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The TSH upper reference limit: where are we at?

Abstract

The diagnosis of subclinical hypothyroidism—serum TSH levels above and T4 levels within the laboratory reference ranges—depends critically on the upper limit of the TSH reference interval. Calls have been made to lower the current upper TSH reference limit of 4.0 mU/l to 2.5 mU/l to exclude patients with occult hypothyroidism. However, data from population studies do not indicate that the distribution of TSH is altered owing to inclusion of such individuals. The opposite suggestion has also been put forward; the TSH upper reference limit is often too low, especially in the elderly, in women and in white individuals, which may lead to unnecessary or even harmful therapy. Studies in elderly individuals have shown that although aging may be associated with increased TSH levels, paradoxically, overt hypothyroidism in this population may be associated with a less robust TSH response than in young individuals. This Review highlights the interindividual and intraindividual variability of TSH levels and discusses the current controversy that surrounds the appropriateness of reference ranges defined on the basis of age, race, sex and amount of iodine intake. Moreover, the current evidence on lowering or increasing the upper limit of the TSH reference interval is reviewed and the need to individualize levothyroxine treatment in patients with elevated TSH levels is discussed.

Key Points

  • Current evidence does not support a change of the upper TSH reference limit; an exception is pregnancy, where trimester-specific reference intervals for thyroid function tests should be used

  • No evidence suggests that serum TSH, as an indicator of thyroid health, should be evaluated differently depending on race, sex or iodine intake

  • Thyroid autoimmunity is very common (50%) in elderly white women, with a high frequency of elevated TSH levels, especially if iodine intake is high

  • Asymptomatic elderly individuals with a serum TSH level <7–10 mU/l probably do not benefit from levothyroxine therapy; however, treatment should be considered in young women with elevated TSH levels who plan a pregnancy

  • TSH is a less sensitive marker of thyroid insufficiency in old individuals, and care should be taken not to overlook clinical hypothyroidism when TSH concentration is elevated

  • In patients with subclinical hypothyroidism, a change in serum TSH level >40% is unlikely to be caused by random variation

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Figure 1: Distribution of serum TSH in two independent Danish population cohorts of young women investigated before and after the Danish iodization of salt in the year 2000.
Figure 2: Age-specific TSH values (log-scaled) at diagnosis in 578 patients with spontaneous (autoimmune) hypothyroidism.

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All authors researched the data for the article and provided a substantial contribution to discussions of the content. P. Laurberg wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Peter Laurberg.

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Laurberg, P., Andersen, S., Carlé, A. et al. The TSH upper reference limit: where are we at?. Nat Rev Endocrinol 7, 232–239 (2011). https://doi.org/10.1038/nrendo.2011.13

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