Figure 47.1. Radioactive Iodine Uptake Scans. Both images are of hyperthyroid patients with suppressed TSH concentrations. (A) Left toxic adenoma: a large left-sided toxic “hot” adenoma, with relative suppression of right-sided activity. (B) Graves’ disease: bilateral diffuse uptake consistent with Graves’ disease.

SOURCE: Dr. Matthew Kim.

    Thyroid storm is defined as a life-threatening condition manifested by an exaggeration of the clinical signs and symptoms of thyrotoxicosis accompanied by systemic decompensation. It is usually caused by rapid release of thyroid hormone in the setting of extreme physiologic stress or illness. Most often the diagnosis of thyroid storm is made when hyperthyroidism also causes coexistent cardiovascular, neurological, or gastroenterologic dysfunction. Early recognition, prompt hospitalization and consultation with endocrinology are the keys to a successful outcome. Thyroid storm is a clinical diagnosis, and there is no degree of thyroid hormone elevation that is diagnostic of the illness.

    The risks of hyperthyroidism are primarily related to arrhythmias, cardiomyopathy, osteoporotic bone loss, and a hypermetabolic state. Graves’ ophthalmopathy (soft tissue inflammation, proptosis, extraocular muscle dysfunction, and optic neuropathy) is present in 10–25% of affected patients, although subclinical enlargement of extraocular muscles may be present in up to 50–70% of patients without overt eye disease. Pretibial myxedema (infiltrative dermopathy characterized by nonpitting scaly thickening and induration of the skin) is a rare complication of Graves’ disease. Once it has been treated effectively, the overall risk associated with hyperthyroidism can be substantially diminished. Early in the treatment of thyrotoxicosis, avoidance of excessive amounts of iodine (including the contrast agents used in CT) scans) and restriction of exercise are recommended.

    If thyroiditis is suspected, conservative follow-up with serial measurement of thyroid function test profiles is indicated over a 3- to 4-month period. Thyrotoxicosis due to thyroiditis is managed conservatively, as it is often self-limited. Beta blockers can be used to treat sympathomimetic symptoms such as tachycardia, tremor, and anxiety. Nonsteroidal antiinflammatory drugs, and rarely glucocorticoids, can also be administered to reduce inflammation and discomfort. For patients with Graves’ disease and autonomously functioning thyroid nodules, antithyroid drugs or radioactive iodine treatment should be considered (box 47.2). Patient preference, age, comorbidity, severity of thyrotoxicosis, and the presence of Graves’ ophthalmopathy must be taken into account when selecting a treatment modality. Antithyroid drugs are used for primary treatment of hyperthyroidism to approximate a euthyroid state in preparation for thyroidectomy, or in conjunction with radioactive iodine treatment in selected patients. Antithyroid drugs are also preferred to radioactive iodine treatment in the presence of severe Graves’ ophthalmopathy and thyroid storm. Many patients in the United States ultimately select radioactive iodine treatment (¹³¹I) as therapy for thyrotoxicosis caused by Graves’ disease, toxic multinodular goiter, or an autonomously functioning thyroid nodule. Radioactive iodine treatment is also indicated in patients failing to achieve a remission after a course of antithyroid drugs. When administered, radioactive iodine treatment is likely to cause permanent thyroid destruction requiring lifelong levothyroxine therapy.

Box 47.2 INITIAL TREATMENT REGIMENS FOR HYPERTHYROIDISM

    When antithyroid drugs are prescribed, methimazole is effective for most patients. It is usually started at an oral dose of 10–40 mg daily. Alternatively, propylthiouracil may be preferred for pregnant patients or those with an allergy to methimazole, though recent data suggests propylthiouracil is associated with a higher side-effect profile. When administered, propylthiouracil is frequently started at a dose of 50–150 mg two to three times daily, depending on the severity of the illness. With either drug, patients should be counseled for the risk of hepatitis and agranulocytosis, both rare but potentially severe side effects. Propylthiouracil has also been associated with vasculitis and concomitant renal dysfunction. If immediate control of severe thyrotoxicosis is required, inorganic iodine in the form of Lugol’s solution or saturated solution of potassium iodine (SSKI) can be administered orally and is highly effective. This therapy is self-limited in duration (usually ~3 weeks) and precludes further use of radioactive iodine for months thereafter. Thyroidectomy is rarely considered but is a reasonable choice for hyperthyroid patients with concomitant suspicious (malignant) nodules or for patients who either cannot tolerate or refuse treatment with antithyroid drugs or radioactive iodine.

    Managing Graves’ hyperthyroidism during pregnancy is highly complex given the differential effects of antithyroid drugs on the fetus in comparison to the mother. In general, the developing fetus is much more sensitive to both methimazole and propylthiouracil. A biochemical euthyroid state in the mother does not predict safe and normal development of the fetus. As a rule, endocrine consultation should be sought in these situations, and the lowest dose of antithyroid medication possible should be administered.

    Graves’ ophthalmopathy is often treated conservatively in patients with mild to moderate disease. In more severe cases, a course of intravenous or oral glucocorticoids may be considered, though it should be administered by physicians with expertise and experience with this illness. Rarely, surgical decompression of the orbit may be required to preserve vision.

HYPOTHYROIDISM

Hypothyroidism may present with a wide range of clinical symptoms and signs (table 47.1). The TSH is elevated (>10 µU/mL) when the thyroid itself begins to fail (primary hypothyroidism) and is low or normal in conjunction with a low free T₄ in rare cases of hypothyroidism due to pituitary or hypothalamic disease (secondary hypothyroidism). Patients with a mildly elevated TSH (5–10 µU/mL) and a normal free T₄ have subclinical hypothyroidism. This distinction is important as patients with subclinical hypothyroidism may not require treatment if asymptomatic and not desiring pregnancy (or not currently pregnant).

    The most common causes of hypothyroidism are chronic lymphocytic thyroiditis (Hashimoto’s disease), prior thyroid surgery, treatment with head or neck radiation, or a history of radioactive iodine treatment. Hashimoto’s disease is an autoimmune disorder that may present at any age but increases in prevalence with aging. Onset is usually insidious and may be associated with a visible or palpable goiter. The presence of elevated concentrations of antithyroid peroxidase antibodies in the serum is highly correlated with the presence of Hashimoto’s disease and can be useful in confirming a suspected diagnosis or assessing the risk of developing hypothyroidism in the future. Subacute and painful thyroiditis are other illnesses that may lead to hypothyroidism, although most patients follow a triphasic thyroid hormone response characterized by mild thyrotoxicosis that gives way to mild hypothyroidism followed by normalization of TSH levels. This triphasic pattern occurs over a 2- to 4-month interval. If the final phase of TSH normalization is impaired, hypothyroidism may persist. This occurs most often in patients with positive antithyroid peroxidase antibodies.

    Levothyroxine is the preferred treatment of hypothyroidism. It safely, effectively, and reliably relieves symptoms while normalizing thyroid hormone levels in hypothyroid patients. Levothyroxine is converted to T₃ (the active hormone) in peripheral tissues at an appropriate rate to meet overall metabolic needs. Treatment with a combination of T₄ and T₃ is not recommended. Although all patients with overt hypothyroidism (TSH >10 µU/mL) should be treated, there is limited evidence that treatment of subclinical hypothyroidism is beneficial in nonpregnant asymptomatic patients. Most patients with subclinical hypothyroidism can be safely monitored with TSH measurements every 4–6 months, evaluating for progression of disease. This recommendation excludes women seeking pregnancy or currently pregnant, who should be treated once TSH is outside the normal range due to greater maternal and fetal risk.

    During initial management, the degree of hypothyroidism should be assessed in affected individuals. Biochemical and clinical parameters often correlate, although at times they may be discordant. For patients with severe hypothyroidism (TSH >100 µU/mL), several important factors must be considered when thyroid hormone replacement is instituted. Importantly, morbidity and mortality in such patients are most often related to simultaneous (though often silent) infection, hypoventilation, or medication overdose. For these reasons sedatives and narcotics should be avoided or administered at significantly reduced doses, given reduced drug clearance caused by hypothyroidism. For patients with mild to moderate hypothyroidism, these considerations usually do not apply.

    A full replacement dose of levothyroxine can be approximated by multiplying 1.7 µg/day × patient weight (kg). The severity of hypothyroidism should determine the urgency for replacement therapy. Whenever possible, a modest dose of levothyroxine (50–75 µg daily) is preferred during the first week of therapy in patients who are not in acute danger. An acute rise in thyroid hormone concentration can rarely induce increased cardiac demand and potential ischemia. For this reason caution should be exercised in those with known coronary artery disease or in patients over 80 years of age. Mild to moderate hypothyroidism can often be treated with 50–100 µg of levothyroxine daily. Once initiated, levothyroxine treatment is usually lifelong. The target TSH level in patients on treatment should be within the normal range. Over the long term, most patients can be safely monitored with TSH measurements every 6–12 months.

    Myxedema coma is a rare and extreme form of hypothyroidism manifested by features such as delayed reflexes, sparse hair, dry skin, and puffy or edematous facies. It is considered to be a life-threatening manifestation of severe hypothyroidism. Frequently, hypothermia (core temperature <95°F) as well as impaired cardiovascular, neurological, and gastroenterologic function may be documented. Similar to thyroid storm, myxedema coma is a clinical diagnosis, and no specific thyroid hormone level defines this illness. Treatment is with thyroid hormone administration. Because this condition is life threatening, both T₄ and T₃ preparations are often used initially following consultation with an endocrinologist. Intravenous preparations are often preferred, as hypothyroidism-associated bowel edema can impair the absorption and action of oral hormone. The possibility of unrecognized adrenal insufficiency should be considered. In severe cases, concomitant treatment with thyroid hormone and glucocorticoids may be warranted.

THYROID NODULES

Thyroid nodules are common, occurring more frequently in women and with increasing age. Most nodules are asymptomatic and come to attention as a mass palpated during a routine physical examination or as an incidental finding on an imaging procedure performed for another indication. Differentiating malignant nodules from benign nodules is the most important consideration. A secondary consideration for evaluation is nodule size, as some large nodules (usually larger than 4 cm in diameter) can cause tracheal deviation or compressive symptoms prompting further intervention. However, most clinically relevant nodules measure between 1 and 3 cm in diameter, are nonmalignant, and cause no adverse symptoms. Such nodules are almost always followed conservatively without further intervention or surgery.

    Approximately 10–15% of thyroid nodules >1 cm are cancerous. This provides the rationale for investigating patients with nodular disease. Ironically, thyroid cancers smaller than 1 cm in diameter (often termed “microcarcinomas”) are almost always indolent and pose little or no risk to the patient. Epidemiological evidence suggests that the properties of well-differentiated thyroid carcinomas appear to change once growth exceeds 1 cm in diameter. Tumors that grow to this diameter increasingly gain potential to invade, spread, and ultimately metastasize. There are few exceptions to this dogma, most of which are primary well-differentiated thyroid cancers measuring 8–9 mm in size. Given these findings, combined with known interobserver variability associated with ultrasound and histopathologic measurement of tumors, consensus expert opinion has recommended that only thyroid nodules larger than 1 cm in diameter undergo further evaluation in the typical patient without cancer risk factors.

    In patients with one or more thyroid nodules larger than 1 cm in diameter, initial evaluation is assessment of thyroid function. This is most accurately measured by obtaining a serum TSH measurement. Patients with suppressed TSH levels (~5–10%) may have an autonomously functioning nodule (Figure 47.1A). This is important because such nodules pose virtually no risk of being malignant and are often treated with radioactive iodine. Patients with normal or elevated TSH levels should be referred for fine needle aspiration (FNA; see Figure 47.2). Most experts recommend that FNA be performed with ultrasound guidance, as improved accuracy and decreased diagnostic error (false-negative results) have been demonstrated. Aspiration of a thyroid nodule is a safe and relatively painless procedure in most cases, especially when performed by an experienced clinician.

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