171 DISORDERS OF THE THYROID
Harrison’s Manual of Medicine
DISORDERS OF THE THYROID
Sick Euthyroid Syndrome
Toxic Multinodular Goiter and Toxic Adenoma
Disorders of the thyroid gland result primarily from autoimmune processes that stimulate the overproduction of thyroid hormones (thyrotoxicosis) or cause glandular destruction and underproduction of thyroid hormones (hypothyroidism). Neoplastic processes in the thyroid gland can lead to benign nodules or thyroid cancer.
The hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates release of thyroid-stimulating hormone (TSH) from the anterior pituitary. TSH is secreted into the circulation and binds to receptors in the thyroid gland, where it controls production and release of thyroxine (T4) and triiodothyronine (T3), which in turn inhibit further release of TSH from the pituitary. Some T3 is secreted by the thyroid, but most is produced by deiodination of T4 in peripheral tissues. Both T4 and T3 are bound to carrier proteins [thyroid- binding globulin (TBG), transthyretin, and albumin] in the circulation. Increased levels of total T4 and T3 with normal free levels are seen in states of increased carrier proteins (pregnancy, estrogens, cirrhosis, hepatitis, and inherited disorders). Conversely, decreased total T4 and T3 levels with normal free levels are seen in severe systemic illness, chronic liver disease, and nephrosis.
Etiology Deficient thyroid hormone secretion can be due to thyroid failure (primary hypothyroidism) or pituitary or hypothalamic disease (secondary hypothyroidism) (Table 171-1). Transient hypothyroidism may occur in silent or subacute thyroiditis. Subclinical hypothyroidism is a state of normal thyroid hormone levels and mild elevation of TSH; despite the name, some pts may have minor symptoms. With higher TSH levels and low free T4 levels, symptoms become more readily apparent in clinical (or overt) hypothyroidism. In areas of iodine sufficiency, autoimmune disease and iatrogenic causes are most common.
Table 171-1 Causes of Hypothyroidism
Clinical Features Symptoms of hypothyroidism include lethargy, dry hair and skin, cold intolerance, hair loss, difficulty concentrating, poor memory, constipation, mild weight gain with poor appetite, dyspnea, hoarse voice, muscle cramping, and menorrhagia. Cardinal features on examination include bradycardia, mild diastolic hypertension, prolongation of the relaxation phase of deep tendon reflexes, and cool peripheral extremities. Carpal tunnel syndrome may be present. Cardiomegaly may be present due to pericardial effusion. The most extreme presentation is a dull, expressionless face, sparse hair, periorbital puffiness, large tongue, and pale, doughy, cool skin. The condition may progress into a hypothermic, stuporous state (myxedema coma) with respiratory depression. Factors that predispose to myxedema coma include cold exposure, trauma, infection, and administration of narcotics.
Diagnosis Decreased serum T4 is common to all varieties of hypothyroidism. An elevated TSH is a sensitive marker of primary hypothyroidism. A summary of the investigations used to determine the existence and cause of hypothyroidism is provided in Figure 171-1. Thyroid peroxidase (TPO) antibodies are increased in 90–95% of patients with autoimmune-mediated hypothyroidism. Serum cholesterol, creatine phosphokinase, and lactic dehydrogenase may be elevated, and bradycardia, low-amplitude QRS complexes, and flattened or inverted T waves may be present on ECG.
FIGURE 171-1. Evaluation of hypothyroidism, TPOAb+, thyroid peroxidase antibodies present: TPOAb–, thyroid peroxidase antibodies not present.
Adult pts <60 years without evidence of heart disease may be started on 50–100 µg of levothyroxine (T4) daily. In the elderly or in pts with known coronary artery disease, the starting dose of levothyroxine is 12.5–25 µg/d. The dose should be adjusted in 12.5-to-25 µg increments at 6–8 week intervals on the basis of TSH levels, until a normal TSH level is achieved. The usual daily replacement dose is 1.5(µg/kg)/d. Women on levothyroxine replacement who become pregnant should have a TSH level checked at each trimester, as dose increases are frequently required during pregnancy. Failure to recognize and treat maternal hypothyroidism may adversely affect fetal neural development. Therapy for myxedema coma should include levothyroxine (200 µg) and liothyroinine (25 µg) as a single IV bolus followed by daily treatment with levothyroxine (50–100 µg/d) and liothyronine (10 µg q8h), along with hydrocortisone (50 mg q6h) for impaired adrenal reserve, ventilatory support, space blankets, and therapy of precipitating factors.
Etiology Causes of thyroid hormone excess include primary hyperthyroidism (Graves’ disease, toxic multinodular goiter, toxic adenoma, iodine excess); thyroid destruction (subacute thyroiditis, silent thyroiditis, amiodarone, radiation); extrathyroidal sources of thyroid hormone (thyrotoxicosis factitia, struma ovarii, functioning follicular carcinoma); and secondary hyperthyroidism (TSH- secreting pituitary adenoma, thyroid hormone resistance syndrome, hCG-secreting tumors, gestational thyrotoxicosis).
Clinical Features Symptoms include nervousness, irritability, heat intolerance, excessive sweating, palpitations, fatigue and weakness, weight loss with increased appetite, frequent bowel movements, and oligomenorrhea. Pts are anxious, restless and fidgety. Skin is warm and moist, and fingernails may separate from the nail bed (Plummer’s nails). Eyelid retraction and lid lag may be present. Cardiovascular findings include tachycardia, systolic hypertension, systolic murmur, and atrial fibrillation. A fine tremor, hyperreflexia, and proximal muscle weakness may also be present. Long-standing thyrotoxicosis may lead to osteopenia.
In Graves’ disease, the thyroid is usually diffusely enlarged to two to three times its normal size, and a bruit or thrill may be present. Infiltrative ophthalmopathy (with variable degrees of proptosis, periorbital swelling, and ophthalmoplegia) and dermopathy (pretibial myxedema) may also be found. In subacute thyroiditis, the thyroid is exquisitely tender and enlarged with referred pain to the jaw or ear, and sometimes accompanied by fever and preceded by an upper respiratory tract infection. Solitary or multiple nodules may be present in toxic adenoma or toxic multinodular goiter.
Thyrotoxic crisis, or thyroid storm, is rare, presents as a life-threatening exacerbation of hyperthyroidism, and can be accompanied by fever, delirium, seizures, arrhythmias, coma, vomiting, diarrhea, and jaundice.
Diagnosis Investigations used to determine the existence and causes of thyrotoxicosis are summarized in Fig. 171-2. Serum TSH is a sensitive marker of thyrotoxicosis caused by Graves’ disease, autonomous thyroid nodules, thyroiditis, and exogenous levothyroxine treatment. Associated laboratory abnormalities include elevation of bilirubin, liver enzymes, and ferritin. Radionuclide uptake may be required to distinguish the various etiologies: high uptake in Graves’ disease and nodular disease vs. low uptake in thyroid destruction, iodine excess, and extrathyroidal sources of thyroid hormone. The ESR is elevated in subacute thyroiditis.
FIGURE 171-2. Evaluation of thyrotoxicosis. aDiffuse goiter, positive TPO antibodies, ophthalmopathy, dermopathy; bcan be confirmed by radionuclide scan.
Graves’ disease may be treated with antithyroid drugs or radioiodine treatment; subtotal thyroidectomy is rarely indicated. The main antithyroid drugs are carbimazole or methimazole (10–20 mg bid-tid initially, titrated to 2.5– 10 mg qd) and propylthiouracil (100–200 mg q6–8h initially, titrated to 50–100 mg qd). These drugs can be given in either a titration regimen or as a block-replace regimen in which levothyroxine supplementation is used to avoid drug-induced hypothyroidism. Thyroid function tests should be checked 3–4 weeks after initiation of treatment, with adjustments to maintain a normal free T4 level. The common side effects are rash, urticaria, fever, and arthralgia (1–5% of pts). Rare but major side effects include hepatitis, an SLE-like syndrome, and agranulocytosis (<1%). All pts should be given written instructions regarding the symptoms of possible agranulocytosis (sore throat, fever, mouth ulcers) and the need to stop treatment pending a complete blood count to confirm that agranulocytosis is not present. Propranolol (20–40 mg q6h) or longer acting beta blockers such as atenolol (50 mg qd) may be useful to control adrenergic symptoms. Anticoagulation with warfarin should be considered in all pts with atrial fibrillation. Radioiodine can also be used as initial treatment or in pts who do not undergo remission after a 1–2 year trial of antithyroid drugs. Antecedent treatment with antithyroid drugs should be considered in elderly pts and those with cardiac problems, with cessation of antithyroid drugs 3–5 days prior to radioiodine administration. Radioiodine treatment is contraindicated in pregnancy; instead, symptoms should be controlled with the lowest effective dose of propylthiouracil (PTU). Corneal drying may be relieved with artificial tears and taping the eyelids shut during sleep. Progressive exophthalmos with chemosis, ophthalmoplegia, or vision loss is treated with large doses of prednisone (60–80 mg qd) and ophthalmologic referral; orbital decompression may be required.
In thyroid storm, large doses of PTU (600-mg loading dose) should be administered orally, per nasogastric tube, or per rectum, followed 1 h later by ipodate or iopanoic acid (0.5 mg PO q12 h) or other available oral contrast agents. PTU (200–300 mg q6h) should be continued, along with propranolol (40–60 mg PO q4h or 2 mg IV q4h) and dexamethasone (2 mg q6h). Any underlying precipitating cause should be identified and treated.
Radioiodine is the treatment of choice for toxic nodular goiter. Subacute thyroiditis should be treated with NSAIDs and beta blockade to control symptoms, with monitoring of the TSH and free T4 levels every 4 weeks. Transient levothyroxine replacement (50–100 µg qd) may be required if the hypothyroid phase is prolonged. Silent thyroiditis (or postpartum thyroiditis if within 3–6 months of delivery) should be treated with beta blockade during the thyrotoxic phase and levothyroxine in the hypothyroid phase, with withdrawal after 6–9 months to assess recovery.
SICK EUTHYROID SYNDROME
Any acute, severe illness can cause abnormalities of circulating thyroid hormone levels or TSH, even in the absence of underlying thyroid disease. Therefore, the routine testing of thyroid function should be avoided in acutely ill pts unless a thyroid disorder is strongly suspected. The most common pattern in sick euthyroid syndrome is a decrease in total and free T3 levels, with normal levels of TSH and T4. More ill pts may additionally have a fall in total T4 levels, with normal free T4 levels. TSH levels may range from <0.1 to >20 mU/L, with normalization after recovery from illness. Unless there is historic or clinical evidence of hypothyroidism, thyroid hormone should not be administered and thyroid function tests should be repeated after recovery.
Amiodarone treatment is associated with (1) acute, transient changes in thyroid function, (2) hypothyroidism, or (3) thyrotoxicosis. There are two major forms of amiodarone-induced thyrotoxicosis (AIT). Type 1 AIT is associated with an underlying thyroid abnormality (preclinical Graves’ disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure. Type 2 AIT occurs in pts with no intrinsic thyroid abnormalities and is the result of destructive thyroiditis. Differentiation between type 1 and type 2 AIT may be difficult as the high iodine load interferes with thyroid scans. The drug should be stopped, if possible, with administration of high-dose antithyroid drugs or potassium perchlorate (200 mg q6h) in type 1 and glucocorticoids in type 2 AIT. Oral contrast agents may also be useful in type 2 AIT because of inhibition of T4 to T3 conversion.
Goiter refers to an enlarged thyroid gland (>20–25 g) and is more common in women than men. Biosynthetic defects, iodine deficiency, autoimmune disease, and nodular diseases can lead to goiter. If thyroid function is preserved, most goiters are asymptomatic. Substernal goiter may obstruct the thoracic inlet and should be evaluated with CT or MRI in pts with obstructive signs or symptoms. Thyroid function tests should be performed in all pts with goiter to exclude thyrotoxicosis or hypothyroidism. Ultrasound is not generally indicated in the evaluation of diffuse goiter, unless a nodule is palpable on physical exam.
Iodine or thyroid hormone replacement induces variable regression of goiter in iodine deficiency. For other causes of nontoxic diffuse goiter, levothyroxine can be used in an attempt to reduce goiter size. Significant regression is usually seen within 3 to 6 months of treatment; after this time it is unlikely to occur. Because underlying autonomy may be present, suppression should be instituted gradually. In younger pts, the dose can be started at 100 µg/d and adjusted to suppress the TSH into the low-normal but detectable range. Treatment of elderly pts should be initiated at 50 µg/d. Surgery is rarely indicated for diffuse goiter; radioiodine reduces goiter size by about 50% in the majority of pts.
TOXIC MULTINODULAR GOITER AND TOXIC ADENOMA
Toxic Multinodular Goiter (MNG) In addition to features of goiter, the clinical presentation of toxic MNG includes subclinical hyperthyroidism or mild thyrotoxicosis. The pt is usually elderly and may present with atrial fibrillation or palpitations, tachycardia, nervousness, tremor, or weight loss. Recent exposure to iodine, from contrast dyes or other sources, may precipitate or exacerbate thyrotoxicosis. The TSH level is low. T4 may be normal or minimally increased; T3 is often elevated to a greater degree than T4. Thyroid scan shows heterogeneous uptake with multiple regions of increased and decreased uptake; 24-h uptake of radioiodine may not be increased. Antithyroid drugs, often in combination with beta blockers, can normalize thyroid function and improve clinical features of thyrotoxicosis but may stimulate goiter growth. A trial of radioiodine should be considered before subjecting pts, many of whom are elderly, to surgery.
TOXIC ADENOMA A solitary, autonomously functioning thyroid nodule is referred to as toxic adenoma. Most pts with solitary hyperfunctioning nodules have acquired somatic, activating mutations in the TSH receptor. A thyroid scan provides a definitive diagnostic test, demonstrating focal uptake in the hyperfunctioning nodule and diminished uptake in the remainder of the gland, as activity of the normal thyroid is suppressed. Radioiodine ablation (e.g., 10–29.9 mCi 131I) is usually the treatment of choice.
Etiology Thyroid neoplasms may be benign (adenomas) or malignant (carcinomas). Benign neoplasms include macrofollicular (colloid) and normofollicular adenomas. Microfollicular, trabecular, and Hurthle cell variants raise greater concern. Carcinomas of the follicular epithelium include papillary, follicular, and anaplastic thyroid cancer. Papillary thyroid cancer is the most common type of thyroid cancer. It tends to be multifocal and to invade locally. Follicular thyroid cancer is difficult to diagnose via fine-needle aspiration because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures. It tends to spread hematogenously, leading to bone, lung, and CNS metastases. Anaplastic carcinoma is rare, highly malignant, and rapidly fatal. Thyroid lymphoma often arises in the background of Hashimoto’s thyroiditis and occurs in the setting of a rapidly expanding thyroid mass. Medullary thyroid carcinoma arises from parafollicular (C) cells and may occur sporadically or as a familial disorder, sometimes in association with multiple endocrine neoplasia type 2.
Clinical Features It is important to distinguish between a solitary nodule or a prominent nodule in the context of a multinodular goiter, as the incidence of malignancy is greater in solitary nodules. Features suggesting carcinoma include recent or rapid growth of a nodule or mass, history of neck irradiation, lymph node involvement, and fixation to surrounding tissues. Glandular enlargement may result in compression and displacement of the trachea or esophagus and obstructive symptoms.
Diagnosis An approach to the evaluation of a solitary nodule is outlined in Fig. 171-3.
FIGURE 171-3. Approach to the patient with a thyroid nodule. *There are many exceptions to the suggested options. See text and references for detail. †About one-third of nodules are cystic or mixed solid-cystic. US, ultrasound.
Benign nodules should be monitored via serial examination, with consideration of TSH suppression with levothyroxine to prevent further growth. Surgical resection or radioiodine ablation may be required in multinodular goiters with compressive effects.
Near-total thyroidectomy with lymph node dissection is required for papillary and follicular carcinoma and should be performed by a surgeon who is highly experienced in the procedure. If risk factors and pathologic features indicate the need for radioiodine treatment, the pt should be treated for several weeks postoperatively with liothyronine (25 µg bid-tid), followed by withdrawal for an additional 2 weeks, in preparation for postsurgical radioablation of remnant tissue. A scanning dose of 131I is administered when the TSH level is >50 IU/L, followed by a therapeutic dose. Subsequent levothyroxine suppression of TSH to a low, but detectable, level should be attempted in pts with a high risk of recurrence, and to 0.1–0.5 IU/L in those with a low risk of recurrence. Follow-up scans and thyroglobulin levels should be performed at regular intervals after either thyroid hormone withdrawal or administration of recombinant human TSH.
The management of medullary thyroid carcinoma is surgical, as these tumors do not take up radioiodine. Testing for the RET mutation should be considered. Elevated serum calcitonin provides a marker of residual or recurrent disease.
For a more detailed discussion, see Jameson JL and Weetman AP: Diseases of the Thyroid, Chap. 330, p. 2060, in HPIM-15.