Subclinical Hypothyroidism: Current Controversies

Two recent studies raise questions about diagnosis and treatment. Where do you stand on the debate?

A completely biochemical diagnosis, subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating hormone (TSH) level and a normal free thyroxine (T4) level. This condition tends to be more common in women, and with increasing age.¹ A TSH of 10 mIU/L is usually the cutoff for distinguishing mild from more severe subclinical hypothyroidism. Progression from subclinical to overt hypothyroidism is estimated to be about 2% to 6% per year. Two recent articles raise important questions about the diagnosis and management of subclinical hypothyroidism-a subject of continuing debate.^2,3 1. What are the long-term cardiovascular risks?In a recent review, Peeters² notes the potential risks of cardiovascular disease (CVD) in patients with subclinical hypothyroidism. A meta-analysis of 55,000 individuals from 11 prospective studies detected an increased risk of both fatal and nonfatal CVD events in those with a higher baseline TSH. 2. Which levels should be checked-and when?Before making the diagnosis of subclinical hypothyroidism, Peeters recommends rechecking TSH, as well as free T4, at least once in 2 to 3 months to exclude a transient increase in TSH caused by, for example, medications, such as amiodarone; recovery from thyroiditis; or a non-thyroid condition. Thyroid peroxidase antibodies are linked with an approximately two-fold greater risk of progression to overt hypothyroidism, although testing at regular intervals for these antibodies does not enhance management, as these levels tend to decrease with time. Thyroid ultrasound is not recommended. 3. To whom should we offer treatment?Consider treating patients with a TSH of 10 mIU/L or higher who are age 70 years or younger. Those who are older than 70 years usually are not advised to start treatment. 4. What are the current recommendations for treatment?Levothyroxine, 25 to 75 µg daily, is recommended; however, start lower-25 µg/d-for those who have stable angina or who are at heightened risk for CVD. Remember to recheck thyroid function tests 6 to 8 weeks after either starting medication or titrating the dose. As with just about everything in medicine, there’s a balance to respect. Suppressed TSH can be associated with an elevated risk of osteoporosis, bone fractures, and atrial fibrillation. Stott and colleagues³ from the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) Study Group examined the impact of levothyroxine on 737 patients age 65 years or older who had persistent subclinical hypothyroidism (TSH, 4.60-19.99 mIU/L, and normal free T4) in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Treatment did not improve quality of life, as measured by the Hypothyroid Symptoms Score and Tiredness Score on a quality-of-life questionnaire. Of note, this study was not powered to assess an effect on cardiovascular events or mortality. 5. What are some directions for future research?Debate continues on the reference ranges for thyroid function tests, especially the upper limit for TSH, and on the definition of a cutoff. Some suggest a higher cutoff for starting treatment in older patients. Should reference ranges be adjusted for age? These and other questions await further study.