Thyroid disorders affect 1 in 200 adults but are more common in women and with advancing age. The incidence of hypothyroidism, for instance, is 0.3–5 cases per 1000 individuals per year, including 7% of women and 3% of men aged 60–89 years. Hypothyroidism is much more common than hyperthyroidism, nodular disease, or thyroid cancer. Thyroid nodules occur in 4–8% of all individuals and, like other thyroid problems, increase in incidence with age.
Thyroid disease is more common in people who have conditions such as diabetes or other autoimmune diseases (eg, lupus); in those with a family history of thyroid disease or a history of head and neck irradiation; and in patients who use certain medications, including amiodarone and lithium. Recent guidelines from the American Thyroid Association suggest that all adults have their serum thyroid-stimulating hormone (TSH) concentrations measured, beginning at age 35 and every 5 years thereafter.
Causes of hypothyroidism are outlined in Table 37-1. The most common noniatrogenic condition causing hypothyroidism in the United States is Hashimoto thyroiditis. Other common causes are post–Graves disease, thyroid irradiation, and surgical removal of the thyroid. Hypothyroidism may also occur secondary to hypothalamic or pituitary dysfunction, most commonly in patients who have received intracranial irradiation or surgical removal of a pituitary adenoma. In addition, some patients may have mild elevations of TSH despite normal thyroxine levels, a condition termed subclinical hypothyroidism.
Table 37–1.Causes of hypothyroidism. ||Download (.pdf) Table 37–1.Causes of hypothyroidism.
|Primary hypothyroidism (95% of cases) |
Idiopathic hypothyroidism (probably old Hashimoto thyroiditis)
Late-stage invasive fibrous thyroiditis
Drugs (lithium, interferon)
Infiltrative diseases (sarcoidosis, amyloid, scleroderma, hemochromatosis)
Secondary Hypothyroidism (5% of cases)
Pituitary or hypothalamic neoplasms
Pituitary necrosis (Sheehan syndrome)
Patients with hypothyroidism present with a constellation of symptoms that can involve every organ system. Symptoms include lethargy, weight gain, hair loss, dry skin, slowed mentation or forgetfulness, depressed affect, cold intolerance, constipation, hair loss, muscle weakness, abnormal menstrual periods (or infertility), and fluid retention. Because of the range of symptoms seen in hypothyroidism, clinicians must have a high index of suspicion, especially in high-risk populations. In older patients, hypothyroidism can be confused with Alzheimer disease or other conditions that cause dementia. In women, hypothyroidism is often confused with depression.
Physical findings that can occur with hypothyroidism include low blood pressure, bradycardia, nonpitting edema, generalized hair thinning along with hair loss in the outer third of the eyebrows, skin drying, and a diminished relaxation phase of reflexes. The thyroid gland in a patient with chronic thyroiditis may be enlarged, atrophic, or of normal size. Thyroid nodules are common in patients with Hashimoto thyroiditis.
The most valuable test for hypothyroidism is the sensitive TSH assay. Measurement of the free thyroxine (T4) level may also be helpful. TSH is elevated and free T4 decreased in overt hypothyroidism (Table 37-2). Other laboratory findings may include hyperlipidemia and hyponatremia. Hashimoto thyroiditis, an autoimmune condition, is one of the most common causes of hypothyroidism. Testing for thyroid autoantibodies (antiperoxidase, antithyroglobulin) is positive in 95% of patients with Hashimoto thyroiditis.
Table 37–2.Laboratory changes in hypothyroidism. ||Download (.pdf) Table 37–2.Laboratory changes in hypothyroidism.
|TSH ||Free T4 ||Free T3 ||Likely Diagnosis |
|High ||Low ||Low ||Primary hypothyroidism |
|High (>10 μIU/mL) ||Normal ||Normal ||Not consistent with the AACE guideline mentioned previously; subclinical hypothyroidism with high risk for future development of overt hypothyroidism |
|High (6–10 μIU/mL) ||Normal ||Normal ||Subclinical hypothyroidism with low risk for future development of overt hypothyroidism |
|High ||High ||Low ||Congenital absence of T4–T3-converting enzyme or amiodarone effect |
|High ||High ||High ||Peripheral thyroid hormone resistance |
|Low ||Low ||Low ||Pituitary thyroid deficiency or recent withdrawal of thyroid replacement after excessive replacement |
Patients with associated subclinical hypothyroidism have a high TSH level (usually in the 5–10 μIU/mL range) in conjunction with normal free T4 level. Between 3% and 20% of these patients will eventually develop overt hypothyroidism. Patients who test positive for thyroid antibodies are at increased risk.
In patients with primary hypothyroidism, therapy should begin with thyroid hormone replacement. In patients with secondary hypothyroidism, further investigation with provocative testing of the pituitary can be performed to determine whether the cause is a hypothalamic or pituitary problem.
Most healthy adult patients with hypothyroidism require ∼1.6 μg/kg of thyroid replacement, with requirements falling to 1 μg/kg for the elderly. The initial dosage may range from 12.5 μg to a full replacement dose of 100–150 μg of levothyroxine (0.10–0.15 mg/d). Doses will vary depending on age, weight, cardiac status, duration, and severity of the hypothyroidism. Therapy should be titrated after at least 6 weeks following any change in levothyroxine dose. The serum TSH level is the most important measure to gauge the dose.
Treatment of subclinical hypothyroidism remains controversial. Subclinical hypothyroidism is characterized by a serum TSH above the upper reference limit in combination with a normal free thyroxine (T4) at a time when thyroid function has been stable for several weeks, the hypothalamic-pituitary-thyroid axis is normal, and there is no recent or ongoing severe illness The prevalence of subclinical hypothyroidism is ~5–10%, more common in white older women. The American Association of Clinical Endocrinologists (AACE) guidelines suggest treating patients with TSH levels of >10 μIU/mL as well as those with TSH levels between 5 and 10 μIU/mL in conjunction with goiter or positive antithyroid peroxidase antibodies, or both (level of evidence for American Thyroid Association recommendations: level 3 or 4, clinical consensus based on the literature). Others base any therapeutic intervention on the individual situation (pregnancy status, cardiovascular risk factors, etc).
Once the TSH level reaches the normal range, the frequency of testing can be decreased. Each patient’s regimen must be individualized, but the usual follow-up after TSH is stable is at 6 months; the history and physical examination should be repeated on a routine basis thereafter.
Thyroid hormone absorption can be affected by malabsorption, age, and concomitant medications such as cholestyramine, ferrous sulfate, sucralfate, calcium, and some antacids containing aluminum hydroxide. Drugs such as anticonvulsants affect thyroid hormone binding, whereas others such as rifampin and sertraline hydrochloride may accelerate levothyroxine metabolism, necessitating a higher replacement dose. The thyroid dose may also need to be adjusted during pregnancy. There has been some interest in using a combination of T4 and triiodothyronine (T3) or natural thyroid preparations in pregnant women with hypothyroidism, but studies to date have been small and findings inconsistent.
Pregnant women with thyroid dysfunction need close attention. Overt maternal hypothyroidism is known to have serious adverse effects on the fetus. The Endocrine Society has developed practice guidelines that address the management of thyroid dysfunction during pregnancy and postpartum.
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Hyperthyroidism has several causes. The most common is toxic diffuse goiter (Graves disease), an autoimmune disorder caused by immunoglobulin G (IgG) antibodies that bind to TSH receptors, initiating the production and release of thyroid hormone. Other causes include toxic adenoma; toxic multinodular goiter (Plummer disease); painful subacute thyroiditis; silent thyroiditis, including lymphocytic and postpartum thyroiditis; iodine-induced hyperthyroidism (eg, related to amiodarone therapy); oversecretion of pituitary TSH; trophoblastic disease (very rare); and excess exogenous thyroid hormone secretion.
Patients with hyperthyroidism usually present with progressive nervousness, tremor, palpitations, weight loss, dyspnea on exertion, fatigue, difficulty concentrating, heat intolerance, and frequent bowel movements or diarrhea. Physical findings include a rapid pulse and elevated blood pressure, with the systolic pressure increasing to a greater extent than the diastolic pressure, creating a wide pulse-pressure hypertension. Exophthalmos (in patients with Graves disease), muscle weakness, sudden paralysis, dependent low extremity edema, or pretibial myxedema may also be present. Cardiac arrhythmias such as atrial fibrillation may be evident on physical examination or electrocardiogram, and a resting tremor may be noted on physical examination.
In patients with subacute thyroiditis, symptoms of hyperthyroidism are generally transient and resolve in a matter of weeks. There may be a recent history of a head and neck infection, fever, and severe neck tenderness. Postpartum thyroiditis may occur in the first few months after delivery. Both types of thyroiditis may have a transient hyperthyroid phase, a euthyroid phase, and occasionally a later hypothyroid phase.
B. Laboratory and Imaging Evaluation
Hyperthyroidism is detected by a decreased sensitive TSH assay and confirmed, if necessary, by the finding of an elevated free T4 level. Testing for thyroid autoantibodies, including TSH receptor antibodies (TRAb) or thyroid-stimulating immunoglobulins (TSI), may be done as necessary. Once hyperthyroidism is identified, radionucleotide uptake and scanning of the thyroid, preferably with iodine-123, is useful to determine whether hyperthyroidism is secondary to Graves disease, an autonomous nodule, or thyroiditis (ie, by showing activity and anatomy of the thyroid). In scans of patients with Graves disease, there is increased uptake on radionucleotide imaging with diffuse hyperactivity. In contrast, nodules demonstrate limited areas of uptake with surrounding hypoactivity, and in subacute thyroiditis, uptake is patchy and decreased overall.
Thyroid storm represents an acute hypermetabolic state associated with the sudden release of large amounts of thyroid hormone. This occurs most often in Graves disease but can occur in acute thyroiditis. Individuals with thyroid storm present with confusion, fever, restlessness, and sometimes with psychosislike symptoms. Physical examination shows tachycardia, elevated blood pressure, and sometimes fever. Cardiac dysrhythmias may be present or develop. Patients will have other signs of high-output heart failure (dyspnea on exertion, peripheral vasoconstriction) and may exhibit signs of cardiac or cerebral ischemia. Thyroid storm is a medical crisis requiring prompt attention and reversal of the metabolic demands from the acute hyperthyroidism.
Radioactive iodine is the treatment of choice for Graves disease (GD) in adult patients who are not pregnant. Pretreatment with methimazole prior to radioactive iodine therapy for GD should be considered in patients who are at increased risk for complications due to worsening of hyperthyroidism (ie, those who are extremely symptomatic or have free T4 estimated at 2–3 times the upper limit of normal). Treatment with β-adrenergic blockers should be done prior to radioactive iodine therapy in patients with GD who are at increased risk for complications due to worsening of hyperthyroidism (ie, those who are extremely symptomatic or have free T4 estimates 2–3 times the upper limit of normal). Iodine-131 has also been used on an individual basis in patients aged <20 years. To date, studies have shown no evidence of adverse effects on fertility, congenital malformations, or increased risk of cancer in women who were treated with radioactive iodine during their childbearing years or in their offspring. Patients should be advised to postpone pregnancy for at least 6 months postablation therapy.
Radioactive iodine should not be used in breastfeeding mothers. There is also concern that the administration of radioactive iodine in patients with active ophthalmopathy may accelerate progression of eye disease. For this reason, some experts initially treat Graves disease with oral suppressive therapy until the ophthalmologic disease has stabilized.
Antithyroid drugs are well tolerated and successful at blocking the production and release of thyroid hormone in patients with Graves disease. These drugs work by blocking the organification of iodine. Methimazole is the drug of choice in patients who choose antithyroid drug therapy for GD, except during the first trimester of pregnancy when propylthiouracil is preferred. Methimazole is administered once a day, and is associated with a reduced risk of major side effects such as agranulocytosis and hepatic injury compared to propylthiouracil (PTU). Patients need a baseline complete blood count, including white count with differential, and a liver profile including bilirubin and transaminases before starting antithyroid drug therapy for GD.
β-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates of >90 bpm or coexistent cardiovascular if there are no relative contraindications such as bronchospasm.
Surgery is reserved for patients in whom medication and radioactive iodine ablation are not acceptable treatment strategies or in whom a large goiter is present that compresses nearby structures or is disfiguring.
D. Treatment of Thyroid Storm
For patients with thyroid storm, aggressive initial therapy is essential to prevent complications. Treatment should include the administration of high doses of PTU (100 mg every 6 hours) to quickly block thyroid release and reduce peripheral conversion of T4 to T3. In addition, high doses of β-blockers (propranolol, 1–5 mg intravenously or 20–80 mg orally every 4 hours) can be used to control tachycardia and other peripheral symptoms of thyrotoxicosis. Hydrocortisone (200–300 mg/d) is used to prevent possible adrenal crisis.
E. Postablation Follow-up
Follow-up is necessary to evaluate possible hypothyroidism postablation. Follow-up can begin 6 weeks after therapy and continue on a regular basis until there is evidence of early hypothyroidism, as confirmed by an elevated TSH level. Therapy should then be started as described earlier in the discussion of hypothyroidism.
American Association of Clinical Endocrinologists and American Thyroid Association. Hyperthyroidism and other causes of thyrotoxicosis. Endocr Practice. 2011;17:456–520.
Thyroid nodules are a common clinical finding, reported in 37% of patients on the basis of palpation. The prevalence of diagnosed thyroid nodules has increased dramatically since the early 1990s because of the widespread use of ultrasonography for the evaluation of thyroid and nonthyroid neck conditions. Autopsy data indicate that thyroid nodules may be present in 50% of the population. Thyroid nodules are more common in women, the elderly, patients with a history of head and neck irradiation, and those with a history of iodine deficiency.
Thyroid nodules may be associated with benign or malignant conditions. Benign causes include multinodular goiter, Hashimoto thyroiditis, simple or hemorrhagic cysts, follicular adenomas, and subacute thyroiditis. Malignant causes include carcinoma (papillary, follicular, Hürthle cell, medullary, or anaplastic), primary thyroid lymphoma, and metastatic malignant lesion.
Many patients with thyroid nodules are asymptomatic. Often the nodule is discovered incidentally on physical examination or by imaging studies ordered for unrelated reasons. Evaluation is needed to rule out malignancy. A thorough history should be obtained, including any history of benign or malignant thyroid disease (see sections on hyper- and hypothyroidism, earlier) and head or neck irradiation. Patients should be asked about recent pregnancy, characteristics of the nodule, and any neck symptoms (eg, pain, rate of swelling, hoarseness, swelling of lymph nodes).
Several features of the history are associated with an increased risk of malignancy in a thyroid nodule. These include prior head and neck irradiation, family history of medullary carcinoma or multiple endocrine neoplasia syndrome type 2, age <20 years or >70 years, male gender, and rapid growth of a nodule. Physical findings that should raise clinical suspicion of malignancy include firm consistency, cervical adenopathy, and symptoms such as persistent hoarseness, dysphonia, dysphagia, or dyspnea.
B. Laboratory and Diagnostic Findings
Laboratory and diagnostic evaluation relies on ultrasound, measurement of TSH level, and fine-needle aspiration (FNA). Ultrasound is not useful as a universal screening tool but can be helpful in screening patients whose history places them at high risk for developing thyroid cancer (see section on symptoms and signs, earlier).
1. Workup of a palpable thyroid nodule
If the nodule is palpable, TSH assay and ultrasonography of the thyroid should be performed. These two modalities will help guide clinical decision making. If the nodule appears suspicious on ultrasound (on the basis of position, shape, size, margins, or echogenic pattern), FNA should be performed irrespective of whether the patient’s TSH level is elevated, normal, or suppressed. For instance, it has been reported that nodules in patients with Graves disease may be malignant in 9% of the cases. If the nodule does not appear suspicious on ultrasound, the clinician can proceed with workup of the abnormal TSH level. For example, if the TSH level is suppressed, the patient may have hyperthyroidism caused by either a single autonomous nodule or a multinodular goiter. The patient would then be evaluated for hyperthyroidism and therapy initiated, as appropriate.
In patients with an elevated TSH level suggestive of hypothyroidism, the next steps would be based on the ultrasound findings. If the nodule does not appear suspicious, thyroid peroxidase antibodies (useful for diagnosing Hashimoto thyroiditis) can be measured and treatment of hypothyroidism initiated (ie, using levothyroxine therapy). If the nodule appears suspicious, FNA should be performed.
2. Workup of an “incidental” thyroid nodule
If the thyroid nodule is found incidentally by ultrasonography, the next step is to obtain a TSH level. If the TSH level is normal, the nodule is <10 mm, the patient does not have risk factors for thyroid malignancy, and the ultrasound findings do not appear suspicious, clinical follow-up is performed. If the nodule is >10 mm or the patient has risk factors for thyroid malignancy, FNA should be performed.
Approximately 70% of FNA specimens are classified as benign, 5% are malignant, 10% are suspicious, and 10–20% are nondiagnostic. If FNA reveals malignant cells, surgical intervention is indicated and further treatment will be based on the characteristics noted at surgery (pathologic findings, positive lymph nodes, etc).
Patients with malignant thyroid nodules should be referred to surgical and medical oncologists familiar with the management of these tumors. The remainder of this discussion focuses on follow-up and management of patients with FNA-negative thyroid nodules.
Use of exogenous levothyroxine therapy in a euthyroid patient in an effort to “suppress the TSH” (ie, decrease TSH level to <0.1 IU/mL) and “shrink” the nodule is of benefit in only a few patients with palpable nodules. The side effects of exogenous thyroid therapy (cardiac arrhythmias, osteoporosis, etc) must be considered, especially in older patients and in postmenopausal women; its use in these populations is thus relatively contraindicated.
Patients with very large nodules may require surgery, especially if symptoms secondary to the size (eg, dysphagia) are present. If there is a change in size of the nodule, a repeat FNA should be performed.
Ultrasound-guided percutaneous ethanol injection (PEI) is a therapeutic option for patients with benign nodules that have a large fluid component (thyroid cysts). Aspiration (eg, during FNA) itself may drain a cyst and shrink the size, but recurrences are common. Surgery is sometimes needed if the cyst is very large. Some data show that PEI is more effective in decreasing the size of a nodule than aspiration alone.
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