Aggressive Screening and Treatment for Subclinical Hypothyroidism: Benefits vs Risks

By Sidra Azim, MD and Christian Nasr, MD

Subclinical hypothyroidism can resolve or progress

“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.1 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,2 although it has been reported to resolve spontaneously in half of cases within two years,3 typically in patients with TSH values of 4 to 6 mIU/L.4 The rate of progression to overt hypothyroidism is estimated to be 33% to 35% over 10 to 20 years of follow-up.4

The risk of progression to clinical disease is higher in patients with thyroid peroxidase antibody, reported as 4.3% per year compared with 2.6% per year in those without this antibody.4,5 In one study, the risk of developing overt hypothyroidism in those with subclinical hypothyroidism increased from 1% to 4% with doubling of the TSH.5 Other risk factors for progression to hypothyroidism include female sex, older age, goiter, neck irradiation or radioactive iodine exposure, and high iodine intake.2,6 Figure 1 shows the natural history of subclinical hypothyroidism.7

Guidelines for screening differ

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values. Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.8

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.9

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every five years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.10

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.11

The American Academy of Family Physicians recommends screening after age 60.2

The American College of Physicians recommends screening patients over age 50 who have symptoms.2

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.9

Clinical presentation

About 70% of patients with subclinical hypothyroidism have no symptoms.12 Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in one study, but other studies have been unable to replicate this finding.13,14

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.12

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.15-17

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.17 An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

References

1. Stedman TL. Stedman’s Medical Dictionary. 28th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2006.
2. Raza SA, Mahmood N. Subclinical hypothyroidism: controversies to consensus. Indian J Endocrinol Metab. 2013;17(suppl 3):S636–S642. doi:10.4103/2230-8210.123555
3. Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87(7):3221–3226. doi:10.1210/jcem.87.7.8678
4. Diez JJ, Iglesias P, Burman KD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 2005;90(7):4124–4127. doi:10.1210/jc.2005-0375
5. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol (Oxf). 1995;43(1):55–68. pmid:7641412
6. Li Y, Teng D, Shan Z, et al. Antithyroperoxidase and antithyroglobulin antibodies in a five-year follow-up survey of populations with different iodine intakes. J Clin Endocrinol Metab. 2008;93(5):1751–1757. doi:10.1210/jc.2007-2368
7. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;379(9821):1142–1154. doi:10.1016/S0140-6736(11)60276-6
8. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160(4):526–534. pmid:10695693
9. Hennessey JV, Klein I, Woeber KA, Cobin R, Garber JR. Aggressive case finding: a clinical strategy for the documentation of thyroid dysfunction. Ann Intern Med. 2015; 163(4):311–312. doi:10.7326/M15-0762
10. Rugge JB, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162(1):35–45. doi:10.7326/M14-1456
11. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med. 2000;160(11):1573–1575. pmid:10847249
12. Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. 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. doi:10.4158/EP12280.GL
13. Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. 2006;91(1):145–153. doi:10.1210/jc.2005-1775
14. Joffe RT, Pearce EN, Hennessey JV, Ryan JJ, Stern RA. Subclinical hypothyroidism, mood, and cognition in older adults: a review. Int J Geriatr Psychiatry. 2013; 28(2):111–118. doi:10.1002/gps.3796
15. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo controlled trial. Ann Intern Med. 1984; 101(1):18–24. pmid:6428290
16. Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg PA, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with ‘subclinical’ hypothyroidism. Clin Endocrinol (Oxf). 1988;29(1):63–75. pmid:3073880
17. Monzani F, Del Guerra P, Caraccio N, et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig. 1993;71(5):367–371. pmid:8508006

This article was originally published in the Cleveland Clinic Journal of Medicine.