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Effects of Reducing the Upper Limit of Normal TSH Values
To the Editor: Measurement of the serum thyrotropin (TSH) concentration is the most sensitive single test of thyroid function. Concentrations of TSH in the apparently healthy population are log-normally distributed; 70% to 80% are between 0.3 and 2.0 mIU/L, while 97.5% are less than 5.0 mIU/L.1 When individuals with thyroid autoantibodies, goiter, or a strong family history of thyroid disease are excluded, the upper bound of the 95% TSH concentration reference range decreases to between 2.5 and 3.0 mIU/L.1-2 It has been argued that such a "refined normal range" is a better reflection of thyroid health than a standard population-based reference range and that elevated values may predict future hypothyroidism.1-5 This decreased upper bound would increase the sensitivity of the diagnosis of subtle hypothyroidism while decreasing its specificity. We investigated the potential impact of the suggested change in reference range.
Methods
The study was approved by the Mayo Foundation institutional review boards. We analyzed the results of all measurements of serum TSH concentration performed on patients attending the Mayo Clinic, Rochester, Minn, between January 1 and December 29, 2001. Approximately one third of all patients had measurements of TSH concentration performed to assess thyroid function. Concentrations of TSH, as well as patient age, sex, and the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes were retrieved from the electronic medical records. Patients refusing research authorization and patients having ICD-9 codes related to thyroid disorders were excluded from the statistical analyses. We then examined the proportion of patients without a history of thyroid disease who would be reclassified as having hypothyroidism based on an upper bound of 3.0 mIU/L vs 5.0 mIU/L.
Results
A total of 109 618 measurements of TSH concentration were performed on 94 429 patients (of 315 095 patients examined). We excluded 3315 patients (3.5%) who had refused research authorization. A total of 75 882 patients without ICD-9 codes related to thyroid disorders were subgrouped by TSH concentration, age, and sex (Table 1). More than 4 times as many patients (20.0% vs 4.64%) would be classified as having elevated TSH concentrations if 3.0 mIU/L rather than 5.0 mIU/L were used as the upper limit of normal. The percentages were slightly higher in female patients than in male patients, and in both groups the percentages increased with age. When 3.0 mIU/L was used as the upper limit of normal for evaluating patients without clinically evident thyroid disease, approximately 15% of patients younger than 50 years, 17% to 23% of patients aged 50 to 70 years, and 25% of men and 29% of women older than 70 years were classified as having abnormal TSH concentrations. These percentages were 3.8 to 5.0 times higher than the percentages of patients classified as having abnormal TSH concentrations when the traditional limit of 5.0 mIU/L is used.
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Table. Effects of Decreasing the Upper Limit of the TSH Concentration Reference Range From 5.0 to 3.0 mIU/L
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Comment
In a tertiary care practice setting, a decreased upper bound of the TSH concentration reference range would result in a large number of patients being reclassified from "normal" to having "biochemical hypothyroidism." The proposed change would result in 1 in 5 patients without known thyroid disease being classified as having biochemical hypothyroidism. Such a change would dramatically increase the diagnosis of biochemical hypothyroidism and the need for investigation and monitoring, and might significantly increase the use of thyroxine therapy for patients for whom there is no demonstrated therapeutic benefit. Before extending the diagnosis of hypothyroidism to include TSH levels of 3.0 to 5.0 mIU/L, studies are needed that demonstrate the benefit of therapy for very mild subclinical hypothyroidism.
Vahab Fatourechi, MD;
George G. Klee, MD, PhD;
Stefan K. Grebe, MD, PhD;
Rebecca S. Bahn, MD;
Michael D. Brennan, MD;
Ian D. Hay, MD, PhD;
Bryan McIver, MD, PhD;
John C. Morris III, MD
Thyroid Group
Mayo Clinic College of Medicine
Rochester, Minn
1. Baloch Z, Carayon P, Conte-Devolx B, 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;13:3-126.
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2. Hollowell JG, Staehling NW, Flanders WD, 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;87:489-499.
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3. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow up of the Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55-68.
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4. AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-467.
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5. Fatourechi V. Adverse effects of subclinical hyperthyroidism. Lancet. 2001;358:856-857.
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Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.
JAMA. 2003;290:3195-3196.
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