Normal thyroxine and elevated thyrotropin concentrations: evolving hypothyroidism or persistent euthyroidism with reset thyrostat.

Background: The natural course in subjects manifesting normal serum thyroxine (T4), and triiodothyronine (T3), with an elevated thyrotropin (TSH) level demonstrated two distinct outcomes, one progressing to well defined hypothyroidism as expressed by onset of subnormal T4, T3 and a further rise in TSH and the other remaining in the same state. However, thyroid hormone concentrations at the time of diagnosis fail to distinguish between the two groups. Therefore, we examined the influence of alteration in circulating TSH levels on thyroid gland function at the time of diagnosis in subjects with this syndrome to assess the role of pituitary thyroid axis in these different outcomes.

Methods: 24 hour 131I thyroidal uptake was determined in 14 men and 3 women manifesting normal T4, T3 and elevated TSH prior to and again after 1) subcutaneous administration of bovine TSH, 10 units daily for 3 days and 2) daily oral administration of L-triiodothyronine 75 micrograms for 7 days in a randomized sequence at interval of 4 weeks. Subjects were then followed for up to 16 years to assess the natural course.

Results: Basal 24 hour 131I uptake values were within the normal range (10-35%) in all subjects and increased on TSH administration and declined following LT3 administration. However, in eight subjects, these responses were markedly lower (< 20%) when compared with the minimum change (50%) noted in normal volunteers. These subjects progressed to manifest hypothyroidism requiring LT4 therapy within two years as reflected by a progressive decrease to subnormal T4 levels with a further rise in serum TSH. The remaining nine subjects, demonstrated normal responses (> 50%) and only one of these became hypothyroid during the follow-up period of 16 years.

Conclusion: All subjects with normal T4 and T3 with elevated TSH do not manifest "subclinical or evolving hypothyroidism". Two distinct populations seem to exist, one with inhibited pituitary thyroid axis progressing to hypothyroidism or true "subclinical hypothyroidism" at the time of diagnosis and the other with normal pituitary thyroid axis, a state of euthyroidism with "reset thyrostat" at a higher TSH concentration, a state probably persisting for their remaining life span.