Nancy A. Melville
November 12, 2018
Elevated levels of the thyroid hormone free thyroxine (free T4) — even within the upper levels of normal reference ranges — were associated with an increased risk of atrial fibrillation in the study, suggesting the possible need for redefining the safest reference ranges in hypothyroidism treatment, according to the work presented here at the American Heart Association (AHA) Scientific Sessions 2018.
"We know patients with hypothyroidism have a higher risk of atrial fibrillation, but we didn't consider increased risk within what's considered the normal range of thyroid hormones," lead author Jeffrey L. Anderson, MD, distinguished clinical and research physician with the Intermountain Medical Center Heart Institute, Salt Lake City, Utah, said in a press statement from his institution.
"These findings show we might want to reconsider what we call 'normal'," he said.
Recent novel findings (J Clin Endocrinol Metab. 2015;100:3718-3724) from the prospective Rotterdam Study and a subsequent analysis published in Circulation, as reported by Medscape Medical News, showed that elevated free T4 levels — but not thyroid stimulating hormone (TSH, a common standard measure of thyroid hormone levels) — still within the normal reference range were linked to an increased risk of atrial fibrillation prevalence and incidence.
To investigate if the association could be replicated in another large population, Anderson and colleagues evaluated data on 174,914 patients in the Intermountain Health System who had records on free T4 levels but were not on thyroid replacement therapy at study entry.
Importantly, the new findings build on previous evidence by replicating the results in a much larger population, commented Jacqueline Jonklaas, MD, PhD, MPH, an assistant professor in the Division of Endocrinology and Medicine, Georgetown University Medical Center, Washington, DC.
"The clinical significance of this study is the very large number of patients (174,914), thus making their findings with respect to free T4 potentially more robust," she told Medscape Medical News.
Increasing Gradient of AF With Quartiles of 'Normal' Range T4
The patients in the study by Anderson and colleagues were a mean age of 63.8 years and 65% were women. They were followed for a mean of 6.3 years (± 4.4 years).
Among them, 7.4% had free T4 levels below the normal reference range (0.75-1.50 ng/dL), 88.4% had levels in the normal range, and 4.2% had levels above the normal range.
Those in the normal range were further stratified into four subgroups, ranging from low-normal to high-normal (0.75-0.90 ng/dL [normal 1]; 0.91-1.01 ng/dL [normal 2]; 1.02-1.14 ng/dL [normal 3]; and 1.15-1.50 ng/dL [normal 4]).
After adjustment, the relative risk of prevalent atrial fibrillation was twice as high among those in the highest normal free T4 quartile compared with those in the lowest (odds ratio [OR], 1.99; P < .0001).
And importantly, an increasing gradient of the prevalence of atrial fibrillation was observed within the normal range quartiles, with greater prevalence seen in the normal 2, 3, and 4 groups compared with the lowest normal 1 group (all P < .001).
No similar associations were seen between the quartiles in terms of another marker of thyroid status, free triiodothyronine (free T3), and the TSH results were "mixed and exploratory," the authors note.
The findings could have particularly important implications in terms of treating even so-called subclinical hypothyroidism and the inclination to push levels into higher normal ranges, Anderson said.
"Thyroid hormones are associated with losing weight and having more energy, which may lead to people being treated at the high end of the normal range," he explained. But, he added, "Are we harming people by putting them at a higher risk of atrial fibrillation, and therefore stroke?"
Further research should take a closer look at the risk of atrial fibrillation, but also include its associated risk factors, including stroke, Anderson added.
"The next step for researchers is to conduct a randomized trial to see if targeting a lower versus a higher upper range of free T4 in patients receiving thyroid hormone replacement therapy leads to a lower risk of atrial fibrillation and stroke along with other possible heart-related issues, like atherosclerosis," he explained.
Different Reference TSH Range Than Normally Used
Jonklaas noted an important caveat of the study by Anderson and colleagues is that the upper level of the TSH reference range used (6.68 mIU/L) differs from the more commonly used level (4.5 mIU/L).
Therefore, some of the atrial fibrillation cases may indeed have occurred in the presence of high TSH according to the more common definition; however, "it is not clear how this might have impacted the results," she noted.
And in terms of the treatment implications, the fact that the patients in the study were not receiving thyroid hormone treatment is important, Jonklaas said.
"Additional studies would be needed to determine if these data also apply to thyroid hormone-treated patients," she explained. "If they do, this might suggest that FT4 levels should be more carefully monitored and kept in a midnormal range."
"Currently, TSH is generally used to adjust thyroid hormone treatment," she explained.
"If these data are confirmed, they might suggest that FT4 levels should be routinely measured, too, and also used to adjust thyroid hormone treatment."
The authors and Jonklaas have reported no relevant financial relationships.