Subclinical Hypothyroidism: When to Treat

The thyroid gland plays a key role in many of the body’s most important functions by producing a hormone known as thyroxine (T4). The active form of T4 in the blood that is available for use by the body’s tissues is called free T4. Production of T4 by the thyroid is stimulated by another hormone known as thyroidstimulating hormone (TSH), which is produced by the pituitary gland, a pea-sized structure located just below the brain.

Many people receive blood test results indicating that their thyroid gland may be functioning at belownormal levels. This is suspected when the TSH level is higher than normal, which is found in about five percent of Americans.[1] However, the vast majority of individuals with high TSH levels actually have normal free T4 blood levels and therefore have no or only mild symptoms of hypothyroidism. Such individuals have a condition called “subclinical hypothyroidism.”[2]

A lingering question for health care providers is whether to treat patients who have subclinical hypothyroidism with thyroid hormone replacement, such as levothyroxine (SYNTHROID). There has been some evidence that certain individuals with high TSH levels and normal free T4 levels should be treated but that others will not benefit from treatment and may be exposed to unnecessary risks.

Diagnosing subclinical hypothyroidism

The initial test for thyroid dysfunction is a measurement of the blood TSH level. The normal range for blood TSH levels is approximately 0.4 to 4.0 milli-international units/liter (mIU/L).[3] If the TSH level is above or below normal, then the blood free T4 level is measured. Normal levels of free T4 range from approximately 4.5 to 11 micrograms/deciliter (mcg/dL).[4]

Patients are diagnosed with subclinical hypothyroidism when they have a high TSH level and a normal free T4 level. Guidelines released by the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA) in 2012 note that testing for the presence of anti-thyroid antibodies in the blood of patients with subclinical hypothyroidism may aid in predicting the likelihood that a specific patient will eventually progress to full-blown clinical hypothyroidism, which is diagnosed when the TSH level is elevated and the free T4 level is below the normal range.[5]

Is treatment effective?

Subclinical hypothyroidism has been linked to an increased risk of cardiovascular disease,[6] central obesity (excessive fat around the stomach and abdomen),[7] adverse pregnancy outcomes,[8] type 2 diabetes complications,[9] and, in certain patients, cognitive dysfunction.[10] However, the evidence that treating subclinical hypothyroidism improves outcomes associated with these conditions has been inconclusive at best.

A 2007 comprehensive review found that just 12 very small randomized clinical trials (enrolling a total of just 350 subjects between them) had attempted to address whether thyroid replacement therapy offered any benefit to patients with subclinical hypothyroidism.[11] The evidence from these trials seemed to indicate that thyroid hormone replacement did not improve symptoms, mood or quality of life, but the trials may not have been large or long enough to answer the question definitively.

Two well-conducted, large randomized clinical trials published in The New England Journal of Medicine (NEJM) in March and June 2017 shed important light on this issue. For the first trial, researchers randomly assigned 677 pregnant women diagnosed with subclinical hypothyroidism before 20 weeks gestation to receive either levothyroxine or a placebo. There were no significant differences between the two groups in pregnancy or newborn outcomes or in intellectual functioning of those women’s children in their first five years of life.[12]

In the second NEJM trial, researchers randomly assigned 737 older adults (65 and older) with subclinical hypothyroidism to receive either levothyroxine or a placebo for one year.[13] The researchers found no significant differences between the two groups on outcome measures of hypothyroidism symptoms, fatigue and quality of life. They concluded that levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism.

However, there are some important caveats to the conclusions that can be drawn from this second trial. First, the subjects were exclusively older patients, mostly with no or mild symptoms. Thus, this study cannot shed any light on the benefits and risks of thyroid replacement therapy for patients younger than 65 or for those with more marked symptoms of hypothyroidism. Second, the majority of subjects had TSH levels of less than 7 mIU/L.[14] This is important because some evidence indicates that the risks of subclinical hypothyroidism might be limited to patients with higher TSH levels, as noted in the 2012 AACE/ATA guidelines.[15]

The AACE/ATA guidelines divide patients with subclinical hypothyroidism into two groups based on their TSH values. The guidelines recommend that patients with a TSH level greater than 10 mIU/L should be “considered for treatment” with levothyroxine, due to an increased risk of cardiovascular disease. For patients with a TSH level between 4 and 10 mIU/L, the guidelines did not have any firm recommendations and instead advised health care providers to consider treatment only if a patient has hypothyroid symptoms, a positive blood test for anti-thyroid antibodies, or evidence of cardiovascular disease or risk factors for such disease.

Risks of treatment

Levothyroxine’s side effects usually are caused by overtreatment, which results in symptoms of hyperthyroidism (overactive thyroid). Cardiovascular complications[16] (irregular heartbeat, chest pain or even heart attack) are the most serious side effect. Osteoporosis (bone loss) also can occur if high doses are taken for a long time, increasing the risk of fractures. Other side effects include rapid heart rate, palpitations, tremors, anxiety, sweating and weight loss.

What You Can Do

If you are pregnant and are diagnosed with subclinical hypothyroidism, you do not necessarily need to be treated with levothyroxine and should instead be followed throughout your pregnancy to monitor for full-blown hypothyroidism.

If you are not pregnant, are diagnosed with subclinical hypothyroidism and have a TSH level higher than 10 mIU/L, you should be treated with levothyroxine and your doctor should follow up with you regularly to ensure that the treatment is working. If your TSH level is 10 mIU/L or lower, then you generally do not need treatment unless you have other evidence of thyroid disease, such as a positive blood test for anti-thyroid antibodies or a large goiter (enlarged thyroid gland). If treatment is not needed, your health care provider should measure your TSH and free T4 levels periodically as long as your TSH is high and begin treatment with levothyroxine only if your TSH level rises above 10 mIU/L or if your free T4 level falls below the normal range.

If your health care provider determines that you have hypothyroidism and need thyroid hormone replacement therapy, opt for levothyroxine and try to keep using the same drug formulation. Always take levothyroxine at least 30 minutes before meals at the same time every day, preferably before breakfast. Never stop this drug, skip a dose or adjust your dose without medical supervision.

Do not use liothyronine or liothyronine- containing drugs as a maintenance treatment of hypothyroidism, because there is no long-term evidence supporting their efficacy or safety relative to levothyroxine-only treatment. Avoid natural thyroid extracts because they are not regulated, effective or safe, despite the push for their use by some misinformed “natural product” enthusiasts. To learn more about treating hypothyroidism, see our November 2016 Worst Pills, Best Pills News article “Oral Treatments for Hypothyroidism”.[17]

References

[1] Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-499.

[2] Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028.

[3] U.S. National Library of Medicine. MedlinePlus. TSH test. https://medlineplus.gov/ency/article/003684.htm. Accessed September 5, 2017.

[4] U.S. National Library of Medicine. MedlinePlus. Free T4 test. https://medlineplus.gov/ency/article/003517.htm. Accessed September 5, 2017.

[5] Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028.

[6] Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365-1374.

[7] Eftekharzadeh A, Khamseh ME, Farshchi A, Malek M. The association between subclinical hypothyroidism and metabolic syndrome as defined by the ATP III criteria. Metab Syndr Relat Disord. 2016;14(3):137-144.

[8] Maraka S, Ospina NM, O'Keeffe DT, et al. Subclinical hypothyroidism in pregnancy: A systematic review and meta-analysis. Thyroid. 2016;26(4):580-590.

[9] Han C, He X, Xia X, et al. Subclinical hypothyroidism and type 2 diabetes: A systematic review and meta-analysis. PLoS One. 2015;10(8):e0135233.

[10] Pasqualetti G, Pagano G, Rengo G, et al. Subclinical hypothyroidism and cognitive impairment: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(11):4240-4248.

[11] Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;(3):CD003419.

[12] Casey BM, Thom EA, Peaceman AM, et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med. 2017;376(9):815-825.

[13] Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534-2544.

[14] Ibid.

[15] Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028.

[16] Garber JR, Cobin RH, Garib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6): 988-1028.

[17] Oral Treatments for Hypothyroidism. Worst Pills, Best Pills News. November 2016. /newsletters/view/1067. Accessed September 7, 2017.