High frequency of inadequate TH replacement therapy

TOPIC: Treatment of hypothyroid patients

Title: High frequency of – and factors associated with – thyroid hormone over-replacement and under-replacement in men & women aged 65 and over.

Authors: Somwaru LL, Arnold AM, Joshi N, Fried LP, & Cappola AR.

Reference: Journal of Clinical Endocrinology & Metabolism (epub – ahead of print) January 6, 2009



Thyroid hormone use is common in older populations, but the frequency of over- or under-replacement is debated.


The authors sought to describe the frequency of – and the factors associated with – thyroid hormone over- or under-replacement in a population of older men and women.


Participants were 3.678 US community-dwelling individuals aged 65 or over enrolled in the Cardiovascular Health Study who had thyroid function tests in 1989-90. Thyroid hormone users (N = 339) were identified and classified into low serum TSH (<0.45 mU/L), euthyroid (0.45-4.5 mU/L), and high serum TSH (>4.5 mU/L).


Of the 339 thyroid hormone users, 41% had a low TSH, 16% a high TSH and 43% were in the euthyroid range. In multivariate analyses, lower weight was independently associated with low TSH status (p<0.001). For every 10 kg of lower weight, the likelihood of having a low serum TSH increased by 65% (OR: 1.65; 95%CI: 1.31-2.07). Patients with renal insufficiency were less likely to have a low TSH (p=0.02). Presence of diabetes was independently associated with having low (OR: 3.35; 95% CI: 1.46-7.65) and high TSH levels (OR: 2.66, 95% CI: 1.14-6.21).


There is a very high prevalence of thyroid function testing abnormalities in older people taking thyroid hormone, particularly in patients with low weight or diabetes. Because of potential adverse cardio-vascular and skeletal effects from over-replacement, older people represent a key population for close monitoring of serum TSH levels on therapy.


Thyroid function was tested in 1989-1990 in 3.678 participants of the Cardiovascular Health Study, of whom 339 used thyroid hormone (TH). The etiology of hypothyroidism for which they received TH replacement therapy was not specified, although it was stated (perhaps somewhat surprisingly) that none of them had a history of thyroid cancer. Thyroid function tests included measurements of serum TSH and, if the TSH was outside the reference range (0.45-4.5 mU/L), serum FT4 was also measured. Based on these data, the patients were classified as being overtly hypothyroid (TSH>20, or TSH>4.5 + low FT4), subclinically hypothyroid (4.5<TSH<20 with normal FT4), euthyroid, subclinically hyperthyroid (TSH: 0.1-0.45 or TSH<0.1 + normal FT4), and finally overtly hyperthyroid (TSH<0.1 with high FT4).

The remarkable observations reported in this article are:

  • Apparently already in 1989-1990, 26% of the subjects were treated with a combination of T4 and T3, and the remainder with T4 alone
  • Independent of the type of substitution therapy, only 43% of subjects had TSH levels in the normal range, while 3.4% were classified as overtly hypothyroid, 12.5% as subclinically hypothyroid, 31.1% as subclinically hyperthyroid and 7.8% as overtly hyperthyroid.

These data suggest that almost 40% of hypothyroid patients received over-replacement. Is this truly the case? The study concerns a population of elderly subjects, and aging is associated with increased morbidity. Serum TSH is often low in patients with nonthyroidal illness, and, therefore, many subjects with subclinical hyperthyroidism may not be over-replaced but rather have a low TSH because of poor health. Although it is stated that low serum TSH was not related to co-morbidity, both decreased & increased serum TSH levels were associated with diabetes. In a previous study cited by the authors, as much as 22% of elderly subjects participating in a community health fair were found to have subclinical hyperthyroidism. It would be very interesting to compare thyroid function tests in the thyroid hormone-treated group of patients with the untreated subjects from the Cardiovascular Health Study.

Undoubtedly, present findings imply that a significant proportion of hypothyroid elderly patients receive over-replacement therapy. There is much debate about the possible benefits of TH treatment in patients with subclinical hypothyroidism. Over-treatment is not always considered in these discussions, and if this would occur with the same high frequency (as suggested by the present study), the remedy could be worse than the disease.

Summary and Commentary prepared by Theo Visser (Related to Chapter 9 of TDM)