Washington Manual Thyroid Disorders

Hyperthyroidism4,5

GENERAL PRINCIPLES

Graves’ disease causes most cases of hyperthyroidism, especially in young patients. This autoimmune disorder may also cause proptosis (exophthalmos) and pretibial myxedema, neither of which is found in other causes of hyperthyroidism. Toxic multinodular goiter (MNG) may cause hyperthyroidism, more commonly in older patients. Unusual causes include iodine-induced hyperthyroidism (precipitated by drugs such as amiodarone or radiographic contrast media), thyroid adenomas, subacute thyroiditis (painful tender goiter with transient hyperthyroidism), painless thyroiditis (nontender goiter with transient hyperthyroidism, most often seen in the postpartum period), and surreptitious ingestion of thyroid hormone. TSH-induced hyperthyroidism is extremely rare. DIAGNOSIS Clinical Presentation History Symptoms include heat intolerance, weight loss, weakness, palpitations, oligomenorrhea, and anxiety. In the elderly, hyperthyroidism may present with only atrial fibrillation, heart failure, weakness, or weight loss, and a high index of suspicion is needed to make the diagnosis. Physical Examination Signs include brisk tendon reflexes, fine tremor, proximal weakness, stare, and eyelid lag. Cardiac abnormalities may be prominent, including sinus tachycardia, atrial fibrillation, and exacerbation of coronary artery disease or heart failure. Key differentiating physical examination findings (Table 24-2) include the following: The presence of proptosis or pretibial myxedema, seen only in Graves’ disease (although many patients with Graves’ disease lack these signs) A diffuse nontender goiter, consistent with Graves’ disease or painless thyroiditis Recent pregnancy, neck pain, or recent iodine administration, suggesting causes other than Graves’ disease Diagnostic Testing In rare cases, 24-hour radioactive iodine uptake (RAIU) is needed to distinguish Graves’ disease or toxic nodules (in which RAIU is elevated) from postpartum thyroiditis, iodine-induced hyperthyroidism, or factitious hyperthyroidism (in which RAIU is very low). In suspected hyperthyroidism, plasma TSH is the best initial diagnostic test. A normal TSH level virtually excludes clinical hyperthyroidism. If plasma TSH is low, plasma-free T4 should be measured to determine the severity of hyperthyroidism and as a baseline for therapy. If plasma-free T4 is elevated, the diagnosis of clinical hyperthyroidism is established. If plasma TSH is <0.1 µU/mL but free T4 is normal, the patient may have clinical hyperthyroidism because of elevation of plasma T3 alone, and plasma T3 should be measured in this case. Mild (or subclinical) hyperthyroidism may suppress TSH to <0.1 µU/mL, and thus suppression of TSH alone does not confirm that symptoms are due to hyperthyroidism. TSH may also be suppressed by severe nonthyroidal illness (see Evaluation of Thyroid Function section). TABLE 24-2   Differential Diagnosis of Hyperthyroidism Type of Goiter Diagnosis Diffuse, nontender goiter Graves’ disease or painless thyroiditis Multiple thyroid nodules Toxic multinodular goiter Single thyroid nodule Thyroid adenoma Tender painful goiter Subacute thyroiditis Normal thyroid gland Graves’ disease, painless thyroiditis, or factitious hyperthyroidism   TREATMENT Some forms of hyperthyroidism (subacute or postpartum thyroiditis) are transient and require only symptomatic therapy. A β-adrenergic antagonist (such as atenolol 25–100 mg daily) relieves symptoms of hyperthyroidism, such as palpitations, tremor, and anxiety, until hyperthyroidism is controlled by definitive therapy or until transient forms of hyperthyroidism subside. The dose is adjusted to alleviate symptoms and tachycardia and then reduced gradually as hyperthyroidism is controlled. Three methods are available for definitive therapy (none of which controls hyperthyroidism rapidly): RAI, thionamides, and subtotal thyroidectomy. During treatment, patients are followed by clinical evaluation and measurement of plasma-free T4. Plasma TSH is useless in assessing the initial response to therapy because it remains suppressed until after the patient becomes euthyroid. Regardless of the therapy used, all patients with Graves’ disease require lifelong follow-up for recurrent hyperthyroidism or development of hypothyroidism. Choice of definitive therapy In Graves’ disease, RAI therapy is our preferred treatment for almost all patients. It is simple and highly effective but cannot be used in pregnancy (see Hyperthyroidism in Pregnancy section). Thionamides achieve long-term control in fewer than half of patients with Graves’ disease, and they carry a small risk of life-threatening side effects (agranulocytosis, liver dysfunction). Thyroidectomy may be used in patients who refuse RAI therapy, have significant Graves’ ophthalmopathy, or who relapse or develop side effects with thionamide therapy. Other causes of hyperthyroidism: We prefer to treat toxic nodules with RAI (except in pregnancy or during breastfeeding), though thionamides or partial thyroidectomy can also be used. Transient forms of hyperthyroidism because of thyroiditis should be treated symptomatically with atenolol. Iodine-induced hyperthyroidism is treated with thionamides and atenolol until the patient is euthyroid. Although treatment of some patients with amiodarone-induced hyperthyroidism with glucocorticoids has been advocated, nearly all patients with amiodarone-induced hyperthyroidism respond well to thionamide therapy. RAI therapy A single dose permanently controls hyperthyroidism in 90% of patients, and further doses can be given if necessary. A pregnancy test is done immediately before therapy in potentially fertile women. A 24-hour RAIU is usually measured and used to calculate the dose. Thionamides interfere with RAI therapy and should be stopped at least 3 days before treatment. If iodine treatment has been given, it should be stopped at least 2 weeks before RAI therapy. Follow-up: Usually, several months are needed to restore euthyroidism. Patients are evaluated at 4- to 6-week intervals, with assessment of clinical findings and plasma-free T4. If thyroid function stabilizes within the normal range, the interval between follow-up visits is gradually increased to annual intervals. If symptomatic hypothyroidism develops, thyroxine therapy is started (see Hypothyroidism section). If symptomatic hyperthyroidism persists after 6 months, RAI treatment can be repeated. Side effects Hypothyroidism occurs in most patients within the first year and thereafter continues to develop at a rate of approximately 3% per year. Because of the release of stored hormone, a slight rise in plasma T4 may occur in the first 2 weeks after therapy. This development is important only in patients with severe cardiac disease, which may worsen as a result. Such patients should be treated with thionamides to restore euthyroidism and to deplete stored hormone before treatment with RAI. There have been mixed results as to whether RAI has a clinically important effect on the course of Graves’ eye disease, but early treatment to prevent hypothyroidism after RAI seems to be beneficial, and patients should be counseled to stop smoking, as this is a known contributor to worsening of the eye disease. It does not increase the risk of malignancy or cause congenital abnormalities in the offspring of women who conceive after RAI therapy. Thionamides: Methimazole and propylthiouracil (PTU) inhibit thyroid hormone synthesis. PTU also inhibits extrathyroidal deiodination of T4 to T3. Once thyroid hormone stores are depleted (after several weeks to months), T4 levels decrease. These drugs have no permanent effect on thyroid function. In the majority of patients with Graves’ disease, hyperthyroidism recurs within 6 months after therapy is stopped. Spontaneous remission of Graves’ disease occurs in approximately one-third of patients during thionamide therapy, and in this minority, no other treatment may be needed. Remission is more likely in mild, recent onset hyperthyroidism and if the goiter is small. Because of a better safety profile, methimazole should be used instead of PTU except in specific situations (see the following text). Initiation of therapy: Before starting therapy, patients must be warned of side effects and precautions. Usual starting doses are methimazole, 10–40 mg PO daily, or PTU, 100–200 mg PO tid; higher initial doses can be used in severe hyperthyroidism. Follow-up: Restoration of euthyroidism takes up to several months. Patients are evaluated at 4-week intervals with assessment of clinical findings and plasma-free T4. If plasma-free T4 levels do not fall after 4–8 weeks, the dose should be increased. Doses as high as methimazole, 60 mg PO daily, or PTU, 300 mg PO qid, may be required. Once the plasma-free T4 level falls to normal, the dose is adjusted to maintain plasma- free T4 within the normal range. No consensus exists on the optimal duration of therapy, but periods of 6 months to 2 years are usually used. Patients must be monitored carefully for recurrence of hyperthyroidism after the drug is stopped. Side effects are most likely to occur within the first few months of therapy. Minor side effects include rash, urticaria, fever, arthralgias, and transient leukopenia. Agranulocytosis occurs in 0.3% of patients treated with thionamides. Other life-threatening side effects include hepatitis, vasculitis, and drug-induced lupus erythematosus. These complications usually resolve if the drug is stopped promptly. Patients must be warned to stop the drug immediately if jaundice or symptoms suggestive of agranulocytosis develop (e.g., fever, chills, sore throat) and to contact their physician promptly for evaluation. Routine monitoring of the white blood cell count is not useful for detecting agranulocytosis, which develops suddenly. Subtotal thyroidectomy: This procedure provides long-term control of hyperthyroidism in most patients. Surgery may trigger a perioperative exacerbation of hyperthyroidism, and patients should be prepared for surgery by one of two methods. A thionamide is given until the patient is nearly euthyroid. Supersaturated potassium iodide (SSKI), 40–80 mg (one to two drops) PO bid, is then added 1–2 weeks before surgery. Both drugs are stopped postoperatively. Atenolol (50–100 mg daily) is started 1–2 weeks before surgery. The dose of atenolol is increased, if necessary, to reduce the resting heart rate below 90 bpm and is continued for 5–7 days postoperatively. SSKI is given as mentioned earlier. Follow-up: Clinical findings and plasma-free T4 and TSH should be assessed 4–6 weeks after surgery. If thyroid function is normal, the patient is seen at 3 and 6 months and then annually. If symptomatic hypothyroidism develops, thyroxine therapy is started. Hyperthyroidism persists or recurs in 3%–7% of patients. Complications of thyroidectomy include hypothyroidism and hypoparathyroidism. Rare complications include permanent vocal cord paralysis, due to recurrent laryngeal nerve injury, and perioperative death. The complication rate appears to depend on the experience of the surgeon. SPECIAL CONSIDERATIONS Subclinical hyperthyroidism is present when the plasma TSH is below normal but the patient has no symptoms that are definitely caused by hyperthyroidism, and plasma levels of free T4 and T3 are normal. Subclinical hyperthyroidism increases the risk of atrial fibrillation in patients older than 65 years and those with heart disease and predisposes to osteoporosis in postmenopausal women; it should be treated in these patients. Treatment should also be considered in asymptomatic individuals without risk factors but with TSH persistently <0.1 µU/mL. Asymptomatic young patients with mild Graves’ disease can be observed for spontaneous resolution of hyperthyroidism or the development of symptoms or increasing free T4 levels that warrant treatment. Urgent therapy is warranted when hyperthyroidism exacerbates heart failure or acute coronary syndromes and in rare patients with severe hyperthyroidism complicated by fever and delirium (thyroid storm). Concomitant diseases should be treated intensively, and confirmatory tests (serum TSH and free T4) should be obtained before therapy is started. PTU 300 mg PO q6h or methimazole 60 mg/d PO should be started immediately. Iodide (SSKI, two drops PO q12h) should be started to inhibit thyroid hormone secretion rapidly. Propranolol, 40 mg PO q6h (or an equivalent dose IV), should be given to patients with angina or myocardial infarction, and the dose should be adjusted to prevent tachycardia. β-Adrenergic antagonists may benefit some patients with heart failure and marked tachycardia but can further impair left ventricular systolic function. In patients with clinical heart failure, it should be given only with careful monitoring of left ventricular function. Plasma-free T4 is measured every 4–6 days. When free T4 approaches the normal range, the doses of methimazole and iodine are gradually decreased. RAI therapy can be scheduled 2–4 weeks after iodine is stopped. Hyperthyroidism in pregnancy: If hyperthyroidism is suspected, plasma TSH should be measured. Plasma TSH declines in early pregnancy but rarely to <0.1 µU/mL due to the stimulatory effect of hCG on TSH receptors. If TSH is <0.1 µU/mL, the diagnosis should be confirmed by measurement of plasma-free T4. RAI is contraindicated in pregnancy, and therefore, patients should be treated with PTU in the first trimester because of its lower risk of severe congenital defects, whereas methimazole can be used in later pregnancy. The dose should be adjusted at 4-week intervals to maintain the plasma-free T4 near the upper limit of the normal range to avoid fetal hypothyroidism. The dose required often decreases in the later stages of pregnancy.

Goiter, Thyroid Nodules, and Thyroid Carcinoma6,7

GENERAL PRINCIPLES

The evaluation of goiter is based on palpation of the thyroid and evaluation of thyroid function. If the thyroid is enlarged, the examiner should determine whether the enlargement is diffuse or nodular. Both forms of goiter are common, especially in women. Thyroid scans and ultrasonography (US) provide no useful additional information about goiters that are diffused by palpation and should not be performed in these patients. In contrast, all palpable thyroid nodules should be evaluated by US. In rare patients, more commonly in those with MNG, the gland compresses the trachea or esophagus, causing dyspnea or dysphagia, and treatment is required. Thyroxine treatment has little, if any, effect on the size of MNGs. Subtotal thyroidectomy is most commonly used to relieve compressive symptoms. RAI therapy will reduce gland size and relieve symptoms in most patients if surgery is not an option, though much higher doses are necessary if the patient is euthyroid. Diffuse goiter Almost all euthyroid diffuse goiters in the United States are due to chronic lymphocytic thyroiditis (Hashimoto thyroiditis). Because Hashimoto thyroiditis may also cause hypothyroidism, plasma TSH should be measured. Diffuse euthyroid goiters are usually asymptomatic, and therapy is seldom required. Patients should be monitored regularly for the development of hypothyroidism. Diffuse hyperthyroid goiter is most commonly because of Graves’ disease, and treatment of the hyperthyroidism usually improves the goiter (see Hyperthyroidism section). Nodular goiter Between 30% and 50% of people have nonpalpable thyroid nodules that are detectable by ultrasound. These nodules rarely have any clinical importance, but their incidental discovery may lead to unnecessary diagnostic testing and treatment. Nodules are more common in older patients, especially women, and 5%–10% of thyroid nodules are thyroid carcinomas. DIAGNOSIS Clinical Presentation History Clinical findings that increase the risk of carcinoma include the presence of cervical lymphadenopathy, a history of radiation to the head or neck, and a family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndromes type 2A or 2B. Physical Examination A hard, fixed nodule, recent nodule growth, or hoarseness due to vocal cord paralysis suggests malignancy. Diagnostic Testing All patients with one or more palpable thyroid nodules on examination or thyroid nodules identified by other imaging modality should undergo a dedicated thyroid ultrasound as this is the most informative imaging for malignancy risk in thyroid nodules. Guidelines from the American Thyroid Association classify malignancy risk and biopsy recommendations based on nodule characteristics and size. Nodules are characterized into the following risk classes based on their ultrasound appearance: high suspicion (>70%–90% malignancy risk), intermediate suspicion (10%–20% malignancy risk), low suspicion (5%–10% malignancy risk), very low suspicion (<3% malignancy risk), and benign (<1% malignancy risk). High and intermediate suspicion nodules warrant evaluation by fine needle aspiration (FNA) when they are >1 cm. Low suspicion nodules should be evaluated at >1.5 cm and very low risk nodules at 2 cm. Benign nodules require no further follow-up. In a few patients, hyperthyroidism develops as a result of “toxic” nodules that overproduce thyroid hormone (see Hyperthyroidism section). These nodules can be identified with a radionuclide scan and do not require FNA evaluation as the malignancy risk is only 1%–2%. TREATMENT Patients with thyroid carcinoma or suspicion for thyroid carcinoma by FNA cytology typically initially undergo surgical resection with either hemi- or total thyroidectomy, sometimes followed by adjuvant therapy with RAI and should be managed in consultation with an endocrinologist. FOLLOW-UP Further follow-up depends on FNA results. Benign nodules should undergo repeat ultrasound depending on initial ultrasound risk: high risk in 6–12 months and low-intermediate in 12–24 months. The utility of following very low risk nodules is unclear. Nodules with benign cytology should also be reevaluated periodically by palpation. Thyroxine therapy has little or no effect on the size of thyroid nodules and is not indicated. Nodules with nondiagnostic cytology because of insufficient sampling should undergo repeat biopsy. The management of thyroid nodules with indeterminate cytology is less clear. Nodules with atypia of undetermined significance or follicular lesion by cytology can be further evaluated with molecular diagnostic testing to estimate risk and guide surgical decision-making.