Screening for Thyroid Disease: An Update

1.0 Introduction In 1990, the American College of Physicians published guidelines [1] and a background paper [2] supporting the appropriate use of thyroid function tests in symptomatic women older than 50 years of age who sought care in the primary care setting. The guidelines recommended against screening for clinically inapparent subclinical or mild thyroid failure because the evidence that earlier detection and treatment improves health outcomes in these patients was insufficient. 1.1 Since 1990, new information about the long-term risks of untreated subclinical thyroid dysfunction has led some experts to support screening in the general population. The sensitive thyroid-stimulating hormone (TSH) test has been proposed as a good screening tool because it can identify persons who have abnormal thyroid function before other clinical or laboratory abnormalities occur. Screening is done with a sensitive TSH test followed by a test of free thyroxine if the result of the sensitive TSH test is abnormal. If the level of TSH is undetectable and the free thyroxine level is normal, a free triiodothyronine test is also done. 1.2 As shown in Table 1, this approach to screening identifies four groups of patients with abnormal thyroid function. Patients with overt hyperthyroidism have an undetectable TSH level and a high free thyroxine or free triiodothyronine level. Patients with overt hypothyroidism have an elevated TSH level and a low free thyroxine level. Patients with subclinical hyperthyroidism have an undetectable TSH level and normal free thyroxine and free triiodothyronine levels. Finally, patients with subclinical hypothyroidism have an elevated TSH level and a normal free thyroxine level. Table 1. Conditions Identified by Screening with a Sensitive Thyroid-Stimulating Hormone Test and a Free Thyroxine Test 1.3 Controversy centers on whether early treatment or close follow-up is warranted in apparently healthy persons in whom the only indication of a thyroid disorder is an abnormal test result. Screening is warranted if the evidence meets three criteria. First, an abnormal test result should be associated with future complications that affect health status and quality of life. Second, follow-up and early treatment should improve outcomes by reducing the risk for these complications. Third, these benefits must clearly outweigh the adverse effects and long-term risks of treatment. 1.4 In this paper, we consider whether primary care physicians should screen for thyroid function in patients who are seen in general medical practice, who have no specific indication for thyroid testing, and who come to the physician for other reasons. For each condition in Table 1, we appraised the evidence supporting early treatment and estimated the number of persons who could benefit from screening. We focus on whether screening should be aimed at detection of subclinical thyroid dysfunction and on whether persons who have mildly abnormal TSH levels can benefit. 2.0 Methods 2.1 We reviewed studies of screening for thyroid dysfunction and studies of the complications, course, or treatment of subclinical hyperthyroidism and subclinical hypothyroidism. We defined screening as the application of a test to detect a potential disease or condition in a person who has no known signs or symptoms of that condition at the time the test is done [3]. Studies of screening can be classified according to the setting in which the decision to screen takes place [3]. In office-based screening, or case finding, testing for thyroid dysfunction is performed in patients who come to their physicians for unrelated reasons. Studies of case-finding programs provide the most realistic estimates of the effects and costs of screening in clinic or office practice [2]. Population-based studies of screening use special methods to recruit, contact, and follow patients in the context of an epidemiologic research effort. Such studies show the extent of unsuspected thyroid disease in a population sample in a particular geographic area but do not reflect the yield or costs of screening in practice. We used population-based studies of screening as a benchmark against which the yield and benefits of more practical office-based screening programs can be measured. 2.2 Data Sources We reviewed the original literature from 1989 to 1996 to identify articles that were not included in the original College background paper [2]. In a MEDLINE search, the Medical Subject Headings thyroid function tests and thyroid diseases were combined with the term mass screening and the text words screening or case finding. We conducted a separate MEDLINE search (1970 to 1996) for controlled studies of the effect of thyroid-directed treatments on potential complications of subclinical thyroid disease (symptoms, hyperlipidemia, coronary heart disease, atrial fibrillation, osteoporosis, and bone fracture). Periodic hand searching of endocrinologic and major medical journals, review of the reference lists of retrieved articles, and retrieval of articles reviewed in the first background paper [2] supplemented the MEDLINE searches. 2.3 Study Selection We selected studies in which a test of serum TSH or thyroxine was performed in the general adult population, in a demographic segment of the adult population, or among patients seen in the general office setting. All controlled studies of treatment in patients with subclinical hypothyroidism or subclinical hyperthyroidism were also included regardless of whether they were performed in patients identified by screening. Studies of screening for congenital or familial thyroid disorders and studies of screening in inpatients; institutionalized patients; and patients known to have diabetes, depression, obesity, or other conditions were excluded. 2.4 Thirty-three screening studies were included. The MEDLINE search identified 56 articles published since 1989, 18 of which were included in the review. Of the 38 excluded studies, 9 concerned inpatients or institutionalized patients and 23 did not report the age and sex of the participants or the results of thyroid function tests; in the latter group, most studies concerned screening for thyroid cancer or familial thyroid disorders. Twenty-three controlled studies of treatment for subclinical thyroid dysfunction were also included in the review. 2.5 Data Extraction For each condition listed in Table 1, we sought to answer three questions. 1. Prevalence. How many persons have the condition? 2. Burden of illness. What are the risks for and severity of each potential complication? 3. Effectiveness. Is there evidence that early treatment reduces the burden of illness? 2.6 We pooled information from population-based and office-based studies of screening to estimate the prevalence of each type of thyroid dysfunction (Table 1). To assess the burden of illness, we pooled longitudinal studies of patients with subclinical hypothyroidism or subclinical hyperthyroidism to estimate how often patients develop the following complications: 1) symptoms, 2) progression of subclinical to overt dysfunction, 3) elevated cholesterol in hypothyroidism, 4) atrial fibrillation in hyperthyroidism, and 5) osteoporosis in hyperthyroidism. We used a variance-weighted equal effects model [4] implemented in FAST*PRO software for meta-analysis [5] to combine information from observational studies. 2.7 To assess effectiveness, we reviewed randomized trials and other comparison studies that contained information about the effect of treatment on each complication. For each controlled trial, we recorded the difference between the probability of a response in the treatment and control groups for each complication studied. The inverse of this difference is the number needed to treat (NNT) to benefit one patient [6]. For each complication, we used estimates of the prevalence and effectiveness of treatment to calculate the NNT and the number needed to screen to benefit one patient. 3.0 Data Synthesis 3.1 Benefits of Detecting Overt Hyperthyroidism and Overt Hypothyroidism Screening can identify patients who have overt but clinically unrecognized thyroid disease [7-11]. Older persons, in particular, may present with subtle, nonspecific signs and symptoms of thyroid dysfunction. Hyperthyroidism can cause weight loss, apathy, tremor, heat intolerance, and muscle weakness. Hypothyroidism can cause muscle cramps, dry skin, intolerance to cold, constipation, poor energy levels, fatigue, and mental slowness. 3.2 The cause of these symptoms may be over-looked until an abnormal result on a screening test leads a physician to ask about them. For example, suppose a 70-year-old woman with varicose veins sees her primary physician for a routine check-up. Because she takes a diuretic for pedal edema, the physician orders a serum potassium test, and the laboratory adds a screening sensitive TSH test to this request. Because the TSH level is elevated, the physician calls the patient, learns that she has noticed slight fatigue and dry skin, and, after finding that she also has a low free thyroxine level, decides to prescribe L-thyroxine. Even though this patient has symptomatic, overt hypothyroidism, it is fair to say that her condition was detected by screening. 3.3 How Many Persons Benefit from Detection of Overt Thyroid Dysfunction? The prevalence of overt thyroid dysfunction depends on the age and sex of the population. Most recent studies concern older persons [11-22] (Table 2 and Table 5). Of women 70 to 80 years of age, 2% had overt hypothyroidism; this rate is significantly higher than that in all other age groups [8, 10-1214, 16-19, 23-31] (Figure 1). Among all women older than 60 years of age, office-based screening detected 14 cases of overt hypothyroidism or hyperthyroidism per 1000 women, or 1 case per 71 women (95% CI, 59 to 111 women) screened (Figure 1, Figure 2, and Figure 3). Table 2. Recent Studies of Screening for Thyroid Dysfunction* Table 5. Table