Medicare Coverage of Routine Screening for Thyroid Dysfunction (2003) / Chapter Skim
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Appendix B: Screening for Thyroid Disease: Systematic Evidence Review
Appendix B: Screening for Thyroid Disease: Systematic Evidence Review
Pages 75-113
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From page 75... ...
About 5 percent of U.S. adults report having thyroid disease or taking thyroid medication.)
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From page 76... ...
The review is intended for use by two expert panels: the United States Preventive Services Task Force, which will make recommendations regarding screening in the general adult population, and the Institute of Medicine, which will focus on the Medicare population. Definition of Screening and Casefinding Screening can be defined 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."4 By this definition, screening with thyroid function tests may identify asymptomatic individuals as well as patients who have mild, nonspecific symptoms such as cold intolerance or feeling "a little tired." The symptoms associated with thyroid dysfunction are shown in Table B-1.5 6 When many of these symptoms and signs occur together, the clinician may have a strong suspicion that the patient has thyroid disease.
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From page 77... ...
Historically, clinical, biochemical, and immunologic criteria have been used to classify patients with milder degrees of thyroid dysfunctions 9 Today, the most common approach is to classify patients primarily according to the results of thyroid function tests (Table Bib. In this classification, "overt hypothyroidism" refers to patients who have an elevated thyroid stimulating hormone (thyrotropin or TSH)
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From page 78... ...
The term "subclinical hyperthyroidism" is used to describe conditions characterized by a low TSH and normal levels of circulating thyroid hormones (thyroxine and triiodothyronine)
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From page 79... ...
In one randomized trial, for example, mildly elevated TSH level reverted to normal in 8 of 19 patients given placebo.~5 In older subjects, only 59 percent (range 14 percent to 87 percent) of patients with an undetectable TSH on initial screening had an undetectable TSH level when the TSH was repeatedly i7 In the Framingham cohort, screening identified 41 people with an undetectable serum TSH(< 0.1 mUIL)
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From page 80... ...
More than 40 studies reported the prevalence of thyroid dysfunction in defined geographic areas, in health systems, in primary care clinics, and at health fairs. i, 2, 23-33 In cross-sectional, population-based studies, a serum TSH 2 4 mUIL in conjunction with a normal thyroxine level (subclinical hypothyroidism)
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From page 81... ...
Evidence Regarding the Complications of Subclinical Hyperthyroidism Advocates of screening for subclinical hyperthyroidism argue that early treatment might prevent the later development of atrial fibrillation, osteoporotic fractures, and complicated overt hyperthyroidism. Other potential benefits are earlier treatment of neuropsychiatric symptoms and prevention of the long-term consequences of exposure of the heart muscle due to excessive stimulation from thyroid hormones.
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From page 82... ...
cohort found similar bone loss among women with undetectable, low, and normal TSH levels.4i Two meta-analyses of older studies42 43 suggest that women who have a low TSH because they take thyroid hormones are at higher risk of developing osteoporosis. Other studies of the risk of osteoporosis concern small numbers of subjects with nodular thyroid disease or Graves' disease44~47 rather than patients who have no obvious clinical signs of thyroid disease.
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From page 83... ...
The number of important baseline differences between cases and controls raises the possibility that some of the women with low TSH levels had multiple factors and that other factors concomitant with age or socioeconomic status could also have been confounders. The study's relevance to screening is limited because 86 percent of the women who had undetectable TSH levels were taking thyroid hormones.
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From page 84... ...
In the setting of nodular thyroid disease, Graves' disease, or long-term use of suppressive doses of levothyroxine, subclinical hyperthyroidism also has been associated with cognitive abnormalities, abnormalities in cardiac contractility, and exercise intolerance.53-58 However, the frequency of symptoms or myocardial contractility abnormalities in patients who have subclinical hyperthyroidism found by screening is not well studied, and no study has linked abnormalities in cardiac contractility or output to the development of clinically important heart failure. Evidence Regarding Complications of Subclinical Hypothyroidism The best studied potential complications of hypothyroidism are hyperlipidemia, atherosclerosis, symptoms, and (for subclinical disease)
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From page 85... ...
There were nonsignificant increases in LDL cholesterol and HDL cholesterol among women who had a serum TSH >10 (LDL cholesterol 143 versus 128 in euthyroid women, p=0.08; HDL cholesterol 41.6 versus 47.5, p=0.053~.3i Conversely, a cross-sectional, population-based study from the Netherlands found that the prevalence of subclinical hypothyroidism was correlated with lipid levels; the prevalence was 4 percent among women with a total cholesterol level < 5 mmol/1; 8.5 percent when total cholesterol was 5 to 8 mmol/1; and 10.3 percent when total cholesterol was >8 mmol/L.63 Another recent cross-sectional study of 279 women over age 65 found a strong relationship between hyperlipidemia and serum TSH levels.64 Of the 279 women, 19 (6.8 percent) had a serum TSH >5.5 mU/L.
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From page 86... ...
. Among subjects taking thyroid hormones but not lipid-lowering medication, a serum TSH 25.5 mUIL was associated with a 15 mg/dL higher total cholesterol.
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From page 87... ...
Symptoms, Mood, and Quality of Life In its 1998 review and guideline, the American College of Physicians concluded that, in the general population, it was not clear that the prevalence and severity of symptoms and the quality of life differs for individuals who have mildly elevated TSH levels.7 74 Since then, two cross-sectional studies in volunteers have addressed this question, with mixed results. A cross-sectional interview survey of 825 Medicare enrollees in New Mexico found no differences in the age-adjusted frequency of self-reported symptoms between participants with serum TSH elevations from 4.7 to 10 mU/L and those with normal TSH concentrations.3i A larger survey from Colorado (n=25,862)
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From page 88... ...
Analytic Framework and Key Questions In this appendix we address whether the primary care physician should screen for thyroid function in patients seen in general medical practice who have no specific indication for thyroid testing and who come to the physician for other reasons. We focus on whether screening should be aimed at detection of subclinical thyroid dysfunction and whether individuals who have mildly abnormal TSH values can benefit.
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From page 89... ...
89 0 0 0 e E e 8- e 8 0 e 8 E ~~ 0 Or ~ 8 rr 0 E :~: ~ cat cO At, ~ .
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From page 90... ...
We also identified observational studies of treatment for subclinical thyroid dysfunction; we included recent ones that had not been included in previous metaanalyses.~3, 24, 25, 88 To assess the prevalence of thyroid disease and the causal relationships between thyroid dysfunction and potential complications, we used the following sources: · Previous meta-analyses and systematic reviews. · More recent cross-sectional, cohort, and case control studies of the prevalence of overt or subclinical thyroid dysfunction.
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From page 91... ...
RESULTS Efficacy of Treatment for Subclinical Hyperthyroidism No controlled trials of treatment for subclinical hyperthyroidism have been done. Small observational studies of patients with nodular thyroid disease not detected by screening have shown improvements in bone metabolism and hemodynamic measures after treatment.53 90-92 Efficacy of Treatment for Subclinical Hypothyroidism We identified 14 randomized trials of levothyroxine therapy.
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From page 92... ...
. Caraccio, Yes, by Not stated Generally yes, Yes No No Probably 2002 individual but mean TSH were aware (6 vs.
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From page 93... ...
., primarily as a before/after study No Probably Yes, No No Yes (when Poor were aware assuming analyzed because that as an ROT) dosing and completion length of of study follow-up was not differed; a criterion not clear for whether inclusion patients were informed of their lipid levels continued
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From page 94... ...
94 MEDICARE COVERAGE OF ROUTINE SCREENING FOR THYROID DYSFUNCTION TABLE B-3 Continued Eligibility Outcome Care Patient Study Random Allocation Groups Similar Criteria Assessors Provider Unaware of and Year Assignment? Concealed?
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From page 95... ...
APPENDIX B 95 Care Patient Intention- Maintenance Reporting Differential Statistical Score Provider Unaware of to-Treat of Comparable of Attrition, Loss to Analysis (Good/ Blinded? Treatment?
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From page 96... ...
The third trial, in patients known to have Hashimoto's thyroiditis and positive antithyroid antibodies who had mildly elevated TSH levels, had a similar flaw.~02 When analyzed as a randomized trial, there were no significant differences between levothyroxine-treated and placebo groups in any lipid parameter. When analyzed as a pre-/post-treatment study, there was a statistically significant reduction in LDL cholesterol levels (3.6 to 3.1 mmol/L)
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From page 97... ...
The last two studies listed in Table B-4 concern patients who have TSH levels in the normal range. In one of these, 50 micrograms of levothyroxine therapy reduced LDL cholesterol levels from 6.8 to 5.9 mmol/L in patients with elevated total cholesterol levels (>7.5 mmol/L)
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From page 98... ...
or Graves' disease (1) internal medicine 7 men randomized trial clinic, Italy No known history or not stated Jaeschke, Randomized, Diagnosis of subclinical Unclear setting, 28 womer 1996 double-blind, hypothyroidism Ontario age 55, m placebo-controlled trial Kong Randomized, Women with a diagnosis Referrals from 45 womer 2002 double-blind of subclinical GPs for thyroid age ~49 y placebo-controlled hypothyroidism function tests, trial London Nystrom Randomized, Women identified by Population-based 20 womer 1988 double-blind screening screening study, placebo controlled Gothenburg crossover trial Biochemically euthyroid patients Michalopoulou, Randomized trial with Patients referred for Preventive Not statec 1998 active control group lipid assessment medicine (lipid)
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From page 99... ...
or (b) no symptoms History of Graves' disease History of autoimmune thyroiditis (n=33)
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From page 100... ...
Total follow-up 50 weeks Caraccio Diabetes, renal or liver Grant from LT4 25 then titrated up Placebo 2002 disease, TC>7.8 mmol/L university No known history or not stated Jaeschke, Medications that Ontario Ministry LT4 25 then titrated up Placebo 1996 interfere with TFTs; of Health, Boots (mean final dose 68+21) serious medical Pharmaceuticals conditions Kong, History of thyroid Medical Research LT4 50 then titrated up Placebo 2002 disease, psychiatric Council to 100 if TSH >6 mU/L disorder, anticipated pregnancy Nystrom, History or signs of Nonindustry grants LT4 50 for 2 weeks, Placebo 1988 thyroid disease, history (Nyegaard then 100 mg for 2 wks, of cardiovascular disease supplied LT4)
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From page 101... ...
; mean TSH in control group increased to ~15 by the end of the study ver Placebo 12.8 (mean) ; NR/NR/66 3/63 an final 5-50 (range)
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From page 102... ...
One meta-analysis of these observational studies found that treatment reduced LDL cholesterol levels by 0.4 mmol/L and a more recent meta-analysis of both observational and randomized studies found that, in previously untreated patients, total cholesterol was reduced by 0.14 mmol/L (-5.6 mg/dL) .~04 Another review concluded that levothyroxine treatment might
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From page 103... ...
and there were borderline improvements in symptom scores (p=0.02) ; Placebo group TSH was stable LT4 group: TC reduced from 5.5 to 5.0; LDLc from 3.6 to 3.1 Placebo group's TSH rose from 9.42 to 10.32 over 6 months Placebo group's TSH dropped from 7.3 to 5.6 over 6 months LDLc reduction was significant in 50 mg group Placebo significantly improved SF-36 general health and physical health scores reduce serum cholesterol by 8 percent in selected patients who have both a serum TSH >10 mUIL and an elevated total cholesterol (>6.2 mmollL)
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From page 104... ...
Based on data from the Whickham study, a previous analysis estimated that if 1,000 women age 35 and over are screened, 80 will be diagnosed to have subclinical hypothyroidism; 43 of these will have a mildly elevated TSH and positive antithyroid antibodies. If these 43 individuals were treated with levothyroxine, by 5 years overt hypothyroidism would be prevented in 3 women (NNT=14.3)
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From page 105... ...
patients taking levothyroxine quit the protocol because of nervousness and a sense of palpitations.74 In another, 2 of the 18 (11 percent) patients assigned to levothyroxine withdrew because of complications: one because of an increase in angina, and one because of new-onset atrial fibrillations In a third, anxiety scores were higher in the levothyroxine group.~03 A systematic review of observational studies published from 1966 to 1997 found that replacement doses of levothyroxine have not been associated with osteoporosis or with any other serious long-term adverse effects.~06 A short-term randomized trial of levothyroxine for subclinical hypothyroidism confirms this view.97 By contrast, thyroid hormone to suppress TSH because of thyroid cancer, goiters, or nodules contributed to osteoporosis in postmenopausal women.~06 Overtreatment with levothyroxine, indicated by an undetectable TSH, is another potential risk.
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From page 106... ...
The ability of screening programs to detect subclinical thyroid dysfunction has been demonstrated in TABLE B-5 Summary of Findings of Systematic Review Arrow in Level and Type Overall Evidence Figure 1 Question of Evidence for the Link Findings 1 Is there direct evidence from None N/A No contra controlled studies linking screening to improved health outcomes? What is the yield of II-2.
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From page 107... ...
in previously untreated patients, but the quality of the observational studies was generally poor. Subclinical hyperthyroidism is a risk factor for developing atrial fibrillation, but no studies have been done to determine whether screening and early treatment are effective in reducing the risk.
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From page 108... ...
2002. Association between thyroid dysfunction and total cholesterol level in an older biracial population: The health, aging and body composition study.
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From page 109... ...
1996. Low TSH levels in nursing home residents not taking thyroid hormone.
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From page 110... ...
1993. Bone mineral density in patients with endogenous subclinical hyperthyroidism: Is this thyroid status a risk factor for osteoporosis?
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From page 111... ...
1996. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community.
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From page 112... ...
Cardiac dysrhythmias and thyroid dysfunction: The hidden menace? J Clin Endocrinol Metab 87:963967.
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From page 113... ...
2001. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: Randomised double blind placebo controlled crossover trial.
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