Over the past decade, doctors have become increasingly aggressive at initiating treatment for borderline hypothyroidism, possibly raising the risk for thyroid suppression as an unintended consequence, a new study suggests.

The American Thyroid Association recommends considering levothyroxine therapy at thyroid-stimulating hormone (TSH; thyrotropin) levels of 10 mIU/L or lower if symptoms of hypothyroidism, positive thyroid autoantibodies, or evidence of atherosclerotic cardiovascular disease or heart failure are present. But starting levothyroxine at or below 10 mIU/L in those without symptoms may do more harm than good, it cautions.

Yet in this new 9-year survey of more than 52,000 individuals in the United Kingdom, the number of individuals who received levothyroxine for a thyrotropin level of less than 10 mIU/L increased by 30% over the course of the study.

“This practice may be harmful, given the high risk of developing a suppressed thyrotropin level after treatment,” say the researchers, led by Peter N. Taylor, MRCP, from the Thyroid Research Group at the Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, United Kingdom, and colleagues, whose findings are published online October 7 in JAMA Internal Medicine.

Asked to comment on the findings for Medscape Medical News, Leonard Wartofsky, MD, chair of the department of medicine, Washington Hospital Medical Center, Washington, DC, said the authors are “raising the red flag that there is potentially overdiagnosis and overtreatment that has some risks.”

Most healthy people have thyrotropin levels less than 2.5 mIU/L, he explained. “If you simply go by the numbers, it’s hard to reconcile a TSH level of 7.9 as being normal when the rest of the population has numbers of 2.5 or less.” However, he added, thyrotropin levels do rise with age, so higher levels are normal for people 70 years of age or more and do not necessarily indicate treatment is necessary.

“Part of the problem is that this is a mild abnormality, and in most published studies it’s been difficult to show a clear benefit of intervention, because the number of subjects participating has been small, the abnormalities are minor, and you can’t show a major clinical effect of intervention,” Dr. Wartofsky observed. “This is a controversial issue, and it’s still unsettled.”

Threshold Lowered After 2004

Using the General Practice Research Database (GPRD; now called the Clinical Practice Research Datalink), which contains the records of more than 5 million patients in 508 primary-care practices across the United Kingdom, Dr. Taylor and coauthors conducted a retrospective cohort study of 52,298 adults who initiated levothyroxine therapy between January 1, 2001, and October 30, 2009, at a median age of 59 years.

Excluded from the study were people with a history of hyperthyroidism, pituitary disease, or thyroid surgery; those who were taking medication that affected thyroid function or whose thyroid problems were related to pregnancy; and/or those whose thyrotropin had been measured more than 3 months prior to beginning treatment.

To gauge the effect of therapy on thyroid function, they also studied thyrotropin levels at 30 to 36 months and 54 to 60 months after treatment began. Female patients outnumbered males by almost 4 to 1.

Following multivariate adjustment, the odds ratio of a patient receiving a levothyroxine prescription for a presenting thyrotropin level of less than 10.0 mIU/L in 2009 compared with 2001 was 1.30 (P < .001), and the number of new levothyroxine prescriptions increased by 74% over the study period.

The median thyrotropin level for initiating treatment fell from 8.7 mIU/L in 2001 to 7.9 mIU/L in 2009.

Individuals prescribed levothyroxine with a thyrotropin level between 4.0 and 10.0 mIU/L instead of exceeding 10.0 mIU/L were more likely to be female, have cardiovascular risk factors, and be older than 70 years when prescribed levothyroxine after 2004, with trends also observed for tiredness and depression, the authors write.

They conclude that “large-scale, prospective studies are required to assess the risk/benefit ratio of current practice.”

Overtreatment Can Lead to Problems, but So Can Undertreatment

Dr. Wartofsky said the study was designed to address whether starting levothyroxine therapy too early may result in overtreatment

Follow-up data showed that the percentage of patients with thyrotropin levels less than 0.1 mIU/L increased from 2.7% to 5.8% and the percentage of those with levels between 0.1 and 0.5 mIU/L increased from 6.3% to 10.2%, suggesting the presence of thyroid suppression. This “could lead to cardiac problems, arrhythmias, and atrial fibrillation and over the long term could lead to loss of bone mineral, osteopenia, and osteoporosis,” he explained.

But, he added, “I’m not particularly overwhelmed by the fact that only 5.8% of the patients were so oversuppressed. I think that is not unusual, even in the hands of expert endocrinologists — sometimes you oversuppress inadvertently.”

And the study does not show what the benefits of earlier treatment might be, probably because it takes longer for them to become apparent, he said. “In my view, there are compelling data that treating these populations does have a salutary effect”: lower serum cholesterol, a lower risk of coronary artery disease, and general symptom relief, among other things.

Source: JAMA