carcinoma are iodine loading in a goiter patient. Note the hyperplasia and scallop-usually in lungs or bones as seen in this coronal magnetic reso- ing of the follicles consistent with increased activity (hematoxylin and nance image. eosin; x40 original magnification).

Figure 1-25. Photomicrograph of the jodbasedow effect following Figure 1-24. Disseminated metastases of follicular carcinoma are iodine loading in a goiter patient. Note the hyperplasia and scallop-usually in lungs or bones as seen in this coronal magnetic reso- ing of the follicles consistent with increased activity (hematoxylin and nance image. eosin; x40 original magnification).

Table 1-4. CLASSIFICATION OF THYROIDITIS

Disease Onset Etiology

Suppurative Acute Bacterial de Quervain's Subacute Viral

Hashimoto's Chronic Autoimmune

Riedel's Chronic Idiopathic ulates the thyroid gland, causing thyrotoxic manifestations proportional to the level of HCG. Evacuation of the molar pregnancy or effective chemotherapy of the choriocarcinoma cures the hyperthyroidism. Some of these patients require symptomatic treatment with P-blockers.16

Jodbasedow Effect

Iodine-induced hyperthyroidism, jodbasedow hyperthyroidism, occurs following iodine replacement in patients with goiters in iodine-deficient areas and following iodine loading. Typically, the patient who has had a nonfunctioning nodular goiter presents with tachyarrhythmia or heart failure after being given an iodine-containing radio contrast agent or being treated with amiodarone. Increased urinary iodine concentrations and low radioiodine uptake in the thyroid gland confirm the diagnosis. In mild cases, antithyroid medications are used. Potassium perchlorate given as 200 mg four times a day can prevent iodine uptake and block thyroid hormone formation.17 Occasionally, these patients require dialysis or emergency thyroidectomy (Figure 1-25).

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