Draft Recommendation Statement
Thyroid Dysfunction: Screening
This opportunity for public comment expired on November 23, 2014 at 5:00 PM EST
Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Draft: Recommendation Summary
Summary of Recommendation and Evidence
|Nonpregnant Asymptomatic Adults|
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant asymptomatic adults.
See the Clinical Considerations section for suggestions for practice regarding the I statement.
The USPSTF makes recommendations about the effectiveness of specific preventive care services for patients without related signs or symptoms.
It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.
The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decisionmaking to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.
Thyroid gland disorders are some of the most common endocrine conditions evaluated and treated by clinicians. Thyroid dysfunction represents a continuum from biochemical changes to clinically symptomatic disease. In rare cases (i.e., myxedema coma or thyroid storm), it can produce life-threatening complications.1, 2
Subclinical hypothyroidism is an asymptomatic condition in which a patient has a serum thyroid-stimulating hormone (TSH) level exceeding the upper threshold of a specified laboratory reference range (commonly but arbitrarily defined as 4.5 mIU/L) but a normal thyroxine (T4) level.3 Patients with subclinical hypothyroidism are further classified as having “mildly elevated” (4.5 to 10.0 mIU/L) or “markedly elevated” (>10.0 mIU/L) TSH levels.
Despite its name, overt hypothyroidism does not require the presence of symptoms, and is defined biochemically by an elevated TSH level and a low T4 level. As such, overt hypothyroidism is often, but not necessarily, associated with a set of relatively subtle and nonspecific clinical symptoms (e.g., fatigue, feeling cold, weight gain, hair loss, and constipation).
Subclinical hyperthyroidism is an asymptomatic condition in which a patient has a serum TSH level beneath the lower threshold of a specified laboratory reference range (usually 0.1 mIU/L) but normal T4 and triiodothyronine (T3) levels. Patients with subclinical hyperthyroidism are further classified as having “low but detectable” (about 0.1 to 0.4 mIU/L) or “clearly low” or “undetectable” (<0.1 mIU/L) TSH levels.3
Again, despite its name, overt hyperthyroidism does not require the presence of symptoms, and is defined biochemically by a low or undetectable TSH level and elevated T4 or T3 levels. When present, symptoms are often relatively nonspecific (e.g., weight loss, heart palpitations, heat intolerance, and hyperactivity).
Although there are clusters of signs and symptoms that are generally associated with hypothyroidism and hyperthyroidism, they are poorly predictive of whether any given person actually has thyroid dysfunction. However, symptoms may become more observable as biochemical hormone levels turn increasingly abnormal. In epidemiological studies, persons who reported experiencing one or two of the commonly cited signs and symptoms of thyroid dysfunction were no more likely to have an abnormal serum TSH level than persons without symptoms in the general population.3-6
For the purposes of this recommendation, thyroid dysfunction is defined as a spectrum of disorders related to the thyroid gland. The spectrum begins with asymptomatic subclinical hypothyroidism and hyperthyroidism. In the middle of the spectrum are asymptomatic overt hypothyroidism and hyperthyroidism, defined biochemically by changes in TSH and T4 levels. At the end of the spectrum is thyroid disease, which is reserved for symptomatic overt hypothyroidism and hyperthyroidism (i.e., patients who have both persistent abnormal serum TSH and T4 levels and clearly associated clinical signs and symptoms that cannot be better explained by another condition).
In making its recommendations about clinical preventive services, the USPSTF focuses on asymptomatic populations not known to have signs or symptoms of disease.
The USPSTF found adequate evidence that screening can detect abnormal serum TSH levels in asymptomatic persons.
However, there is uncertainty as to what constitutes an “abnormal” TSH level. Laboratory reference ranges are based on the distribution of TSH levels across the general population (e.g., using the 97.5th percentile as an upper boundary for normal), rather than according to a TSH level’s association with adverse outcomes or particular risk factors for disease.3 There is professional disagreement about the appropriate cut-points for the lower and upper boundaries of normal TSH levels in the general population, as well as in subgroups such as older adults, where values differ from the overall population distribution.7-10 Accurate interpretation of serum TSH levels is further complicated by measurement variability, as well as its sensitivity to conditions other than thyroid dysfunction.
These issues have led multiple professional groups to recommend repeating abnormal thyroid function tests for confirmation of persistent dysfunction (e.g., after 3- to 6-month intervals) before making a diagnosis or considering any treatment strategies, unless the observed TSH level is markedly abnormal (e.g., >10.0 or <0.1 mIU/L) or the individual is notably symptomatic.3, 11, 12
Benefits of Early Detection and Treatment
The USPSTF found inadequate evidence that screening for thyroid dysfunction in nonpregnant asymptomatic adults leads to clinically important benefits. In particular, there is inadequate evidence to determine whether screening for thyroid dysfunction reduces cardiovascular disease or related morbidity and mortality.
The USPSTF found adequate evidence that screening for and treatment of thyroid dysfunction in nonpregnant asymptomatic adults does not improve cognitive function or quality of life or provide clinically meaningful improvements in blood pressure, body mass index, bone mineral density, or lipid levels.1, 2
Harms of Early Detection and Treatment
The USPSTF found inadequate evidence on the harms of screening for and treatment of thyroid dysfunction. Indirect evidence points to the likelihood of important and frequent harms associated with screening. Foremost among these are false-positive results, the psychological effects of labeling, and overdiagnosis and overtreatment of biochemically defined abnormal TSH levels that may revert to normal or never result in health problems for patients, particularly those with “mildly elevated” TSH levels.
The USPSTF concludes that the evidence is insufficient and that the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant asymptomatic adults cannot be determined.
If screening for thyroid dysfunction is offered, clinicians should first ensure that patients clearly understand the uncertainties surrounding any potential clinical benefit of screening, as well as the possibility of harm this choice may engender.
Draft: Clinical Considerations
This recommendation applies to nonpregnant asymptomatic adults.
Suggestions for Practice Regarding the I Statement
Potential Preventable Burden
About 5% of women and 3% of men in the United States have subclinical hypothyroidism.7 Importantly, several studies have shown that about 37% of persons with subclinical hypothyroidism spontaneously revert to an euthyroid state without intervention after several years.13, 14 Approximately 2% to 5% of persons with subclinical hypothyroidism develop overt thyroid dysfunction.15
One retrospective cohort study found that levothyroxine use in persons with subclinical hypothyroidism was associated with a lower risk for ischemic heart disease events and overall mortality;16 however, the USPSTF did not identify any clinical trials that evaluated the causal relationship between treatment and subsequent cardiac events. The USPSTF did not identify any trials or observational studies that evaluated the effects of treatment of overt hypothyroidism (with or without symptoms).
Subclinical hyperthyroidism affects about 0.7% of the U.S. population and is more common in women than men.7 One fourth of persons with subclinical hyperthyroidism will revert to an euthyroid state without medical intervention over time.13, 17 An estimated 1% to 2% of persons with a TSH level of less than 0.1 mIU/L will develop overt hyperthyroidism (with or without symptoms). Persons with a TSH level between 0.1 and 0.45 mIU/L are unlikely to progress to overt hyperthyroidism.11
The USPSTF did not identify any studies that evaluated the benefits of treatment of subclinical hyperthyroidism on final health outcomes (e.g., cardiovascular morbidity or mortality). Except for one small (n=67), nonrandomized study that examined bone mineral density, no evidence was found on the effects of treatment of overt hyperthyroidism (with or without symptoms).1, 2
The harms of treatment of thyroid dysfunction have not been adequately studied. The most important potential harms are false-positive results, labeling, and overdiagnosis and overtreatment.
False-positive results are likely because TSH secretion is highly variable and is sensitive to a number of common factors, such as acute illness or certain medications. Ascertaining true- versus false-positive results is further complicated by a lack of consensus on what constitutes a normal reference range.
There is also a lack of consensus on the appropriate point for clinical intervention, particularly for hypothyroidism. Based on expert opinion, a TSH level of greater than 10.0 mIU/L is generally considered the threshold for initiating treatment (in part because of the higher likelihood of progression to overt thyroid dysfunction). The decision of whether and when to begin therapy in patients with TSH levels between 4.5 and 10.0 mIU/L is more controversial.3, 18 An important magnitude of overdiagnosis and overtreatment is a likely consequence of screening for thyroid dysfunction, particularly because the disorder is largely defined by biochemical parameters rather than reliably specific clinical symptoms. The high variability of TSH secretion levels, as well as the frequency of reversion to normal thyroid function without treatment, underscore the importance of not relying on a single abnormal laboratory value as a basis for diagnosis or the decision to start therapy.
Currently, it is not possible to differentiate which persons will experience advancing thyroid dysfunction of clinical importance from those whose TSH levels will remain biochemically stable or even normalize. Treating the latter group (at minimum) will not lead to benefit, and these persons may experience the harms associated with antithyroid medications, ablation therapy, and long-term thyroid hormone therapy.
Although exact estimates are not available for the United States, screening for thyroid dysfunction by primary care providers appears to be a common practice.19 In the United Kingdom, an estimated 18% to 25% of the adult population receives thyroid function testing each year.20
The annual number of dispensed prescriptions of levothyroxine sodium in the United States increased 42% over a 5-year period, from 50 million prescriptions in 2006 to 71 million in 2010.21 In 2013, there were more than 23 million new prescriptions and refills for a single name brand of thyroid hormone in the United States, making it the most commonly prescribed drug in the country.22
In 1996, a cross-sectional study of a U.S. population found that 39% of participants with a TSH level between 5.1 and 10.0 mIU/L received treatment.23 More recent evidence suggests that the median TSH level at initiation of thyroid hormone therapy has decreased over time; a retrospective cohort study in the United Kingdom found that the median TSH level at time of first levothyroxine prescription decreased from 8.7 to 7.9 mIU/L between 2001 and 2009.20
Data on the proportion of asymptomatic persons with thyroid dysfunction who receive treatment with thyroid hormone therapy are lacking. However, given the high number of prescriptions for levothyroxine dispensed in the United States and the low prevalence of overt thyroid disease compared with other forms of thyroid dysfunction, it is reasonable to conclude that many asymptomatic persons receive treatment. Clinicians are treating more persons with thyroid dysfunction, at earlier times after initial diagnosis and at less abnormal TSH levels.
Assessment of Risk
The most common cause of hypothyroidism in the United States is chronic autoimmune (Hashimoto’s) thyroiditis. Risk factors for an elevated TSH level include female sex, advancing age, white race, type 1 diabetes, Down syndrome, family history of thyroid disease, goiter, previous hyperthyroidism (possibly due in part to ablation therapy leading to iatrogenic thyroid dysfunction), and external beam radiation in the head and neck area.1, 2
Common causes of hyperthyroidism include Graves’ disease, autoimmune thyroiditis (i.e., Hashitoxicosis), and functional thyroid nodules. Risk factors for a decreased TSH level include female sex, advancing age, black race, low iodine intake, personal or family history of thyroid disease, and ingestion of iodine-containing drugs such as amiodarone.1, 2
The serum TSH test is the primary screening test for thyroid dysfunction. Followup testing of serum T4 levels can differentiate between subclinical (normal T4 levels) and overt (abnormal T4 levels) thyroid dysfunction.
The optimal screening interval for thyroid dysfunction—if any—is unknown.
The principal treatment of hypothyroidism is oral T4 monotherapy (i.e., levothyroxine sodium).
Hyperthyroidism is treated with antithyroid medications, such as methimazole, or nonreversible thyroid ablation therapy, such as radioactive iodine or surgery. Treatment is generally recommended for patients with an undetectable TSH level or a TSH level of less than 0.1 mIU/L, particularly those with Graves’ disease or nodular thyroid disease. Treatment is not typically recommended for patients with a TSH level between 0.1 and 0.45 mIU/L or when thyroiditis is the etiology.1, 2
Draft: Other Considerations
Research Needs and Gaps
Although the detection and treatment of abnormal TSH levels among asymptomatic persons is common practice, evidence that this clinical approach improves important health outcomes is lacking. Randomized, controlled trials of screening for thyroid dysfunction would provide the most direct evidence on any potential benefits of this widespread practice.
Before conducting screening trials, however, it may be more feasible to first conduct well-designed treatment trials of either subclinical or overt thyroid dysfunction versus watchful waiting (including intervention if overt thyroid disease becomes symptomatic) using final health outcomes, such as cardiovascular-related morbidity and mortality, rather than intermediate markers as the endpoints of interest. For such treatment trials to be most informative, they should have clearly-defined patient populations, intervention protocols (e.g., treatment doses and target TSH levels), and study outcomes, including short- and long-term benefits and harms.
Currently, the evidence does not demonstrate important benefits of treatment of subclinical thyroid dysfunction on blood pressure, body mass index, lipid levels, cognitive function, or quality of life. Treatment is likely associated with harms. However, treatment could possibly have important long-term benefits on final health outcomes, such as reductions in bone fractures and cardiovascular- and cancer-related morbidity and mortality (currently, available evidence indicates that fracture prevention is due to factors other than improvements in bone mineral density).16, 24 The need for randomized trials that evaluate the effect of treatment of subclinical thyroid dysfunction on cardiac outcomes has been previously emphasized.16 Given the increasingly popular clinical practice of routine identification and treatment of asymptomatic persons with thyroid dysfunction and the treatment of those with vague and nonspecific symptoms, these trials are warranted.
Studies evaluating the harms of screening for and treatment of thyroid dysfunction are critically lacking. The USPSTF believes that false-positive results, labeling, and overdiagnosis and overtreatment are important harms of any screening and prevention program, and that attempts should be made to minimize these harms.
Burden of Disease
Disorders of the thyroid gland are some of the most common endocrine conditions evaluated and treated by clinicians. According to data from the U.S. National Health and Nutrition Examination Survey, about 46 per 1,000 persons in the United States have subclinical hypothyroidism, 7 per 1,000 persons have subclinical hyperthyroidism, 3 per 1,000 persons have overt hypothyroidism, and 5 per 1,000 persons have overt hyperthyroidism.7
At present, the most common argument in favor of early treatment of thyroid dysfunction is the possible association among untreated subclinical hypothyroidism, risk factors for heart disease, and subsequent coronary disease or heart failure. However, the epidemiological evidence for this argument is mixed, and available studies (including several meta-analyses) have important methodological limitations, precluding certainty in the findings.3, 25-30
Recently, two prospective studies—the Health, Aging, and Body Composition Study31 and the Cardiovascular Health Study32—demonstrated a correlation between subclinical hypothyroidism and congestive heart failure, particularly in persons with a serum TSH level of greater than 10.0 mIU/L (hazard ratio [HR], 3.26 [95% CI, 1.37 to 7.77] and 1.88 [95% CI, 1.05 to 3.34], respectively). This possible association is worthy of additional study; however, it remains unknown whether thyroid replacement therapy would modify this potential risk.3
Scope of Review
The USPSTF commissioned a systematic evidence review to update its 2004 recommendation on screening for thyroid disease. The review assessed the evidence on the benefits and harms of screening for subclinical and overt thyroid dysfunction, as well as the effects of treatment of screen-detected subclinical and overt thyroid dysfunction on intermediate and final health outcomes. The review also evaluated the proportion of patients screened for thyroid dysfunction who have overt disease, the proportion of persons with “mildly elevated” TSH levels who are treated in current practice, and the cardiovascular consequences of untreated subclinical thyroid dysfunction.
Accuracy of Screening Tests
When used to confirm clinically suspected thyroid disease in patients referred to an endocrinologist, the serum TSH test has a sensitivity of about 98% and a specificity of about 92%.33 However, when the serum TSH test is used to screen asymptomatic persons for thyroid dysfunction, its accuracy is more challenging to ascertain, for several reasons. First, there is no consensus on which TSH level is the appropriate cutoff to make a diagnosis of subclinical hypothyroidism or hyperthyroidism. Most laboratories define an abnormal TSH test result using the upper and lower limits of the particular assay’s 95% reference range (generally about 0.1 to 4.5 mIU/L).3 However, laboratories use varying types of assays.34 More importantly, this threshold is basically arbitrary, as it is not based on the risk for an adverse health outcome, but simply a normal population distribution of values.
Second, TSH secretion varies among different subpopulations, such as by race/ethnicity, sex, and age. For example, 12% of persons age 80 years and older with no evidence of thyroid disease have been found to have TSH levels of greater than 4.5 mIU/L.35 Therefore the “standard” population reference range for older adults is likely inappropriate.13, 36, 37
Third, TSH secretion is highly sensitive to factors other than thyroid disorders. For example, serum TSH is frequently suppressed during phases of acute illness.3 TSH levels may also be affected by the administration of drugs or substances, such as iodine, dopamine, glucocorticoids, octreotide, or bexarotene.1, 18 Adrenal insufficiency, pregnancy (particularly during the first trimester), anorexia nervosa, certain autoimmune diseases, and pituitary adenomas can all also interfere with normal circulating levels of TSH hormone.3, 18
Fourth, serum TSH levels vary considerably on a day-to-day basis, by as much as 50% of mean values, with up to 40% variation of values obtained from serial TSH measurements performed at the same time of day.38, 39
All this confirms the importance of not relying on a single TSH value to establish a diagnosis of thyroid dysfunction. Serial TSH measurements are an essential step in establishing that a thyroid disorder is real and persistent.
Effectiveness of Early Detection and Treatment
Treatment of Hypothyroidism
Three trials found no statistically significant effect of treating subclinical hypothyroidism on blood pressure.1, 2 Similarly, six trials found no statistically significant effect of treatment on body mass index or weight.1, 2
The evidence on the effect of treating subclinical hypothyroidism on lipid levels is mixed. Several trials suggested potential beneficial effects, but the results are inconsistent and of uncertain clinical importance. In eight good- or fair-quality trials (of which only three reported statistically significant results), differences between the treatment and control groups ranged from -28 to 0 mg/dL for mean total cholesterol and from -22 to 2 mg/dL for mean low-density lipoprotein cholesterol.1, 2 No studies reported statistically significant differences for high-density lipoprotein cholesterol or triglycerides.1, 2 Whether changes in these intermediate outcomes due to treatment are adequate surrogates for cardiovascular morbidity or mortality is not known, and no trials directly evaluated the effects of treatment of subclinical hypothyroidism on final health outcomes, such as cardiac morbidity or mortality.
A single fair-quality retrospective cohort study examined the association between treatment of subclinical hypothyroidism and the risk for cardiac events. The study identified 4,735 persons age 40 years and older from the U.K. General Practice Research Database with subclinical hypothyroidism (based on a single TSH value of 5.01 to 10.0 mIU/L). Mean followup was 7.6 years, and participants were categorized a priori into two age groups (40 to 70 years and >70 years). After adjustment for age, sex, body mass index, socioeconomic status, blood pressure, total cholesterol, smoking status, history of diabetes mellitus, levothyroxine use, and index serum TSH level, levothyroxine use in the first age group was associated with a lower risk for fatal or nonfatal ischemic heart disease events (4.2% vs. 6.6%; HR, 0.61 [95% CI, 0.39 to 0.95]), death due to circulatory diseases (1.4% vs. 2.4%; HR, 0.54 [95% CI, 0.37 to 0.92]), and all-cause mortality (1.2% vs. 2.2%; HR, 0.59 [95% CI, 0.21 to 0.88]). There were no statistically significant associations between treatment and cardiovascular outcomes in the second age group.
One limitation of this study is that it did not adjust for the use of medications that reduce risk for cardiovascular disease (such as aspirin or lipid-lowering therapy). Residual confounding for these and other variables could be present, although baseline data did not find differences between the treatment groups.16 Although the results are promising and justify the prioritization of further research in this area, this study is ultimately hypothesis generating rather than proof of effect.
The same study, by Razvi et al, also reported an association between the use of levothyroxine and a reduced risk for any cancer death in persons ages 40 to 70 years (1.2% vs. 2.2%; HR, 0.59 [95% CI, 0.21 to 0.88]).16 The authors commented that this was an unexpected finding, and it should be interpreted with caution, particularly because it was not the primary study outcome. This finding further underscores the probable presence of residual confounding and emphasizes the need for experimental research to ascertain the true effect of treatment of subclinical hypothyroidism on cardiovascular outcomes.
In 2004, the USPSTF identified five trials that evaluated the effects of treatment on quality of life in persons with subclinical hypothyroidism. Only one trial found a positive effect of treatment, in patients with recent Graves’ disease.40 Since then, four good- or fair-quality trials have been published, and none have found a difference between groups receiving treatment and those receiving placebo.1, 2
Two studies included in the previous USPSTF review evaluated the effects of treatment of subclinical hypothyroidism on cognitive function and found mixed results; one trial that included euthyroid patients found no effect, and a second trial found an improvement of small clinical importance using a composite outcome in patients older than age 55 years.1, 2 Since then, one good- and one fair-quality trial have each found no effect of treatment of screen-detected subclinical hypothyroidism on various measures of cognitive function (such as cognitive skills and performance, cognitive status, speed of cognitive processing, and psychomotor tests of executive function) after 1 year.41, 42
No studies evaluated the effects of treatment of overt hypothyroidism on any outcome.1
Treatment of Hyperthyroidism
No fair- or good-quality studies evaluated the benefits of treatment of subclinical hyperthyroidism.1, 2 Two small (n=14 and 20), poor-quality trials found no differences between treatment and no treatment of subclinical hyperthyroidism on blood pressure, body mass index, bone mineral density, or lipid levels.1, 2
One small (n=67), nonrandomized study evaluated the effects of treatment of overt hyperthyroidism on bone mineral density.43 This study did not meet inclusion criteria and was not formally assessed as part of the systematic evidence review. Bone mineral density was examined via dual energy x-ray absorptiometry in 25 actively hyperthyroid patients, 20 formerly hyperthyroid patients receiving treatment, and 22 control patients. There were statistically significant differences in the bone mineral density z score (as measured by p values) between actively and formerly hyperthyroid patients and the control group, although the magnitude of the changes—and thus the potential clinical importance of the findings—were not provided.
No trials evaluated the effects of treatment of hyperthyroidism on final health outcomes.
Potential Harms of Early Detection and Treatment
No studies directly examined the harms of screening for thyroid dysfunction. However, it is clear that the potential for harm exists. The most important harms associated with screening for thyroid dysfunction are false-positive results, psychological effects of disease labeling, and overdiagnosis and overtreatment.
False-positive results for thyroid dysfunction using the serum TSH test are likely very common. This is because of several factors. TSH secretion is sensitive to multiple factors unrelated to thyroid conditions; varies across time intervals, sometimes as short as a single day; and varies depending on the population being considered (i.e., average TSH values may differ by age, sex, and race/ethnicity). In addition, there is no universal agreed upon “normal” TSH reference value, in part because it is not linked to the risk for actual adverse health outcomes.
Reliable estimates for the frequency of false-positive results from serum TSH tests are not available. A prospective observational study followed a cohort of 599 older adults after a single baseline TSH test, with repeat testing of 376 participants at the end of the study. It found that 37% (11/30) of participants with an initial elevated TSH level and 29% (5/17) of participants with an initial low TSH level reverted to normal thyroid function after 3 years without intervention. Limitations of this study include the small number of affected participants, high loss to followup, and inability to distinguish between false-positive findings and overdiagnosis with the methodological approach.13
Labeling someone with a diagnosis of disease may have adverse psychological consequences, particularly in the case of an otherwise asymptomatic condition. Although the patient may have previously felt healthy, being informed that he or she has a disorder that requires medical surveillance or intervention can result in anxiety or changes to that patient’s sense of well-being. A cross-sectional study of almost 34,000 persons ages 40 to 70 years found that women with known hypothyroidism were less likely to report good self-rated health compared with women without thyroid dysfunction (adjusted odds ratio, 0.49 [95% CI, 0.41 to 0.59]).44
Overdiagnosis of thyroid dysfunction is likely common, in part because it is biochemically rather than clinically defined, and because disagreements persist about the appropriate cut-points for classifying disease. The exact proportion of diagnoses of thyroid dysfunction that represent overdiagnosis is not known. However, many persons labeled with hypothyroidism or hyperthyroidism spontaneously revert to an euthyroid state over time; others never progress to noticeable health problems, especially those who are asymptomatic and have “mildly elevated” (i.e., 4.5 to 10.0 mIU/L) TSH values.
In one prospective study, 102 women age 60 years and older with subclinical hyperthyroidism (defined as TSH level of 0.1 to 0.4 mIU/L, as measured at baseline and 12 weeks after study entry) but normal T3/T4 levels were followed for a mean of 41 months without intervention. At the end of the study, 24 women (24%) had TSH levels that had spontaneously normalized.17 A second prospective study evaluated the natural history of subclinical hypothyroidism. The study followed 107 persons age 55 years and older with newly diagnosed subclinical hypothyroidism (defined as TSH level of >5.0 mIU/L, as measured by two serial serum TSH tests before study entry) for a mean of 32 months without intervention. After this time, 40 participants (37%) had reverted to an euthyroid state. Of note, nearly half of this population had been referred to the endocrine clinic performing the study by general practitioners because of the incidental discovery of an elevated TSH level during routine “analytical lab checking.” Forty-four percent of the study population also reported one or more of the symptoms commonly associated with hypothyroidism.14
Overdiagnosis is of concern because it may lead to the psychological consequences of labeling and unnecessary treatment, and is a fundamental harm that should be avoided in disease prevention and health promotion.
As with screening, very limited evidence is available to assess the harms of treatment of thyroid dysfunction.
Levothyroxine therapy is a synthetic preparation of a natural hormone found in the body; treatment of hypothyroidism with levothyroxine is generally chronic (i.e., lasting for years). Despite its previous widespread use in the United States, levothyroxine sodium was not approved by the U.S. Food and Drug Administration until 2000. However, its approval process did not include studies evaluating short- or long-term adverse effects. The product label cites possible adverse effects on bone mineral density and the cardiovascular system, such as angina, arrhythmia, and increased cardiac wall thickness.3
In the previous review, studies reported four cases of patients “feeling worse,” one case of angina, one case of atrial fibrillation, several cases of worsened anxiety and vitality scores on the 36-Item Short-Form Health Survey, and two withdrawals due to adverse events after treatment with levothyroxine.33 The review also found that one fourth of patients who received levothyroxine were inadvertently maintained on doses high enough to make TSH levels undetectable. Although the ultimate effect of long-term overdosing with levothyroxine therapy is unknown, it could potentially increase risk for osteoporosis or fractures and abnormal cardiac output or ventricular hypertrophy.33
Five trials published since the previous review assessed the harms of levothyroxine treatment of hypothyroidism, and generally reported either no indication of harms or no or minimal (n=0 to 2) withdrawals from treatment due to adverse effects. However, harms were poorly assessed and reported, and the studies were not designed or powered to evaluate long-term or serious harms or any harms related to overtreatment.1, 2
In the case of asymptomatic hyperthyroidism, overtreatment may be of even greater concern, as one treatment option is ablation of the thyroid gland with subsequent thyroid replacement therapy. Patients who are overdiagnosed and overtreated could develop unnecessary iatrogenic hypothyroidism and become dependent on lifelong replacement of thyroid hormone. Overtreatment is also of concern because it introduces opportunity costs; that is, the clinician and patient spend time focused on areas of health at the expense of other conditions or care needs of higher priority for that patient’s overall well-being.
Estimate of Magnitude of Net Benefit
The USPSTF found no evidence on the direct benefits and harms of screening for thyroid dysfunction in nonpregnant adults, and therefore considered the indirect evidence on screening accuracy, benefits of early treatment, and harms. There is adequate evidence that the serum TSH test can identify abnormal levels of the hormone; however, there is substantial debate about what constitutes an abnormal TSH level. Thresholds vary for different populations (such as older adults). Although a single, fair-quality observational study found that there may be an association between levothyroxine treatment of subclinical hypothyroidism and a reduced risk for cardiac events, there is no evidence from randomized trials to prove that early treatment of thyroid dysfunction leads to clinically important benefits. The harms of screening for and treatment of thyroid dysfunction have been poorly studied. However, screening for and treatment of thyroid dysfunction have real potential for harms, and these harms are likely common. Overall, the USPSTF was unable to estimate the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant adults.
Draft: Update of Previous USPSTF Recommendation
This recommendation replaces the 2004 USPSTF recommendation on screening for thyroid disease. In this update, the USPSTF has restricted its definition of thyroid disease to symptomatic overt hypothyroidism and hyperthyroidism (i.e., patients who have both persistent abnormal serum TSH and T4 levels and clearly associated clinical signs and symptoms that cannot be better explained by another condition). There is a broad spectrum of thyroid disorders, and the USPSTF recognizes that screening with the serum TSH test can detect changes along any point in this spectrum. Thus, the USPSTF has changed the scope of its recommendation statement to screening for thyroid dysfunction to emphasize that screening will detect biochemical abnormalities as well as potentially clinically important disease. Despite this change, the USPSTF’s ultimate assessment remains the same as in the previous recommendation: the current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant asymptomatic adults (I statement).
Draft: Recommendations of Others
The American Thyroid Association recommends screening for thyroid dysfunction in all nonpregnant adults beginning at age 35 years and every 5 years thereafter.45 The American Association of Clinical Endocrinologists recommends routine TSH measurement in older patients (age range not specified), with an emphasis on women.46 In 2006, three British professional associations (the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation) jointly recommended against routine screening for thyroid dysfunction in a healthy adult population, although the panel favors aggressive case-finding in women with nonspecific symptoms.47 The American Academy of Family Physicians is in the process of updating its recommendation.
1. Rugge JB, Bougatsos C, Chou R. Screening for and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 118. AHRQ Publication No. 15-05217-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2014.
2. Rugge JB, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; Oct 28. [Epub ahead of print]
3. Rugge J, Balshem H, Sehgal R, Relevo R, Gorman P, Helfand M. Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism. Comparative Effectiveness Review No. 24. Rockville, MD: Agency for Healthcare Research and Quality; 2011. Accessed at http://www.ncbi.nlm.nih.gov/books/NBK83496/ on 7 October 2014.
4. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Assessment of a screening process to detect patients aged 60 years and over at high risk of hypothyroidism. Br J Gen Pract. 1991;41(351):414-6.
5. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526-34.
6. Lindeman RD, Schade DS, LaRue A, Romero LJ, Liang HC, Baumgartner RN, et al. Subclinical hypothyroidism in a biethnic, urban community. J Am Geriatr Soc. 1999;47(6):703-9.
7. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-99.
8. Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid. 2011;21(1):5-11.
9. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3-126.
10. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005;90(9):5483-8.
11. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228-38.
12. Shrier DK, Burman KD. Subclinical hyperthyroidism: controversies in management. Am Fam Physician. 2002;65(3):431-8.
13. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292(21):2591-9.
14. Díez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab. 2004;89(10):4890-7.
15. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab. 2005;90(1):581-5.
16. Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012;172(10):811-7.
17. Rosario PW. Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/l: a prospective study. Clin Endocrinol (Oxf). 2010;72(5):685-8.
18. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-35.
19. Meyerovitch J, Rotman-Pikielny P, Sherf M, Battat E, Levy Y, Surks MI. Serum thyrotropin measurements in the community: five-year follow-up in a large network of primary care physicians. Arch Intern Med. 2007;167(14):1533-8.
20. Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, et al. Falling threshold for treatment of borderline elevated thyrotropin levels—balancing benefits and risks: evidence from a large community-based study. JAMA Intern Med. 2014;174(1):32-9.
21. IMS Institute for Healthcare Informatics. The Use of Medicines in the United States: Review of 2010. Parsippany, NJ: IMS Institute for Healthcare Informatics; 2011. Accessed at http://www.imshealth.com/deployedfiles/imshealth/Global/Content/IMS%20Institute/Static%20File/IHII_UseOfMed_report.pdf on 7 October 2014.
22. Brooks M. Top 100 selling drugs of 2013. Medscape Medical News. January 30, 2014. Accessed at http://www.medscape.com/viewarticle/820011 on 7 October 2014.
23. Fatourechi V, Lankarani M, Schryver PG, Vanness DJ, Long KH, Klee GG. Factors influencing clinical decisions to initiate thyroxine therapy for patients with mildly increased serum thyrotropin (5.1-10.0 mIU/L). Mayo Clin Proc. 2003;78(5):554-60.
24. Wirth CD, Blum MR, da Costa BR, Baumgartner C, Collet TH, Medici M, et al. Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis. Ann Intern Med. 2014;161(3):189-99.
25. Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis. Int J Cardiol. 2008;125(1):41-8.
26. Völzke H, Schwahn C, Wallaschofski H, Dörr M. Review: the association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship? J Clin Endocrinol Metab. 2007;92(7):2421-9.
27. Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008;148(11):832-45.
28. Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. J Clin Endocrinol Metab. 2008;93(8):2998-3007.
29. Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab. 2010;95(4):1734-40.
30. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid. 1996;6(3):155-60.
31. Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005;165(21):2460-6.
32. Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure: the Cardiovascular Health Study. J Am Coll Cardiol. 2008;52(14):1152-9.
33. Helfand M. Screening for Thyroid Disease. Systematic Evidence Review No. 23. Rockville, MD: Agency for Healthcare Research and Quality; 2004. Accessed at http://www.ncbi.nlm.nih.gov/books/NBK42812/ on 7 October 2014.
34. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76-131.
35. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92(12):4575-82.
36. Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009;94(4):1251-4.
37. Simonsick EM, Newman AB, Ferrucci L, Satterfield S, Harris TB, Rodondi N, et al; Health ABC Study. Subclinical hypothyroidism and functional mobility in older adults. Arch Intern Med. 2009;169(21):2011-7.
38. Caron PJ, Nieman LK, Rose SR, Nisula BC. Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endocrinol Metab. 1986;62(5):960-4.
39. Karmisholt J, Andersen S, Laurberg P. Variation in thyroid function tests in patients with stable untreated subclinical hypothyroidism. Thyroid. 2008;18(3):303-8.
40. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism: a double-blind, placebo-controlled trial. Ann Intern Med. 1984;101(1):18-24.
41. Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. 2006;91(1):145-53.
42. Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab. 2010;95(8):3623-32.
43. Safi S, Hassikou H, Hadri L, Sbihi A, Kadiri A. Evaluation of bone mineral density in hyperthyroid patients before and after medical therapy. [French] Ann Endocrinol (Paris). 2006;67(1):27-31.
44. Jørgensen P, Langhammer A, Krokstad S, Forsmo S. Is there an association between disease ignorance and self-rated health? The HUNT Study, a cross-sectional survey. BMJ Open. 2014;4(5):e004962.
45. Ladenson PW, Singer PA, Ain KB, Bagchi N, Bigos ST, Levy EG, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med. 2000;160(11):1573-5.
46. Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, et al; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8(6):457-69.
47. Beastall GH, Beckett GJ, Franklyn J, Fraser WD, Hickey J, John R, et al. UK Guidelines for the Use of Thyroid Function Tests. London: Association for Clinical Biochemistry, British Thyroid Association, and British Thyroid Foundation; 2006. Accessed at http://www.british-thyroid-association.org/info-for-patients/Docs/TFT_guideline_final_version_July_2006.pdf on 8 October 2014.
Internet Citation: Draft Recommendation Statement: Thyroid Dysfunction: Screening. U.S. Preventive Services Task Force. September 2017.