Subclinical Hypothyroidism: The When and Why of Starting Treatment

Subclinical Hypothyroidism: The When and Why of Starting Treatment
Kristin Howlett, Pharm.D., Park Nicollet Health Services

Background: Subclinical hypothyroidism is defined as an elevated thyroid stimulating hormone (TSH) with free thyroxine (T4) in the normal range, whereas overt hypothyroidism is defined as higher than normal TSH with lower than normal free T4. It has been estimated that 3-15% of the population has subclinical hypothyroidism by this definition. Higher rates of subclinical hypothyroidism are seen in females, elderly, and those with low iodine intake.

Current American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) guidelines recommend initiating treatment in patients ≤ 70 years old with subclinical hypothyroidism if TSH > 10 mU/L. For patients with subclinical hypothyroidism with TSH < 10 mU/L or those who are over 70 years old, guidelines suggest treatment decisions should be based on the individual factors of symptoms, cardiac risk factors and autoimmune involvement. Patients who are pregnant have alternative guidelines and are not included in this discussion.

Evidence: Studies have shown increased rates of depression, fatigue, weight gain, cold intolerance, constipation and reduced cognitive function, memory and quality of life in those with subclinical hypothyroidism as compared to age-matched controls. Interestingly, elderly patients (over 70 years of age), have reported fewer symptoms than younger patients which may be why they are often not treated for subclinical hypothyroidism based on lab results.

There have been few randomized controlled trials evaluating long-term treatment of subclinical hypothyroidism; however, the studies that exist point to increased symptoms and cardiovascular events in those with untreated subclinical hypothyroidism if the TSH >10 mU/L. In comparison, studies of elderly patients and those with only mildly elevated TSH have shown little benefit of treatment.

In regards to cardiovascular risk, a large meta-analysis of 11 prospective cohorts with over 55,000 subjects found patients with TSH levels of 10.0-19.9 mU/L had increased risk of fatal and nonfatal coronary heart disease events than patients within a normal TSH range, HR 1.89 [95% CI 1.28 - 2.80].  In contrast, no statistical difference was found among participants with TSH ranging from 7.0-9.9 mU/L or 4.5-6.9 mU/L. Other previous meta-analyses have associated increased risk of cardiovascular risk in those with TSH > 7.0 mU/L; however, benefit of treatment in this group is less clear and generally not recommended.

Discussion: Observational studies have shown lower risk of heart failure events, death from any cause and ischemic heart disease events among patients 70 years of age or younger with subclinical hypothyroidism and TSH > 10 mu/L when treated with levothyroxine.  Since there is some evidence for increased cardiovascular risk at TSH > 7.0 mU/L, treatment may be considered if symptoms are present, although evidence is not as strong. There appears to be little benefit to treating those over 70 years old or those with mild elevations in TSH and normal free T4.

Clinical Impact:

Initial considerations when subclinical hypothyroidism is suspected:

  • It is recommended to repeat TSH and T4 two to three months later to rule out a transient TSH increase prior to diagnosis. TSH levels may normalize within two years in up to 46% of patients with subclinical hypothyroidism and TSH < 7 mU/L.

  • A one-time lab value of thyroid peroxidase antibodies can be used to determine the presence of an autoimmune cause which correlates to twice the risk of progression to overt hypothyroidism.

  • Consider other factors that may increase TSH such as an acute illness or medications like amiodarone or lithium.

Treatment considerations after diagnosis of subclinical hypothyroidism (with repeated TSH/T4 levels):

 

TSH < 10 mU/L

TSH > 10 mU/L

Age ≤ 70 yr

Recheck TSH in 6 months or consider a 6 month trial treatment if symptoms are present

Treatment recommended

Age > 70 yr

Treatment not recommended

Treatment generally not recommended, could consider 6 month trial if symptoms are present

The goal of therapy for patients receiving treatment for subclinical hypothyroidism is to achieve TSH within normal limits to lower cardiovascular risk factors and improve patient symptoms. Use caution to prevent over-suppressing TSH which can result in increased risk of atrial fibrillation, osteoporosis and fractures.

References:

  1. Peeters RP. Subclinical hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2556-2565.

  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 Nov-Dec;18(6):988-1028.

  3. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017; 376:2534-44.

  4. Rodondi N, den Elzen WP, Bauer DC, et al. JAMA. 2010 Sep 22;304(12):1365-74.

  5. Chaker L, Baumgartner C, den Elzen WP, et al. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis. J Clin Endocrinol Metab. 2015 Jun;100(6):2181-91.