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Levels of thyroid function considered "normal" were still associated with increased mortality, according to a study suggesting that cardiovascular disease (CVD) plays an important role.

People considered to have subclinical hypothyroidism -- serum thyrotropin (TSH) levels over 5.60 mIU/L but normal serum free thyroxine -- were at greater risk of all-cause mortality over more than 7 years compared to those with TSH in the middle of the normal range (HR 1.90, 95% CI 1.14-3.19).

Yet even the upper end of the normal TSH range, dubbed high-normal TSH, showed greater risk of death during follow-up than the middle-normal group (HR 1.36, 95% CI 1.07-1.73), reported a group led by Kosuke Inoue, MD, of the University of California Los Angeles, in a study published online in .

Statistical analysis showed that CVD indirectly mediated roughly 5% to 15% of the association between thyroid function and death -- namely in women and people age 60 or older.

"[H]igher TSH level may be a risk factor for CVD and also mortality, even when TSH levels are only modestly elevated," the authors concluded, raising the question of whether hypothyroidism should be treated early on during the subclinical phase.

The American Thyroid Association and European Thyroid Association currently do not recommend treating subclinical hypothyroidism when TSH is ≤10 mIU/L, according to Inoue's team.

"Further studies are needed to examine the clinical benefit of targeted to a middle-normal TSH concentration or active CVD screening for people with elevated TSH concentrations," the investigators suggested.

Their results did not track thyroid function over time, so they couldn't say if treatment with thyroid hormone replacement would help these patients.

Individuals included in the study were 9,020 adults participating in the National Health and Nutrition Examination Survey. The cohort was 51.6% men, with a mean age of 49.4 years.

Serum TSH levels were classified as low-normal (0.34-1.19 mIU/L), middle-normal (1.20-1.95 mIU/L), high-normal (1.96-5.60 mIU/L), and subclinical hypothyroidism (>5.60 mIU/L).

Participants with subclinical hypothyroidism or high-normal TSH were generally older.

Individuals at the low end of the normal TSH range (approaching hyperthyroidism) had increased odds for mortality compared to the middle-normal group (HR 1.36, 95% CI 1.01-1.83), but there was no evidence of CVD mediation for this finding, Inoue and colleagues said.

Given the lack of mediation or only a slight mediation through CVD between high TSH and death in men, Inoue and colleagues noted that women are known to be at an increased risk of progression from subclinical to overt hypothyroidism.

The possibility of reverse causation was a major limitation of the study, even if it is unlikely that CVD affected serum TSH concentrations, according to the authors.

"In addition, our data did not capture all of the CVD events during the follow-up period; therefore, effect size of the CVD mediation might be underestimated," they wrote.

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