Screening and Treating Subclinical Thyroid Disease: Getting Past the Impasse
Authors: Anne R. Cappola, David S. Cooper
Journal: Annals of Internal Medicine (2015)

Editorials5 May 2015Screening and Treating Subclinical Thyroid Disease: Getting Past the ImpasseFREEAnne R. Cappola, MD, ScM and David S. Cooper, MDAnne R. Cappola, MD, ScMFrom Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, and The Johns Hopkins University School of Medicine, Baltimore, Maryland. and David S. Cooper, MDFrom Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, and The Johns Hopkins University School of Medicine, Baltimore, Maryland.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M15-0640 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Thyroid dysfunction is common, and both insufficient and excess thyroid hormone can cause myriad systemic effects resulting in symptoms and, in extreme cases, serious illness and even death. There are sensitive and specific blood tests to diagnose thyroid dysfunction and readily available therapies to treat it. This supports the potential utility of screening.In this issue, the U.S. Preventive Services Task Force (USPSTF) presents its findings on screening for thyroid dysfunction (1). Not surprisingly, the USPSTF concluded that evidence is insufficient to assess the balance of potential benefits and harms of screening nonpregnant adults. This conclusion is based on the absence of large prospective randomized, controlled trials (RCTs) demonstrating a benefit of treatment of subclinical hypothyroidism or subclinical hyperthyroidism (2). Indeed, the recommendation is similar to the one made by the USPSTF in 2004 (3), and it is disheartening to see that so little progress seems to have been made in trying to address this important clinical problem.This leaves the health care provider and the patient in a familiar vacuum of management using the imperfect data available. The current USPSTF statement provides a useful summary of the few short-term clinical trials and highlights the disappointingly small number of new RCTs since the last report, with no trials conducted in the United States. However, it fails to acknowledge the publication in the intervening period of 3 individual-patient data meta-analyses of observational studies (4–6). These meta-analyses provide important information about potential risks from untreated subclinical thyroid dysfunction and support a dose–response relationship between thyroid-stimulating hormone (TSH) concentrations at either extreme and an increased risk for cardiovascular events and death. They also support potential serum TSH thresholds for increased risk of less than 0.45 and greater than 7 mIU/L and more confident thresholds of less than 0.1 and greater than 10 mIU/L, although the benefits and harms of treatment at these thresholds have not been defined in RCTs.We agree that the first step in moving from a recommendation of "insufficient evidence" to a more clinically useful recommendation requires data from RCTs with hard end points. Although an effort to fund a U.S. trial in subclinical hypothyroidism was unsuccessful, the European TRUST (Thyroid Hormone Replacement for Subclinical Hypothyroidism) study is currently under way (www.clinicaltrials.gov/ct2/show/NCT01660126?term=TRUST+trial&rank=1). Two European trials designed to examine treatment of subclinical hyperthyroidism failed to complete recruitment due to the lower prevalence of the condition and were terminated. Therefore, there is little hope of data on the risks and benefits of treating this condition. Subclinical hyperthyroidism is associated with atrial fibrillation, congestive heart failure, and osteoporosis in older persons and postmenopausal women (7). These are precisely the unfavorable health effects seen in older persons with overt hyperthyroidism, which is why professional groups recommend treating subclinical hyperthyroidism in these vulnerable populations, especially those with serum TSH concentrations less than 0.1 mIU/L (8).As practicing endocrinologists, we find 2 themes in the USPSTF statement troublesome. The first is the reference to "measurement variability" of serum TSH. This variability is not due to poor assay performance but to inherent biological variability related to the exquisite sensitivity of the hypothalamic–pituitary–thyroid axis to even minimal perturbations in thyroid secretion. Superimposed on these clinically insignificant changes are potential episodes of silent thyroiditis and systemic illness. This is the reason for confirming the persistence of a serum TSH abnormality with a single repeated measurement several months later. The rationale in the USPSTF statement for "[m]ultiple tests … over a 3- to 6-month interval" is neither biologically relevant nor supported by data.The second disturbing issue in the USPSTF statement is the use of the term "asymptomatic" in the context of thyroid dysfunction. By definition, a patient with symptoms of fatigue, hair loss, or palpitations who has a TSH test done is undergoing "case finding," not screening. It is hard to justify withholding TSH testing in a patient who does not have an obvious alternative cause for any of these symptoms. The clinical conundrum arises when a patient with any of the nonspecific symptoms of thyroid dysfunction has test results consistent with subclinical thyroid dysfunction. Were the patient's symptoms due to a mild thyroid problem, or is there an unrelated biochemical abnormality that may or may not be clinically significant? The effectiveness of treatment of either type of subclinical thyroid dysfunction in reversing the symptoms that triggered testing has never been evaluated in placebo-controlled trials. Therefore, it is not clear that the management of a symptomatic patient with subclinical thyroid dysfunction should differ from that of an asymptomatic patient, given the potential for beneficial effects on cardiovascular outcomes and bone health, which might occur with therapy even in asymptomatic persons.We also reiterate concerns expressed in the public comment section of the USPSTF statement about not treating asymptomatic overt thyroid disease (defined by serum concentrations of free thyroxine or triiodothyronine that are outside their reference ranges), as would occur in the placebo group of an RCT. The implicit suggestion that there would only be benefit to treating symptomatic overt thyroid disease shows how far astray one can go in pursuit of the "holy grail" of the RCT. This is particularly concerning in elderly adults, in whom symptoms are often absent and atypical symptoms may prevail (9). We strongly disagree with the proposal to conduct treatment trials of asymptomatic overt thyroid dysfunction. In the case of overt hypothyroidism, treatment with levothyroxine is recommended, and patients with overt hyperthyroidism are treated with antithyroid medications, radioiodine, or surgery, depending on the clinical circumstances and patient preference. There should be no debate about this.We hope that when the USPSTF evaluates screening for thyroid dysfunction in another 10 years, there will be additional RCT data to provide guidance. We agree that these data are urgently needed and call on researchers and funding agencies to partner to make this happen. However, without definitive information—and this is highly probable for subclinical hyperthyroidism—we will need to continue to rely on lower-quality evidence to make important clinical decisions that, admittedly, have the potential to both help and harm patients. The decades-long impasse only enhances the importance of evidence-based clinical practice guidelines designed to assist clinicians in making the best decisions for their patients (8, 10).Anne R. Cappola, MD, ScMPerelman School of Medicine at the University of PennsylvaniaPhiladelphia, PennsylvaniaDavid S. Cooper, MDThe Johns Hopkins University School of MedicineBaltimore, MarylandReferences1. LeFevre ML; U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;162:641-50. doi:10.7326/M15-0483 LinkGoogle Scholar2. 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. 2015;162:35-45. [PMID: 25347444] doi:10.7326/M14-1456 LinkGoogle Scholar3. Helfand M; U.S. Preventive Services Task Force. Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004;140:128-41. [PMID: 14734337] doi:10.7326/0003-4819-140-2-200401200-00015 LinkGoogle Scholar4. Rodondi N, denElzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304:1365-74. [PMID: 20858880] doi:10.1001/jama.2010.1361 CrossrefMedlineGoogle Scholar5. Collet TH, Gussekloo J, Bauer DC, denElzen WP, Cappola AR, Balmer P, et al; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012;172:799-809. [PMID: 22529182] doi:10.1001/archinternmed.2012.402 CrossrefMedlineGoogle Scholar6. Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, et al; Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012;126:1040-9. [PMID: 22821943] CrossrefMedlineGoogle Scholar7. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;379:1142-54. [PMID: 22273398] doi:10.1016/S0140-6736(11)60276-6 CrossrefMedlineGoogle Scholar8. Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al; American Thyroid Association. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17:456-520. [PMID: 21700562] CrossrefMedlineGoogle Scholar9. Boelaert K, Torlinska B, Holder RL, Franklyn JA. Older subjects with hyperthyroidism present with a paucity of symptoms and signs: a large cross-sectional study. J Clin Endocrinol Metab. 2010;95:2715-26. [PMID: 20392869] doi:10.1210/jc.2009-2495 CrossrefMedlineGoogle Scholar10. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS; etal. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670-751. [PMID: 25266247] doi:10.1089/thy.2014.0028 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Anne R. Cappola, MD, ScM; David S. Cooper, MDAffiliations: From Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, and The Johns Hopkins University School of Medicine, Baltimore, Maryland.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0640.Corresponding Author: David S. Cooper, MD, Division of Endocrinology, Diabetes, & Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21287; e-mail, [email protected]edu.Current Author Addresses:Dr. Cappola: Perelman School of Medicine at the University of Pennsylvania, 718 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021.Dr. Cooper: Division of Endocrinology, Diabetes, & Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD 21287.This article was published online first at www.annals.org on 24 March 2015. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoScreening for Thyroid Dysfunction: U.S. Preventive Services Task Force Recommendation Statement Michael L. 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