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Levothyroxine Dose and Measurement of TSH

      To the Editor:
      The article by Pecina et al
      • Pecina J.
      • Garrison G.M.
      • Bernard M.E.
      Levothyroxine dosage is associated with stability of thyroid-stimulating hormone values.
      raises several issues that need further clarification, especially in the light of the new guidelines by the American Association of Clinical Endocrinologists for management of hypothyroidism.
      • Garber J.R.
      • Cobin R.H.
      • Gharib H.
      • et al.
      Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.
      The reference range of thyroid stimulating hormone (TSH) used in the study to classify the normal range (0.3-5.0) may not be entirely accurate given that the National Health and Nutrition Examination Surveys III (NHANES III) database has shown significant ethnic and age-related differences in the 97.5th percentile values of TSH, with the upper limit of TSH being 4.5 mIU/L.
      • Hollowell J.G.
      • Staehling N.W.
      • Flanders W.D.
      • 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).
      Moreover, if the population specifically excluded (eg, pregnant women) from the study is considered, the upper limit is even lower (4.12 mIU/L ).
      • Hollowell J.G.
      • Staehling N.W.
      • Flanders W.D.
      • 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).
      The physicians treating the subjects may have targeted a different TSH level individually for adjusting the levothyroxine dose based on their own knowledge and experiences.
      In addition to the selection bias toward more compliant patients (as mentioned by the authors), by not controlling for subclinical hypothyroidism, there might be a lead-time bias. The absolute risk of progression of untreated subclinical hypothyroidism to overt disease is low, especially in the course of 3-6 years.
      • Diez J.J.
      • 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.
      The doses required for treating subclinical hypothyroidism in order to achieve euthyroid TSH levels also are much lower.
      • Rosenbaum R.L.
      • Barzel U.S.
      Clinical hypothyroidism in the elderly—a preventable disorder?.
      The initial TSH level has been found to be the most significant predictor for progression to overt disease.
      • Diez J.J.
      • 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.
      Early treatment with lower doses of levothyroxine might be shifting the TSH towards reference ranges with similar future progression rates. In summary, lower levothyroxine doses might be a surrogate marker for their subclinical hypothyroid status.

      References

        • Pecina J.
        • Garrison G.M.
        • Bernard M.E.
        Levothyroxine dosage is associated with stability of thyroid-stimulating hormone values.
        Am J Med. 2014; 127: 240-245
        • Garber J.R.
        • Cobin R.H.
        • Gharib H.
        • et al.
        Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.
        Endocr Pract. 2012; 18: 988-1028
        • Hollowell J.G.
        • Staehling N.W.
        • Flanders W.D.
        • 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
        • Diez J.J.
        • 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: 4890-4897
        • Rosenbaum R.L.
        • Barzel U.S.
        Clinical hypothyroidism in the elderly—a preventable disorder?.
        J Am Geriatr Soc. 1981; 29: 221-223

      Linked Article

      • Levothyroxine Dosage Is Associated with Stability of Thyroid-stimulating Hormone Values
        The American Journal of MedicineVol. 127Issue 3
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          In patients treated for hypothyroidism, the usual practice is to monitor thyroid-stimulating hormone values yearly once a therapeutic dosage of levothyroxine is determined. This study investigates whether there are any clinical predictors that could identify a subset of patients who might be monitored safely on a less frequent basis.
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      • The Reply
        The American Journal of MedicineVol. 128Issue 1
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          We thank Santhanam for his interesting thoughts on our study.1 While we are aware that there is significant controversy in the literature on what constitutes the upper limits of normal for a thyroid-stimulating hormone (TSH) value, we chose to use the range of 0.3-5.0 mIU/L to define normal in our study, as this is the reference range for the test used at our institution. This is in accordance with the 2012 American Association of Clinical Endocrinologist's guidelines for management of hypothyroidism state, “In patients who are not pregnant, the target range should be within the normal range.
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