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Thyroid disease is relatively common in the primary care setting. This chapter reviews the basic approach to hyperthyroidism, hypothyroidism and thyroid nodules.

A detailed medical history will usually reveal clues to the diagnosis of hyperthyroidism. Patients should be asked about nervousness, fatigue, palpitations, dyspnea, weight loss, heat intolerance, irritability, tremor, muscle weakness, sleep disturbance or change in menstrual pattern, bowel function, appetite, neck size or vision. Iodide exposure, thyroid hormone use and family history of thyroid disease should also be considered. Symptoms of hyperthyroidism in older patients may be predominantly cardiac - angina, palpitations or congestive heart failure - or may be entirely absent. 

When hyperthyroidism is suspected, measurement of serum thyrotropin (TSH) and free thyroxine (T4) should confirm the diagnosis. These are usually present in low and high concentrations, respectively. If the TSH level is low but the thyroxine level is normal, serum triiodothyronine (T3) should be measured; this will be elevated in cases of T3 thyrotoxicosis. Total T4 concentrations may be increased in patients with high levels of thyroxine-binding globulin (TBG), but serum concentrations of free T4 and TSH will be normal. A normal serum TSH level will almost always exclude the diagnosis of hyperthyroidism (except in the rare case of a TSH-producing tumor).

The most common cause of hyperthyroidism is Graves’ disease. Other common causes include multinodular goiter, toxic thyroid adenoma and thyroiditis (which may be painful or painless). In the absence of typical physical findings of Graves’ disease - diffuse goiter, ophthalmopathy or pretibial myxedema - measurement of radioiodine uptake should be performed. Low uptake values are indicative of thyroiditis or iodine-induced thyrotoxicosis.

Medical therapy of hyperthyroidism is summarized in Table 1. Patients with Graves’ disease are usually treated with antithyroid drugs until remission, or prior to treatment with radioiodine (inpatients over 40 years old).[i] Treatment is usually started with 20 to 30 mg of methimazole once a day or 50 to 100 mg of propylthiouracil (PTU) three times a day. The dose should be adjusted every four to six weeks to maintain normal thyroid secretion. The interval between follow-up visits can then be extended to three months. Serious side effects include agranulocytosis (particularly with PTU), jaundice, hepatitis, vasculitis and lupus-like syndromes, which mandate discontinuation of therapy. Patients may also experience pruritic skin rashes. In the absence of serious side effects, therapy is usually continued for one to two years and then re-evaluated. PTU is the drug of choice for pregnant or lactating women.

If relapse occurs, ablative therapy with radioiodine should be considered.[ii] Hypothyroidism requiring thyroxine supplementation often occurs within the first six months after treatment and may be transient or permanent. Occasionally, radiation thyroiditis causes a temporary worsening of hyperthyroidism, especially in patients not pretreated with antithyroid drugs.

Subtotal thyroidectomy is indicated in the therapy of Graves’ disease when patients are pregnant or refuse radioiodine therapy. Prior to surgery, patients should be medically treated until euthyroid or should receive a beta-blocking agent. Patients with prominent symptoms of hyperthyroidism may be treated with beta-adrenergic antagonists for symptomatic relief. In the presence of asthma, or other contraindications to beta-blockade, calcium channel blockers may be tried.

Hyperthyroidism caused by nodular disease (toxic adenoma or toxic nodular goiter) does not remit spontaneously. The most appropriate therapies are radioiodine ablation or surgery. Hyperthyroidism associated with thyroiditis, which is common after pregnancy, is usually mild and temporary, requiring only observation or symptomatic treatment with a beta-adrenergic antagonist. If thyroid pain and tenderness are present, they can be treated with short-term salicylate or glucocorticoid therapy.

TABLE 1: Medical treatment of hyperthyroidism ^1,[iii]
 

Therapeutic Agent	Actions	Indications
Antithyroid drugs Propylthiouracil      Methimazole	Inhibit thyroid hormone synthesis (PTU also exhibits extrathyroidal production of tri-iodothyronine); might exert immunosuppressive actions	First-line therapy for Graves’ hyperthyroidism, short-term therapy before radioiodine or surgery
Beta blockers	ameliorate action of thyroid hormone in tissue	adjunctive therapy
Iodine-containing compounds Potassium iodide, Lugol’s solution	inhibit thyroxine & tri-iodothyronine release	preparation for surgery, thyrotoxic crisis
Miscellaneous agents: Potassium perchlorate Lithium carbonate Glucocorticoids	inhibits iodine transport inhibits thyroid hormone synthesis & release ameliorate actions of thyroid hormone in tissue exerts immunosuppressive actions (Graves’)	Amiodarone toxicity severe subacute thyroiditis, thyrotoxic crisis

The majority of cases of hypothyroidism are due to primary thyroid gland failure resulting from chronic autoimmune thyroiditis (Hashimoto’s disease), radioactive iodine therapy or surgery. Patients should be asked about symptoms of fatigue, weakness, sleepiness, cold intolerance, constipation, muscle cramps, mental impairment, depression, menstrual disturbances, infertility and weight gain (due to water retention).[iv] Clinical findings suggestive of hypothyroidism include goiter, bradycardia, edema, hoarseness, delayed relaxation of deep tendon reflexes, slow speech and cool, dry skin.

To establish the diagnosis of hypothyroidism, a serum TSH measurement and a free T4 estimate should be performed. If the TSH is low, normal or insufficiently elevated in the presence of low T4 values, central hypothyroidism should be excluded.

L-thyroxine is the drug of choice for hypothyroidism. Recent studies have shown that some brands of generic L-thyroxine are bioequivalent to the brand-name product,[v] although some endocrinologists continue to recommend Synthroid. Adults require approximately 1.7 micrograms/kilogram a day and are usually started on 50 micrograms with dose escalation every two months.[vi] Patients over the age of 50, or younger patients with cardiac disease, should be started on a lower initial dose of 25 micrograms. Clinical and biochemical evaluation should be performed every six to eight weeks until the TSH concentration is normalized, and thereafter at six to 12 month intervals. If a change in dosage is required, the TSH concentration should be re-measured after two to three months.

Five to ten percent ofadult women, and as many as 15 percent of all patients over the age of 65 have “subclinical hypothyroidism,” or mild thyroid failure, defined as normal T4 and elevated TSH but no symptoms.[vii] As strikingly, two percent of women and 0.5-1 percent of men over 70 have unsuspected but symptomatic hypothyroidism, with elevated TSH and low T4 levels.[viii] When treated, symptoms of this overt but undiagnosed hypothyroidism are clearly reversible. Unsuspected hyperthyroidism is also present in the geriatric population, although to a lesser extent. The prevalence of undiagnosed thyroid disease has led some experts to recommend routine screening in older adults, particularly women over 50.[ix]

When considering the controversial topic of screening for thyroid dysfunction, it is important to distinguish the two different syndromes mentioned above: subclinical hypothyroidism and symptomatic but undiagnosed hypothyroidism. The latter is clearly worth finding – symptomatic patients who are treated with thyroid replacement usually feel better.^2,[x] The utility of treating patients in the former category – those with abnormal laboratory tests but no symptoms – has not been convincingly proven. Although subclinical hypothyroidism has been shown to be an independent risk factor for atherosclerosis and myocardial infarction in older women,[xi] there have not been large randomized controlled trials to demonstrate prevention of hypothyroid symptoms, prevention of thyroid disease progression, or reduction in coronary heart disease (due to improved lipid profiles[xii] and decreased homocysteine levels[xiii]), all possible but unproven benefits of treatment. The three small randomized studies that have been done have had conflicting results.[xiv]^,[xv],[xvi] Risks of treatment include osteoporosis: in post-menopausal women who are treated for subclinical hypothyroidism, L-thyroxine replacement prevents the bone-conserving effects of hormone replacement therapy.[xvii]Some authors recommend treating all patients with subclinical hypothyroidism,[xviii] but most concede that more data are required.[xix]

Current guidelines from the American College of Physicians conclude that there is insufficient evidence to recommend for or against routine screening, but that “office-based screening to detect overt thyroid dysfunction may be indicated in women older than 50 years of age.”[xx] The guidelines also note that screening all women over 50 and treating all those with subclinical hypothyroidism would result in four million new lifetime prescriptions for L-thyroxine in the first year and 600,000 to 1 million per 5 years thereafter. 

While screening (and treating) completely asymptomatic patients is controversial, thyroid function tests are recommended for older patients with a history of thyroid disease, other autoimmune diseases, depression, unexplained cognitive dysfunction[xxi] or hyperlipidemia. Some patients with these findings in the setting of an elevated TSH will feel better with thyroxine replacement: for patients with one symptom, it is estimated that 25 percent will have a clinical response to thyroxine replacement. Elderly patients with asymptomatic hypothyroidism and positive antimicrosomal antibodies or TSH levels greater than twice normal have a high frequency of progression to overt hypothyroidism and thyroid replacement is generally recommended for this group. The goal of therapy should be to normalize TSH levels; overtreatment runs the risk of precipitating angina or reducing bone mineral density. If treatment is not given to these patients, their thyroid function tests should be monitored every one to two years. 

In the absence of conclusive data, we recommend following the ACP guidelines and considering routine periodic TSH testing in all women over 50 years. This testing should be done in the outpatient setting, as screening for thyroid disease in inpatients is clearly less accurate.[xxii] If the TSH is undetectable or 10 mU/L or greater, free thyroxine levels should be tested as well. Women with overt hypothyroidism should be treated. Those with TSH higher than 4 mU/L, normal thyroxine levels, and no symptoms of hypothyroidism have subclinical hypothyroidism; it is reasonable to treat the subset with positive autoantibodies, or TSH levels more than twice normal. Treatment of women without these markers is left to the discretion of physician and patient. 

Case-finding – testing patients with specific disorders for thyroid dysfunction – is also a reasonable approach. The prevalence of subclinical hypothyroidism in men with hyperlipidemia was 1.8 percent; among women with hyperlipidemia the prevalence was 7.6 percent.[xxiii] Other studies have shown a similar doubling of rates of hypothyroidism among markedly hyperlipidemic patients.[xxiv] Diabetic patients, as well, have higher rates of hypothyroidism; one survey showed a prevalence of 10.8 percent among diabetics in a general medicine practice.[xxv]

Any thyroid disease can appear as one or more thyroid nodules. The differential diagnosis of a solitary nonfunctional thyroid nodule includes adenoma, carcinoma, cyst, a nodule of an unrecognized multinodular colloid goiter or - very rarely - inflammatory thyroid disease or a developmental abnormality.

The only biochemical test that is routinely needed in this situation is serum TSH, used to identify patients with unsuspected thyrotoxicosis. Fine-needle aspiration is the next test of choice and leads to the selection of patients who require surgery. The main indications for surgery are malignant or indeterminate cytology, local symptoms or neck disfigurement. Iodine radionuclide scanning should be reserved for patients with indeterminate cytologic features or thyrotoxicosis. Benign nodules are treated with thyroxine or observation (Figure 1).

Figure 1: Evaluation of patients with a thyroid nodule[xxvi]

We thank Dr. Robert McConnell for his helpful comments and suggestions.

Many drugs inhibit absorption of exogenously administered T4, or influence thyroid function by changing the production, secretion, transport or metabolism of T4 and T3:

 

Drugs that decrease TSH secretion ·dopamine, glucocorticoids, octreotide

Drugs that alter thyroid hormone secretion ·decreased secretion: lithium, iodide, amiodarone, aminoglutethimide ·increased secretion: colestipol, cholestyramine, ferrous sulfate, sucralfate, aluminum hydroxide

Drugs that alter T3 and T4 transport in serum ·increased serum TBG concentration: estrogens, tamoxifen, methadone, heroin, fluorouracil ·decreased serum TBG concentration: androgens, anabolic steroids, glucocorticoids ·displacement from protein-binding sites: furosemide, salicylates, phenytoin, carbamazepine

Drugs that alter T3 and T4 metabolism ·increased hepatic metabolism: phenobarbitol, rifampin, phenytoin, carbamazepine ·decreased T45’-deiodinase activity: propylthiouracil, amiodarone, beta agonists ·glucocorticoids

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