Should We Be Screening for Thyroid Disease?

PERSPECTIVE

Should We Be Screening for Thyroid Disease? Gay Canaris, MD, MSPH

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hyroid disease is a common medical problem. The prevalence of hyperthyroidism ranges from 0.3% to 1.9%, and the prevalence of hypothyroidism ranges from 0.5% to 24% [1–11]. On average, across multiple studies, about 5% of people have a thyrotropin or thyroid-stimulating hormone (TSH) level greater than 6 mU/L [12]. The wide range of reported prevalence rates between studies, particularly with regard to hypothyroidism, is likely due to differences in population composition, definitions of disease, and the thyroid function tests that are used. Testing for thyroid dysfunction is best done with the thirdgeneration, “supersensitive” immunometric TSH assay. The first TSH test used after the late 1960s was the radioimmunoassay, which was not able to distinguish thyrotoxic states [13]. Thyrotropin-releasing hormone stimulation tests were thus used. Today’s third-generation assay defines hypo- and hyperthyroidism and defines borderline states when used with thyroid hormone levels. Thyroid hormone levels by themselves cannot discriminate between thyroid states. The total thyroxine (T4) level is affected by anything that increases thyroxine-binding globulin, and the free T4 does not distinguish between disease states since it can be normal in both hypo- and hyperthyroidism. There are rare cases where the third-generation TSH may not be helpful, as with central hypothyroidism. Despite a good laboratory test, thyroid disorders still go undiagnosed. This is particularly true of hypothyroidism. Hypothyroidism develops gradually. Many patients do not notice classic symptoms, and often the symptoms that are reported are neither sensitive nor specific for thyroid disease. It is estimated that up to 10% of people have undetected thyroid dysfunction [5,14]. Since thyroid disease is common, and much of it remains undetected, screening would seem appropriate. Yet screening remains controversial. This article will review thyroid disease in light of factors that justify screening, review the recommendations of medical societies and other organizations with regard to thyroid screening, and examine the controversy surrounding screening for subclinical disease. Criteria for Screening Certain criteria need to be met to justify a screening program. The following are recommendations adapted from Sackett’s group [15]. www.turner-white.com

1. The burden of suffering of the disease should warrant screening 2. The test used to screen for the disease should have a high sensitivity and specificity 3. Those being screened should be likely to comply with the screening test, any subsequent evaluation that may be needed, and the treatment options 4. The cost of the screening test should be acceptable 5. There should be effective treatment for the disorder 6. The current health system should be able to accommodate such a screening program 7. Early diagnosis should lead to improved clinical outcomes with respect to function, quality of life, and survival 1. The burden of suffering of the disease warrants screening The burden of suffering attributed to thyroid disease is significant. There is a high prevalence of thyroid disease, particularly in older patients and in women more than men. People who have other autoimmune endocrine disease, who have affected family members, and who report traditional symptoms (especially symptoms that have changed in the previous year) are at greater risk for thyroid disease [1,5,8,9,16,17]. There is also significant morbidity associated with thyroid disease. Hyperthyroidism is associated with atrial arrhythmias, decreased bone density, and higher prevalence of hip and vertebral fractures [18–24]. Hypothyroidism is associated with increased symptoms, elevated lipid levels, and coronary artery disease [5,16,25–29]. 2. The test used to screen for the disease has a high sensitivity and specificity The test used to screen for thyroid disease is the thirdgeneration TSH. It is the preferred test for screening in a costeffectiveness comparison done by Schectman and Pawlson [30] and is the test recommended by the American College of

From the Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.

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SCREENING FOR THYROID DISEASE Physicians [31]. As discussed above, the TSH with the free T4 defines thyroid function in most cases. Most TSH assays are capable of detecting serum TSH concentrations as low as 0.005 mU/L [13]. 3. Those being screened are likely to comply with the screening test, any subsequent evaluation that may be needed, and the treatment options A TSH level is available as a simple blood draw and at a reasonable cost. Patients are generally receptive to having their blood drawn, so those offered screening are likely to comply. Subsequent evaluation and treatment depends upon the results of the test. Patients who are hypothyroid require thyroid hormone replacement, such as oral daily levothyroxine. Evaluation and treatment may vary for hyperthyroid patients, who may be thyrotoxic for various reasons. Evaluation may include thyroid scanning; treatment may range from medications such as β-adrenergic blockers and analgesics for acute viral thyroiditis to antithyroid drugs, radioactive iodine, or even surgery. Most therapies for thyroid disease are relatively acceptable to patients. Although the increased invasiveness of some therapies, such as surgery, are not desirable, most patients find treatment options acceptable. 4. The cost of the screening test is acceptable The cost of the serum TSH test is reasonable. (Charges for the third-generation TSH at our institution are approximately $37.) Using the TSH test to screen for thyroid disease has been shown to be cost-effective. Danese and others found that the cost-effectivesness of screening for thyroid failure was comparable to the cost-effectiveness of other generally accepted preventive medical practices when included with routine cholesterol testing [32]. 5. There is effective treatment for the disorder There are good treatment options for thyroid disease. Hypothyroidism constitutes the vast majority of what is detected by screening with the serum TSH assay, and it is relatively easy to treat: patients receive levothyroxine replacement as 1 pill per day. Replacement levothyroxine is generally welltolerated and inexpensive, approximately $5 per month for a 100-µg daily dose. Hyperthyroidism has several treatment options that are usually effective, although many of the treatments result in hypothyroidism, which requires subsequent hormone replacement. 6. The current health system can accommodate screening The current health system can accommodate screening for thyroid disease. Several ways to implement such a screening program have been proposed. Danese and colleagues advocate requesting a measurement of serum TSH concentration at the same time a lipid profile is ordered [32]. Drake et al 28 JCOM September 2001 Vol. 8, No. 9

reported that screening was most cost-effective when only those patients who reported 5 or more classic symptoms of thyroid disease at a clinic appointment were tested [33]. Some authors recommend a case-finding approach. That is, rather than screening the general public, patients are screened when they present to their care providers for unrelated reasons. This is the model used in hypertension screening, in which all patients seen for a clinic appointment have their blood pressure measured. Case-finding has some advantages over generalized screening. Case-finding typically reaches a greater proportion of the population than does mass screening (eg, screening done at a health fair). In case-finding, screening for the target disorder is continuous, whereas health fair screenings are sporadic. In addition, appropriate followup is better facilitated in case-finding through the clinic where the patient receives his or her care [15]. 7. Early diagnosis leads to improved clinical outcomes It is arguable whether early diagnosis of thyroid disease results in improved outcomes, but the body of evidence is growing. Because hypothyroidism is associated with hyperlipidemia and coronary artery disease [5,25–29], treating hypothyroidism would seem desirable to avoid poor cardiovascular outcomes. Replacing thyroid hormone to euthyroid levels does result in decreased lipid levels [26,29,34–36]. It has also been shown that hypertension associated with hypothyroidism reverses with thyroid hormone replacement [37]. Relief of symptoms is another benefit of screening, but the benefit is difficult to quantify. In 1 study, Cooper and colleagues found that in patients with subclinical hypothyroidism, symptoms improved in 8 of 14 patients receiving thyroxine and in 3 of 12 patients receiving placebo (P < 0.05) [38]. Zulewski also showed symptom improvement among treated patients [39]. Similarly, treating hyperthyroidism would seem desirable to avoid adverse symptoms, atrial arrhythmias, osteopenia, and subsequent hip and vertebral fractures [18–22]. Summary of Screening Recommendations Despite arguments that screening for thyroid disease is beneficial and appropriate, no organization currently recommends mass screening. However, some groups suggest testing individuals who have a higher pre-test probability of disease, that is, who have a greater likelihood of having thyroid disease. Some of the factors that increase risk for thyroid disease are listed in Table 1. Screening recommendations are available from several organizations (Table 2). The American College of Physicians (ACP), The American Association of Family Practice and the American Association of Clinical Endocrinology recommend periodic testing of all older women [31,40,41]. The ACP states “it is reasonable to screen women older than 50 years of age for unsuspected but symptomatic thyroid www.turner-white.com

PERSPECTIVE disease.” It does not recommend screening women younger than age 50 nor men of any age because of the lower prevalence of overt disease in these demographic groups. Although there is significantly more subclinical disease than overt hypo- or hyperthyroidism in most populations, the ACP does not recommend for or against the treatment of subclinical thyroid disease, so does not include the identification of subclinical disease as a benefit of screening [31]. The American Thyroid Association (ATA) recommendations published in 1990 suggested testing the elderly for thyroid disease, as well as testing persons with a family history of thyroid disease or with a personal history of other autoimmune disease and women who are postpartum [42]. In 1995, the ATA modified their screening guidelines to state that “because of high prevalence of hypothyroidism in women past 60 years of age, it is recommended that such individuals be screened with a serum TSH measurement.” They suggested annual screening with a serum TSH for all patients with a prior history of any medically or surgically treated thyroid disease. They further expanded their screening recommendations to include not only patients with coexisting autoimmune diseases as before, but also patients with unexplained depression, cognitive dysfunction, or hypercholesterolemia [43]. Their most recent guidelines state that women and men should be screened beginning at 35 and then every 5 years after that [44]. The Canadian Task Force on the Periodic Health Examination concluded that there is not enough evidence to recommend the inclusion of screening for thyroid dysfunction (hyperthyroidism and hypothyroidism) in asymptomatic adults.” They state that “the line between truly asymptomatic and mildly symptomatic adults may, however, be difficult to draw. Considering the high prevalence of thyroid disease, particularly hypothyroidism in women, and the fact that some studies have shown that affected women may benefit from early treatment, it is recommended that clinicians maintain a high index of suspicion and not hesitate to use immunometric thyroid stimulating hormone (TSH) assays to investigate individuals with vague symptoms that could be related to thyroid dysfunction [45].

The United States Preventive Services Task Force (USPSTF) states that routine screening for thyroid disease with thyroid function tests is not recommended for asymptomatic children or adults. There is insufficient evidence to recommend for or against screening for thyroid disease with thyroid function tests in high-risk patients, but recommendations may be made on other grounds. Clinicians should remain alert to subtle symptoms and signs of thyroid dysfunction when examining such patients [46].

The primary objection that most of these groups have to screening is that the prevalence of overt thyroid disease is www.turner-white.com

Table 1. Factors That Increase Risk for Thyroid Disease Advancing age Female sex Down syndrome Classic thyroid symptoms (particularly symptoms that have changed in the last year) [16,33] Family history of thyroid disorders Personal history of autoimmune disorders Personal history of radiation (such as for lymphoma or head and neck cancer) Hypothalamic or pituitary disease Certain medications (eg, lithium) Sufficient amounts of iodine (such as with amiodarone therapy) Goiter Postpartum status Previous thyroid surgery or radioactive iodine therapy [17]

too low to warrant it. The majority of what is found on thyroid screening is subclinical hypothyroidism, and not everyone agrees that subclinical hypothyroidism should be treated. The ACP says that “screening remains controversial because the results of randomized trials of treatment in symptomatic patients have been inconclusive and because asymptomatic persons have not been shown to benefit from treatment” [31]. The ATA guidelines acknowledge the high prevalence of subclinical hypothyroidism and that some patients feel better when treated with levothyroxine. The ATA states that “therapy for subclinical hypothyroidism is probably advisable, especially if thyroid autoantibodies are positive, because overt hypothyroidism develops with high frequency in such patients” [43]. The USPSTF cites conflicting evidence regarding the treatment of subclinical hypothyroidism in their recommendation against screening, and expresses concern for potential adverse outcomes from overreplacing thyroid hormone. This may be a legitimate concern. Of the patients who reported being on thyroid hormone in the Colorado Thyroid Disease Prevalence Study, 40% were not within the euthyroid range [5]. However, this side effect is easily avoided with thyroid function testing at regular intervals. Conclusion The debate over screening for thyroid disease may come down to whether or not to screen for and treat subclinical hypothyroidism. Subclinical hypothyroidism is defined by an elevated TSH and normal or elevated free T4. The prevalence is greater than that of overt hypothyroidism, ranging from 3% to nearly 14%, depending again on the population studied [1,2,8,9,47]. Subclinical hypothyroidism often develops into overt disease. Various studies following patients Vol. 8, No. 9 September 2001 JCOM 29

SCREENING FOR THYROID DISEASE Table 2. Recommendations of 6 Organizations Regarding Screening of Adults for Thyroid Dysfunction Organization

Screening Recommendations

American College of Physicians [31]

Women > 50 yr of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated. Screening in women younger than age 50 or in men of any age is not recommended. Women and men > 35 yr should be screened every 5 yr Periodic testing in older patients, especially women

American Thyroid Association [44] American Association of Clinical Endocrinology [41] American Academy of Family Physicians [40] Canadian Task Force on the Periodic Health Examination [45] U.S. Preventive Services Task Force [46]

Periodic testing in older patients ( ≥ 60 yr) Insufficient evidence to recommend screening in asymptomatic adults, but clinicians should maintain a high index of suspicion and consider testing in patients with vague symptoms suggestive of thyroid dysfunction Insufficient evidence for or against screening in asymptomatic adults, but physicians should remain alert to subtle symptoms and signs of thyroid dysfunction when examining high-risk patients

TSH = thyroid-stimulating hormone.

with subclinical hypothyroidism found that the rate of developing overt disease ranged from about 2% per year to 53% over an 8-year period [8,38,48–51]. With regard to the criteria for a screening program, the burden of suffering with subclinical hypothyroidism warrants screening. The prevalence is considerable, and some of the same morbidity associated with overt hypothyroidism is seen with subclinical hypothyroidism. Patients with subclinical hypothyroidism have elevated lipid levels [5,25,28] and respond to thyroid hormone replacement with decreased lipid levels [52]. Those with subclinical hypothyroidism also report more symptoms than euthyroid subjects [5,27,39]. In 2 studies by Monzani et al, neuromuscular and behavioral symptoms associated with subclinical hypothyroidism improved with levothyroxine replacement [53,54]. The test used to screen for the disease is the third-generation TSH. Those being screened are likely to tolerate a simple blood test and treatment with daily levothyroxine replacement. The treatment is effective, and the cost of treatment is acceptable. The current health system can accommodate such a program. But again, we are left with some controversy regarding whether or not early diagnosis leads to improved clinical outcomes with respect to function, quality of life, and survival. The functional status of patients with subclinical hypothyroidism, their quality of life, and their long-term survival have not yet been studied in large numbers. Despite this, Cooper deftly argues that the evidence is adequate to justify therapy in most patients who have subclinical hypothyroidism [55]. Indeed, it is not difficult to rationalize ordering a serum TSH on most patients who come through the doors of the primary care clinic. Even the ACP guidelines state that “physicians who believe that significant morbidity accompanies progression to overt hypothyroidism may wish to prescribe levothyroxine to all asymptomatic patients who have a TSH level of 10 mU/L or more” [31]. 30 JCOM September 2001 Vol. 8, No. 9

Corresponding author: Gay Canaris, MD, MSPH, 983331 Nebraska Medical Center, Omaha, NE 68198-3331.

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