Treatment of Hypothyroidism WILLIAM J

COVER ARTICLE PRACTICAL THERAPEUTICS

Treatment of Hypothyroidism WILLIAM J. HUESTON, M.D., Medical University of South Carolina, Charleston, South Carolina

Thyroid disease affects up to 0.5 percent of the population of the United States. Its prevalence is higher in women and the elderly. The management of hypothyroidism focuses on ensuring that patients receive appropriate thyroid hormone replacement therapy and monitoring their response. Hormone replacement should be initiated in a low dosage, especially in the elderly and in patients prone to cardiac problems. The dosage should be increased gradually, and laboratory values should be monitored six to eight weeks after any dosage change. Once a stable dosage is achieved, annual monitoring of the thyroid-stimulating hormone (TSH) level is probably unnecessary, except in older patients. After full replacement of thyroxine (T4) using levothyroxine, the addition of triiodothyronine (T3) in a low dosage may be beneficial in some patients who continue to have mood or memory problems. The management of patients with subclinical hypothyroidism (a high TSH in the presence of normal free T4 and T3 levels) remains controversial. In these patients, physicians should weigh the benefits of replacement (e.g., improved cardiac function) against problems that can accompany the excessive use of levothyroxine (e.g., osteoporosis). (Am Fam Physician 2001;64:1717-24.)

ypothyroidism is second ation of the thyroid subsequent to only to diabetes mellitus Graves’ disease and surgical removal of as the most common the thyroid gland. endocrine disorder in Long-term thyroid dysfunction after the United States, and its subacute granulomatous thyroiditis Hprevalence may be as high as 18 cases per (de Quervain’s thyroiditis) or subacute 1,000 persons in the general population.1 lymphocytic thyroiditis (silent or pain- The disorder becomes increasingly com- less thyroiditis) is fairly rare. Full thyroid mon with advancing age, affecting about function is regained in 90 percent of 2 to 3 percent of older women.2 Because patients with these conditions.6 hypothyroidism is so common, family Hypothyroidism can also develop sec- physicians need to know how to diag- ondary to hypothalamic and pituitary nose the disorder and select appropriate disorders. These endocrine conditions thyroid hormone replacement therapy. occur primarily in patients who have undergone intracranial irradiation or Etiology surgical removal of a pituitary adenoma. A number of conditions can lead to hypothyroidism (Table 1).3 Of noniatro- Signs and Symptoms Members of various fam- genic causes, Hashimoto’s thyroiditis, or The signs and symptoms of hypothy- ily practice departments chronic lymphocytic thyroiditis, is the roidism are nonspecific and may be con- develop articles for “Practical Therapeutics.” most common inflammatory thyroid fused with those of other clinical condi- This article is one in a disorder and the most frequent cause of tions, especially in postpartum women series coordinated by the goiter in the United States.4 For an and the elderly. Because of the variety of Department of Family unknown reason, the prevalence of possible manifestations, family physi- Medicine at the Medical Hashimoto’s thyroiditis has been in- cians must maintain a high index of sus- University of South Car- olina, Charleston. Guest creasing dramatically in this country picion for the disorder, especially in 5 editor of the series is over the past 50 years. Other common high-risk groups. William J. Hueston, M.D. causes of hypothyroidism include irradi- Patients with severe hypothyroidism

NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1717 TABLE 1 TABLE 2 Causes of Hypothyroidism Common Signs and Symptoms of Hypothyroidism* Primary hypothyroidism (95% of cases) Idiopathic hypothyroidism* Sign or symptom Affected patients (%) Hashimoto’s thyroiditis Weakness 99 Irradiation of the thyroid subsequent to Graves’ disease Skin changes 97 (dry or coarse skin) Surgical removal of the thyroid Late-stage invasive fibrous thyroiditis Lethargy 91 Iodine deficiency Slow speech 91 Drug therapy (e.g., lithium, interferon) Eyelid edema 90 Infiltrative diseases (e.g., sarcoidosis, amyloidosis, Cold sensation 89 scleroderma, hemochromatosis) Decreased sweating 89 Secondary hypothyroidism (5% of cases) Cold skin 83 Pituitary or hypothalamic neoplasms Thick tongue 82 Congenital hypopituitarism Facial edema 79 Pituitary necrosis (Sheehan’s syndrome) Coarse hair 76

*—Probably old Hashimoto’s thyroiditis (i.e., a Skin pallor 67 “burned out” thyroid from Hashimoto’s thyroiditis). Forgetfulness 66 Adapted with permission from Hueston WJ. Thyroid Constipation 61 disease. In: Rosenfeld JA, Alley N, Acheson LS, Admire JB, eds. Women’s health in primary care. Bal- *—Only signs and symptoms that occur in 60 per- timore: Williams & Wilkins, 1997:617-31. cent or more of patients with hypothyroidism are listed in this table. Adapted with permission from Larsen PR, Davies TF, Hay ID. The thyroid gland. In: Wilson JD, Foster DW, generally present with a constellation of signs Kronenberg HM, Larsen PR, eds. Williams Textbook and symptoms that may include lethargy, of endocrinology. 9th ed. Philadelphia: Saunders, 1998:461. weight gain, hair loss, dry skin, forgetfulness, constipation and depression. Not all of these signs and symptoms occur in every patient, and many may be blunted in patients with tum thyroiditis, which has many of the same mild hypothyroidism. The most common symptoms as postpartum depression. manifestations of hypothyroidism are listed Physical findings in patients with hypothy- in Table 2.7 roidism are also nonspecific. These findings In older patients, hypothyroidism can be can include lowered blood pressure with confused with Alzheimer’s disease and other bradycardia, nonpitting edema, generalized conditions that cause cognitive impairment. hair loss (especially along the outer third of Because depression can be a manifestation the eyebrows), dry skin and a diminished of hypothyroidism, patients with this endo- relaxation phase of reflexes. crine condition may be treated as depressed, A primary challenge is to differentiate the and other signs and symptoms of the disor- generalized symptoms of early hypothy- der may be overlooked. This is particularly roidism from the similar symptoms of true with hypothyroidism that develops or fatigue and depression that occur in many worsens during pregnancy, or with postpar- other conditions.

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Diagnosis In primary hypothyroidism, the thyroid-stimulating hormone The evaluation of patients with new-onset (TSH) level is elevated, and free thyroid hormone levels are hypothyroidism is quite limited. In patients depressed. In secondary hypothyroidism, the TSH level is low with primary hypothyroidism, the thyroid- or undetectable. A follow-up assessment of the free thyrox- stimulating hormone (TSH) level is elevated, indicating that thyroid hormone production ine level can help distinguish between primary and secondary is insufficient to meet metabolic demands, hypothyroidism. and free thyroid hormone levels are depressed. In contrast, patients with secondary hypothyroidism have a low or undetectable TSH level. with secondary hypothyroidism, further TSH results have to be interpreted in light investigation with provocative testing of the of the patient’s clinical condition. A low TSH pituitary gland can be performed to deter- level should not be misinterpreted as hyper- mine if the underlying cause is a hypothala- thyroidism in the patient with clinical mani- mic or pituitary disorder. In patients with festations of hypothyroidism. When symp- pituitary dysfunction, imaging is indicated to toms are nonspecific, a follow-up assessment detect microadenomas, and levels of other of the free thyroxine (T4) level can help distin- hormones that depend on pituitary stimula- guish between primary and secondary hypo- tion should also be measured. In general, evi- thyroidism. A guide to the laboratory diagno- dence of decreased production of more than sis of hypothyroidism and the interpretation one pituitary hormone is indicative of panhy- of TSH, T4 and triiodothyronine (T3) levels is popituitary problems. provided in Table 3. Once the diagnosis of primary hypothy- Thyroid Hormone Replacement roidism is made, additional imaging or sero- SELECTING THE APPROPRIATE AGENT logic testing is unnecessary if the thyroid Thyroid medications were once prepared gland is normal on examination. In patients from desiccated samples of ground thyroid

TABLE 3 Laboratory Values in Hypothyroidism

TSH level Free T4 level Free T3 level Likely diagnosis

High Low Low Primary hypothyroidism High (>10 µU per mL Normal Normal Subclinical hypothyroidism with high risk for future [10 mU per L]) development of overt hypothyroidism High (6 to 10 µU per mL Normal Normal Subclinical hypothyroidism with low risk for future [6 to 10 mU per L]) development of overt hypothyroidism

High High Low Congenital absence of T4-T3–converting enzyme;

amiodarone (Cordarone) effect on T4-T3 conversion High High High Peripheral thyroid hormone resistance Low Low Low Pituitary thyroid deficiency or recent withdrawal of thyroxine after excessive replacement therapy

TSH = thyroid-stimulating hormone; T4 = thyroxine; T3 = triiodothyronine.

NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1719 In most healthy young adults, replacement is Because levothyroxine can cause increases in the resting heart initiated using levothyroxine in a dosage of rate and blood pressure, replacement should begin at a low 0.075 mg per day, with the dosage increased slowly as indicated by continued elevation of dosage in older patients and patients at risk for cardiovascular the TSH level. compromise. Levothyroxine should be initiated in a low dosage in older patients and those at risk for the cardiovascular compromise that could glands from cows, and standardization was occur with a rapid increase in resting heart based on the iodine content of the extract rate and blood pressure.9 In these patients,

rather than its T3 or T4 content. The actual the usual starting dosage is 0.025 mg per day. thyroid hormone content of the products This dosage can be increased in increments of varied considerably from manufacturer to 0.025 to 0.050 mg every four to six weeks manufacturer, and even within products from until the TSH level returns to normal. the same manufacturer, depending on the Thyroid hormone is usually given once thyroid status of the cows. Fortunately, this daily, but some evidence suggests that weekly method of preparing thyroid hormone has dosing may also be effective. In a small study10 been abandoned, and replacement is now of 12 patients with hypothyroidism, a bolus accomplished primarily with synthetic thy- dose of thyroid hormone equal to seven times roid hormones. the usual daily dose was well tolerated. Before A recent analysis8 of four levothyroxine weekly replacement can be recommended, preparations, including two brand-name however, more investigation is required, products (Synthroid and Levoxyl) and two including definitions of the populations in generic preparations, demonstrated relative which this approach is indicated. bioequivalence. Patients switched from any In a study11 of 33 middle-aged patients one of the four preparations to another (mostly women) with stable hypothyroidism showed insignificant variations in their thy- who were already receiving levothyroxine, roid function tests. Among the four products, small improvements in mood, memory and the only difference noted was that Synthroid cold tolerance occurred after triiodothyro- produced a more rapid and higher rise in the nine was added, in a dosage of 0.0125 mg per

T3 level after administration. However, the day, with a concomitant 0.05-mg decrease in difference was not statistically significant and the usual levothyroxine dosage. Although this is of questionable clinical importance. study was small, it suggests that some patients who are chemically euthyroid but have linger- INITIATING TREATMENT ing neuropsychiatric problems might benefit Most otherwise healthy adult patients with from triiodothyronine. Further investigation hypothyroidism require thyroid hormone is required to determine the role of tri- replacement in a dosage of 1.7 µg per kg per iodothyronine in these patients, as well as the day, with requirements falling to 1 µg per kg long-term consequences of its use. per day in the elderly. Thus, levothyroxine in a dosage of 0.10 to 0.15 mg per day is needed MONITORING THYROID FUNCTION to achieve euthyroid status. For full replace- In patients with an intact hypothalamic- ment, children may require up to 4 µg per kg pituitary axis, the adequacy of thyroid hor- per day.9 mone replacement can be followed with ser- In young patients without risk factors for ial TSH assessments. However, changes in the cardiovascular disease, thyroid hormone TSH level lag behind serum thyroid hormone replacement can start close to the target goal. levels. Thus, the TSH level should be evalu-

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ated no earlier than four weeks after an adjustment in the levothyroxine dosage. The SUBCLINICAL HYPOTHYROIDISM full effects of thyroid hormone replacement The TSH level can be mildly elevated when on the TSH level may not become apparent the free T4 and T3 levels are normal, a situation until after eight weeks of therapy.12 that occurs most often in women and becomes In patients with pituitary insufficiency, increasingly common with advancing age. measurements of free T4 and T3 levels can be This condition has been termed “subclinical performed to determine whether patients hypothyroidism,” based on the supposition remain euthyroid. In these patients, the goal is that it reflects early failure of the thyroid hor- to maintain free thyroid hormone levels in mone and eventual development of hypothy- the middle to upper ranges of normal to roidism.17 However, it appears that patients ensure adequate replacement. with a TSH level between 6 and 10 µU per mL

TSH or free T4 levels are monitored annually in most patients with hypothyroidism, although no data support this practice. Gener- Treatment of Hypothyroidism ally, once a stable maintenance dosage of levothyroxine is achieved, that dosage will re- Is there a documented need for main adequate until patients are 60 to 70 years thyroid hormone replacement? of age. With age, thyroid binding may decrease, and the serum albumin level may decline. In this setting, the levothyroxine Is the patient >50 years of age dosage may need to be reduced by up to and/or at risk for cardiac disease? 20 percent.13,14 Although less frequent than annual monitoring could be justified in Yes No younger adult patients whose weight is stable, annual monitoring in older patients is neces- Start levothyroxine, 15 Start levothyroxine, sary to avoid overreplacement. 0.025 to 0.05 mg per day. 0.075 mg per day. A guideline for initiating and monitoring thyroid hormone replacement therapy is provided in Figure 1. Monitor TSH level (if primary hypothyroidism) INTRAVENOUS REPLACEMENT or free T4 level (if secondary hypothyroidism) every 6 to 8 weeks; adjust levothyroxine Because thyroid hormone has a large vol- dosage until laboratory tests are normal. ume of distribution and long half-life, parenteral replacement is unnecessary in patients who are unable to take medication Does the patient still have orally for a few days to a week. However, lethargy or memory problems? some patients may be unable to take oral medications for much longer periods. Intra- venous administration is advised in these Yes No patients and in those who need to begin thyroid hormone replacement but cannot take Consider adding triiodothyronine, Continue to monitor TSH 0.0125 mg per day (although or T4 levels annually. oral medications. Only about 70 to 80 per- long-term effects are not known). cent of an oral dose of replacement medication is absorbed. Therefore, parenteral replacement should be initiated at 70 to 80 FIGURE 1. Initiation and monitoring of treatment for hypothyroidism. percent of the usual oral dose.16 (TSH = thyroid-stimulating hormone; T4 = thyroxine)

NOVEMBER 15, 2001 / VOLUME 64, NUMBER 10 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1721 (6 to 10 mU per L) are not at risk for subse- subclinical hypothyroidism. More research is quent hypothyroidism.1 In contrast, patients needed to sort out the most appropriate with a higher TSH level (above 10 µU per mL) management. progress to overt hypothyroidism at a rate of 1 to 20 percent per year.1 Conditions Affecting Thyroid Hormone Thyroid hormone replacement may have Replacement Requirements some benefits in patients with subclinical Because thyroid hormone is highly protein hypothyroidism, but there is also a potential bound, medical conditions that alter the for adverse effects, particularly in older amount of binding hormones and drugs that patients. Some studies have shown that sup- compete for binding may change the amount plementation of thyroid hormone accelerates of available free thyroid hormone. The thy- bone mineral loss in older women with sub- roid replacement dosage must be changed in clinical hypothyroidism, and that estrogen response to alterations in binding status. replacement therapy does not counteract this With conditions that cause an increase in effect.17 Bone-wasting effects have not been serum binding proteins, such as high estro- observed in patients who are clinically hypo- gen states (e.g., pregnancy), oral contracep- thyroid and receive adequate thyroid hor- tive use or postmenopausal estrogen replace- mone replacement therapy.18 ment, the dosage of levothyroxine must be Thyroid hormone replacement has also increased. In contrast, androgens decrease been reported to decrease serum homocys- levels of thyroid binding proteins, necessitat- teine levels.19 Along with changes in lipids, ing a reduction in the dosage. Older patients hyperhomocysteinemia may be one of the also have lower serum protein levels and may mechanisms through which hypothyroidism require reductions in their maintenance is associated with an increased risk for cardio- dosage over time. Nephrosis, protein-losing vascular disease.20 enteropathies and cirrhosis are other condi- At this time, the approach to patients with tions that require a reduced thyroid hor- subclinical hypothyroidism must be individ- mone dosage. ualized. In patients at higher risk for osteo- A number of medications reduce the porosis or fractures, the deleterious effects of absorption of thyroid hormone from the excessive thyroid hormone can be avoided by intestines, necessitating an increase in the 21 withholding replacement until the free T4 replacement dosage (Table 4). Other drugs

and T3 levels drop below normal. In patients accelerate the metabolism of thyroid hor- with hyperhomocysteinemia, existing car- mone, and an increase in the replacement diac disease or risk factors for heart disease, dosage is then required. When these medica- early thyroid hormone replacement may tions are started or adjusted, the TSH value offer more advantages. Right now, consensus should be monitored to determine whether is lacking on how to manage patients with additional thyroid hormone replacement is indicated.

Persistently Elevated TSH Despite The Author Thyroid Hormone Replacement WILLIAM J. HUESTON, M.D., is professor and chair of the Department of Family Medi- Poor compliance is the most common rea- cine at the Medical University of South Carolina, Charleston. He received his medical son for continued elevation of the TSH level degree from Case Western Reserve University School of Medicine, Cleveland, and com- pleted a family practice residency at Riverside Methodist Hospital, Columbus, Ohio. in patients receiving presumably adequate thyroid hormone replacement. Patients who Address correspondence to William J. Hueston, M.D., Department of Family Medicine, Medical University of South Carolina, P.O. Box 250192, Charleston, SC 29425 (e-mail: do not regularly take their replacement med- [email protected]). Reprints are not available from the author. ication and then try to “catch up” just before

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a physician visit may restore their free T4 lev- vated, and the patients continue to have els to normal but continue to have an elevated symptoms of hypothyroidism. These patients TSH level. should be referred to an endocrinologist for Very rarely, patients have tissue-level unre- further evaluation and management. sponsiveness to thyroid hormone. This condition reflects a mutation in the gene that Screening for Hypothyroidism 23 controls a receptor for T3, rendering it unable The U.S. Preventive Services Task Force to bind with the hormone. The genetic muta- does not recommend routine screening for tion has been identified in only 300 families.22 hypothyroidism in asymptomatic persons. In these patients, adequate amounts of thy- Recently, some expert panels24 noted that roid hormone are produced but are ineffec- screening may be beneficial in high-risk pop- tive. Consequently, the TSH level remains ele- ulations such as elderly women. However, widespread screening is not likely to be cost- effective. Because of the nonspecific symp- TABLE 4 toms of hypothyroidism, many patients Drugs Potentially Altering Thyroid would be tested because of their symptoms. Hormone Replacement Requirements This practice should not be confused with asymptomatic screening. Increase replacement requirements The author indicates that he does not have any con- Drugs that reduce thyroid hormone production flicts of interest. Sources of funding: none reported. Lithium Iodine-containing medications REFERENCES Amiodarone (Cordarone) 1. Helfand M, Crapo LM. Screening for thyroid dis- Drugs that reduce thyroid hormone absorption ease. Ann Intern Med 1990;112:840-9. Sucralfate (Carafate) 2. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach Ferrous sulfate (Slow Fe) P. The aging thyroid. Increased prevalence of ele- Cholestyramine (Questran) vated serum thyrotropin levels in the elderly. JAMA 1979;242:247-50. Colestipol (Colestid) 3. Hueston WJ. Thyroid disease. In: Rosenfeld JA, Aluminum-containing antacids Alley N, Acheson LS, Admire JB, eds. Women’s Calcium products health in primary care. Baltimore: Williams & Wilkins, 1997:617-31. Drugs that increase metabolism of thyroxine 4. Farwell AP, Braverman LE. Inflammatory thyroid Rifampin (Rifadin) disorders. Otolaryngol Clin North Am 1997;29: Phenobarbital 541-56. Carbamazepine (Tegretol) 5. Hay ID. Thyroiditis: a clinical update. Mayo Clin Warfarin (Coumadin) Proc 1985;60:836-43. 6. Schubert MF, Kountz DS. Thyroiditis. A disease Oral hypoglycemic agents with many faces. Postgrad Med 1995;98(2):101- Increase thyroxine availability and may decrease 3,107-8,112. replacement requirements 7. Larsen PR, Davies TF, Hay ID. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, Drugs that displace thyroid hormone from protein eds. Williams Textbook of endocrinology. 9th ed. binding Philadelphia: Saunders, 1998:461. Furosemide (Lasix) 8. Dong BJ, Hauck WW, Gambertoglio JG, Gee L, Mefenamic acid (Ponstel) White JR, Bubp JL, et al. Bioequivalence of generic and brand-name levothyroxine products in the Salicylates treatment of hypothyroidism. JAMA 1997;277: 1205-13. Adapted with permission from Surks MI, Sievert R. 9. Singer PA, Cooper DS, Levy EG, Ladenson PW, Drugs and thyroid function. N Engl J Med 1995; Braverman LE, Daniels G, et al. Treatment guidelines for patients with hyperthyroidism and hypothy- 333:1688-94. roidism. Standards of Care Committee, American Thyroid Association. JAMA 1995;273:808-12.

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