Overtreating Hypothyroidism: Link to Atrial Fibrillation

CHICAGO — For patients with hypothyroidism, being treated with too much medication could lead to an increased risk of atrial fibrillation, a new study of more than 174,000 patients indicates.

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 in a large healthcare systems database, in which patients were not actually being treated with any thyroid hormone, according to the presentation here at the American Heart Association (AHA) Scientific Sessions 2018.

But this suggests the possible need for redefining the safest reference ranges in hypothyroidism treatment, according to the lead author Jeffrey L. Anderson, MD, distinguished clinical and research physician with the Intermountain Medical Center Heart Institute, Salt Lake City, Utah.

"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," Anderson said in a press statement from his institution.

"These findings show we might want to reconsider what we call 'normal'," he said.

To Medscape, Anderson elaborated: "There can be a tendency [when treating hypothyroidism] with levothyroxine (T4) to push the dose up — people want to have more energy, lose more weight," but this work suggests this practice might not be without risk, he noted.

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.

Anderson and colleagues wanted to see if this could be replicated in another large population, so they 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 40% higher for patients in the highest quartile of fT4 levels compared to patients in the lowest quartile and this translated into a 16% increase in newly developing atrial fibrillation during long-term follow-up (which averaged 6.3 years).

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 suggest that the optimal healthy range of free T4 should be reconsidered and redefined, particularly given the inclination to push T4 levels into higher normal ranges when treating hypothyroidism, 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.

American Heart Association (AHA) 2018 Scientific Sessions: Abstract 450. Presented November 11, 2018.

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