Identifying Subclinical Hypothyroidism

By Sidra Azim, MD and Christian Nasr, MD

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

High TSH, normal free T4 levels

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T4).1 The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T4 and triiodothyronine (T3) levels go down even a little, TSH levels go up a lot.2

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.3

What is the upper limit of normal for TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.3

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.4 Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.5

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 million to 28 million people in the United States.4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.7 The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.3 Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,9 although higher TSH cutoffs for treatment are advised in elderly patients.10 Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.11

Authors of the NHANES III8 and Hanford Thyroid Disease study12 have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

Subclinical hypothroidism is common

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.1,8,13 The prevalence is higher in women and increases with age.8 It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.14

Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.8 A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly and pregnant women.10,15

A variety of causes

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,2 in which thyroid peroxidase antibodies are usually present.2,16

Other causes include suboptimal treatment of hypothyroidism due to other reasons, such as thyroidectomy, radioactive iodine treatment, external radiation, infiltrative diseases (e.g., amyloidosis, sarcoidosis, hemochromatosis) and drugs (e.g., iodinated contrast, amiodarone, lithium, tyrosine kinase inhibitors).1,2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (e.g., heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

References

1. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;379(9821):1142–1154. doi:10.1016/S0140-6736(11)60276-6
2. Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84(1):65–71. doi:10.4065/84.1.65
3. Laurberg P, Andersen S, Carle A, Karmisholt J, Knudsen N, Pedersen IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol. 2011;7(4):232–239. doi:10.1038/nrendo.2011.13
4. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005;90(9):5483–5488. doi:10.1210/jc.2005-0455
5. Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National Health and Nutrition Examination Survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol Metab. 2007;92(11):4236–4240. doi:10.1210/jc.2007-0287
6. Fatourechi V, Klee GG, Grebe SK, et al. Effects of reducing the upper limit of normal TSH values. JAMA. 2003;290(24):3195–3196. doi:10.1001/jama.290.24.3195-b
7. Surks MI, Hollowell JG. Age-specifi c distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92(12):4575–4582. doi:10.1210/jc.2007-1499
8. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4,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. doi:10.1210/jcem.87.2.8182
9. Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24(12):1670–1751. doi:10.1089/thy.2014.0028
10. Hennessey JV, Espaillat R. Diagnosis and management of subclinical hypothyroidism in elderly adults: a review of the literature. J Am Geriatr Soc. 2015;63(8):1663–1673. doi:10.1111/jgs.13532
11. Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a meta-analysis. J Clin Endocrinol Metab. 2008;93(8):2998–3007. doi:10.1210/jc.2008-0167
12. Hamilton TE, Davis S, Onstad L, Kopecky KJ. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab. 2008; 93(4):1224–1230. doi:10.1210/jc.2006-2300
13. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160(4):526–534. pmid:10695693
14. Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med. 2006;354(26):2783–2793. doi:10.1056/NEJMoa054022
15. Negro R, Stagnaro-Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ. 2014; 349:g4929. doi:10.1136/bmj.g4929
16. Baumgartner C, Blum MR, Rodondi N. Subclinical hypothyroidism: summary of evidence in 2014. Swiss Med Wkly. 2014; 144:w14058. doi:10.4414/smw.2014.14058

Note: This article originally appeared in the Cleveland Clinic Journal of Medicine.