Subclinical hypothyroidism: When to treat

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Subclinical hypothyroidism: When to treat
Author(s)
Sidra Azim, MD
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 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 HYPOTHYROIDISM 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

Causes of elevated thyroid-stimulating hormone
Other causes include suboptimal treatment of hypothyroidism due to other reasons such as thyroidectomy, radioactive iodine treatment, external radiation, infiltrative diseases (eg, amyloidosis, sarcoidosis, hemochromatosis), and drugs (eg, iodinated contrast, amiodarone, lithium, tyrosine kinase inhibitors) (Table 1).1,2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, 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.

 

 

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.17 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,18 although it has been reported to resolve spontaneously in half of cases within 2 years,19 typically in patients with TSH values of 4 to 6 mIU/L.20 The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.18

Natural course of subclinical hypothyroidism
Figure 1. Natural course of subclinical hypothyroidism (TSH = thyroid-stimulating hormone, T4 = free thyroxine).
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.20,21 In one study, the risk of developing overt hypothyroidism in those with subclinical hypothyroidism increased from 1% to 4% with doubling of the TSH.21 Other risk factors for progression to hypothyroidism include female sex, older age, goiter, neck irradiation or radioactive iodine exposure, and high iodine intake.18,22

Figure 1 shows the natural history of subclinical hypothyroidism.1

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.23

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.24

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.25

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.26

The American Academy of Family Physicians recommends screening after age 60.18

The American College of Physicians recommends screening patients over age 50 who have symptoms.18

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.24

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.13

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.13

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.29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.31 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.

 

 

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

Adverse effects of subclinical hypothyroidism and the role for levothyroxine
Subclinical hypothyroidism has been associated with adverse metabolic, cardiovascular, neuromuscular, and cognitive effects and has been shown to have a detrimental impact on quality of life. However, studies of levothyroxine therapy in subclinical hypothyroidism have yielded mixed results.16 Subclinical hypothyroidism affects many biologic systems, and levothyroxine may have a role (Table 2).32–117

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

Factors favoring levothyroxine therapy in subclinical hypothyroidism
There is some evidence to support levothyroxine treatment in nonpregnant patients with overt hypothyroidism (TSH > 10 mIU/L) or in patients with TSH 5 to 10 mIU/L with symptoms or hyperlipidemia and in younger patients at risk of cardiovascular disease.118 Table 3 describes various patient factors that should be considered during clinical evaluation and decisions about levothyroxine treatment in subclinical hypothyroidism.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
Figure 2. Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
The strongest evidence in favor of treating subclinical hypothyroidism is in patients with TSH levels higher than 10 mIU/L.2 Thyroid dysfunction with this degree of TSH elevation has been associated with adverse cardiometabolic, neuromuscular, cognitive, and psychiatric effects as described above, and has been shown to improve with levothyroxine therapy.

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122

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  71. Christ-Crain M, Meier C, Huber PR, Staub J, Muller B. Effect of L-thyroxine replacement therapy on surrogate markers of skeletal and cardiac function in subclinical hypothyroidism. Endocrinologist 2004; 14(3):161–166. doi:10.1097/01.ten.0000127932.31710.4f
  72. Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 2006; 16(4):375–380. doi:10.1089/thy.2006.16.375
  73. Reuters VS, Teixeira Pde F, Vigario PS, et al. Functional capacity and muscular abnormalities in subclinical hypothyroidism. Am J Med Sci 2009; 338(4):259–263. doi:10.1097/MAJ.0b013e3181af7c7c
  74. Mainenti MR, Vigario PS, Teixeira PF, Maia MD, Oliveira FP, Vaisman M. Effect of levothyroxine replacement on exercise performance in subclinical hypothyroidism. J Endocrinol Invest 2009; 32(5):470–473. doi:10.3275/6106
  75. Lankhaar JA, de Vries WR, Jansen JA, Zelissen PM, Backx FJ. Impact of overt and subclinical hypothyroidism on exercise tolerance: a systematic review. Res Q Exerc Sport 2014; 85(3):365–389. doi:10.1080/02701367.2014.930405
  76. Lee JS, Buzkova P, Fink HA, et al. Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med 2010; 170(21):1876–1883. doi:10.1001/archinternmed.2010.424
  77. Svare A, Nilsen TI, Asvold BO, et al. Does thyroid function influence fracture risk? Prospective data from the HUNT2 study, Norway. Eur J Endocrinol 2013; 169(6):845–852. doi:10.1530/EJE-13-0546
  78. Di Mase R, Cerbone M, Improda N, et al. Bone health in children with long-term idiopathic subclinical hypothyroidism. Ital J Pediatr 2012; 38:56. doi:10.1186/1824-7288-38-56
  79. Boelaert K. The association between serum TSH concentration and thyroid cancer. Endocr Relat Cancer 2009; 16(4):1065–1072. doi:10.1677/ERC-09-0150
  80. Haymart MR, Glinberg SL, Liu J, Sippel RS, Jaume JC, Chen H. Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension. Clin Endocrinol (Oxf) 2009; 71(3):434–439. doi:10.1111/j.1365-2265.2008.03489.x
  81. Fiore E, Vitti P. Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease. J Clin Endocrinol Metab 2012; 97(4):1134–1145. doi:10.1210/jc.2011-2735
  82. Fiore E, Rago T, Provenzale MA, et al. L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27,914 patients. Endocr Relat Cancer 2010; 17(1):231–239. doi:10.1677/ERC-09-0251
  83. Hercbergs AH, Ashur-Fabian O, Garfield D. Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 2010; 17(5):432–436. doi:10.1097/MED.0b013e32833d9710
  84. Thvilum M, Brandt F, Brix TH, Hegedus L. A review of the evidence for and against increased mortality in hypothyroidism. Nat Rev Endocrinol 2012; 8(7):417–424. doi:10.1038/nrendo.2012.29
  85. Stott DJ, Rodondi N, Kearney PM, et al; TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 2017; 376(26):2534–2544. doi:10.1056/NEJMoa1603825
  86. Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril 2015; 104(3):545–753. doi:10.1016/j.fertnstert.2015.05.028
  87. Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21(10):1081–1125. doi:10.1089/thy.2011.0087
  88. Goldsmith RE, Sturgis SH, Lerman J, Stanbury JB. The menstrual pattern in thyroid disease. J Clin Endocrinol Metab. 1952; 12(7):846-855. doi:10.1210/jcem-12-7-846
  89. Plowden TC, Schisterman EF, Sjaarda LA, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab 2016; 101(6):2358–2365. doi:10.1210/jc.2016-1049
  90. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017; 27(3):315–389. doi:10.1089/thy.2016.0457
  91. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006; 91(7):2587–2591. doi:10.1210/jc.2005-1603
  92. Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 2001; 38(pt 4):329–332. doi:10.1258/0004563011900830
  93. Lepoutre T, Debieve F, Gruson D, Daumerie C. Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases. Gynecol Obstet Invest 2012; 74(4):265–273. doi:10.1159/000343759
  94. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97(8):2543–2565. doi:10.1210/jc.2011-2803
  95. Crawford NM, Steiner AZ. Thyroid autoimmunity and reproductive function. Semin Reprod Med 2016; 34(6):343–350. doi:10.1055/s-0036-1593485
  96. 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. doi:10.1089/thy.2015.0418
  97. Wiles KS, Jarvis S, Nelson-Piercy C. Are we overtreating subclinical hypothyroidism in pregnancy? BMJ 2015; 351:h4726. doi:10.1136/bmj.h4726
  98. Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 2012; 119(5):983–988. doi:10.1097/AOG.0b013e318250aeeb
  99. Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014; 3(2):76–94. doi:10.1159/000362597
  100. Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab 2012; 97(12):4464–4472. doi:10.1210/jc.2012-2540
  101. Toulis KA, Stagnaro-Green A, Negro R. Maternal subclinical hypothyroidsm and gestational diabetes mellitus: a meta-analysis. Endocr Pract 2014; 20(7):703–714. doi:10.4158/EP13440.RA
  102. van den Boogaard E, Vissenberg R, Land JA, et al. Significance of subclinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 2011; 17(5):605–619. doi:10.1093/humupd/dmr024
  103. Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol 2012; 119(2 Pt 1):315–320. doi:10.1097/AOG.0b013e318240de6a
  104. Ashoor G, Maiz N, Rotas M, Jawdat F, Nicolaides KH. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death. Thyroid 2010; 20(9):989–993. doi:10.1089/thy.2010.0058
  105. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105(2):239–245. doi:10.1097/01.AOG.0000152345.99421.22
  106. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95(9):E44–E48. doi:10.1210/jc.2010-0340
  107. Su PY, Huang K, Hao JH, et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab 2011; 96(10):3234–3241. doi:10.1210/jc.2011-0274
  108. Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7(3):127–130. doi:10.1136/jms.7.3.127
  109. Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009; 160(6):985–991. doi:10.1530/EJE-08-0953
  110. Korevaar TI, Medici M, de Rijke YB, et al. Ethnic differences in maternal thyroid parameters during pregnancy: the generation R study. J Clin Endocrinol Metab 2013; 98(9):3678–3686. doi:10.1210/jc.2013-2005
  111. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112(1):85–92. doi:10.1097/AOG.0b013e3181788dd7
  112. Li Y, Shan Z, Teng W, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf) 2010; 72(6):825–829. doi:10.1111/j.1365-2265.2009.03743.x
  113. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341(8):549–555. doi:10.1056/NEJM199908193410801
  114. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010; 95(9):4227–4234. doi:10.1210/jc.2010-0415
  115. Behrooz HG, Tohidi M, Mehrabi Y, Behrooz EG, Tehranidoost M, Azizi F. Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid 2011; 21(10):1143–1147. doi:10.1089/thy.2011.0053
  116. Julvez J, Alvarez-Pedrerol M, Rebagliato M, et al. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 2013; 24(1):150–157. doi:10.1097/EDE.0b013e318276ccd3
  117. Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 2017; 376(9):815–825. doi:10.1056/NEJMoa1606205
  118. Burns RB, Bates CK, Hartzband P, Smetana GW. Should we treat for subclinical hypothyroidism?: Grand rounds discussion from Beth Israel Deaconess Medical Center. Ann Intern Med 2016; 164(11):764–770. doi:10.7326/M16-0857
  119. Kucukler FK, Akbaba G, Arduc A, Simsek Y, Guler S. Evaluation of the common mistakes made by patients in the use of levothyroxine. Eur J Intern Med 2014; 25(9):e107–e108. doi:10.1016/j.ejim.2014.09.002
  120. McMillan M, Rotenberg KS, Vora K, et al. Comorbidities, concomitant medications, and diet as factors affecting levothyroxine therapy: results of the CONTROL surveillance project. Drugs R D 2016; 16(1):53–68. doi:10.1007/s40268-015-0116-6
  121. Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: Randomised double blind placebo controlled crossover trial. BMJ 2001; 323(7318):891–895. pmid:11668132
  122. Peeters RP. Subclinical hypothyroidism. N Engl J Med 2017; 376(26):2556–2565. doi:10.1056/NEJMcp1611144
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Sidra Azim, MD
Starling Physicians Endocrinology; Medical Staff, Hartford Hospital, Hartford, CT; Clinical Assistant Professor, Department of Medicine, University of Connecticut School of Medicine, Hartford

Christian Nasr, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Christian Nasr, MD, Department of Endocrinology, Diabetes, and Metabolism, F20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; NASRC@ccf.org

Dr. Nasr has disclosed teaching and speaking for Eisai, Genzyme/Sanofi, and Shire and membership on an advisory committee or review panel for Exelixis, Nevro, and Pfenex.

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subclinical hypothyroidism, thyroid gland, hypothyroid, thyroid-stimulating hormone, TSH, thyrotropin, thyroxine, T4, pituitary, Hashimoto thyroiditis, antiperoxidase antibodies, thyroid antibodies, Christian Nasr, Sidra Azim
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Christian Nasr, MD
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Christian Nasr, MD
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Sidra Azim, MD
Starling Physicians Endocrinology; Medical Staff, Hartford Hospital, Hartford, CT; Clinical Assistant Professor, Department of Medicine, University of Connecticut School of Medicine, Hartford

Christian Nasr, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Christian Nasr, MD, Department of Endocrinology, Diabetes, and Metabolism, F20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; NASRC@ccf.org

Dr. Nasr has disclosed teaching and speaking for Eisai, Genzyme/Sanofi, and Shire and membership on an advisory committee or review panel for Exelixis, Nevro, and Pfenex.

Author and Disclosure Information

Sidra Azim, MD
Starling Physicians Endocrinology; Medical Staff, Hartford Hospital, Hartford, CT; Clinical Assistant Professor, Department of Medicine, University of Connecticut School of Medicine, Hartford

Christian Nasr, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Christian Nasr, MD, Department of Endocrinology, Diabetes, and Metabolism, F20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; NASRC@ccf.org

Dr. Nasr has disclosed teaching and speaking for Eisai, Genzyme/Sanofi, and Shire and membership on an advisory committee or review panel for Exelixis, Nevro, and Pfenex.

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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 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 HYPOTHYROIDISM 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

Causes of elevated thyroid-stimulating hormone
Other causes include suboptimal treatment of hypothyroidism due to other reasons such as thyroidectomy, radioactive iodine treatment, external radiation, infiltrative diseases (eg, amyloidosis, sarcoidosis, hemochromatosis), and drugs (eg, iodinated contrast, amiodarone, lithium, tyrosine kinase inhibitors) (Table 1).1,2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, 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.

 

 

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.17 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,18 although it has been reported to resolve spontaneously in half of cases within 2 years,19 typically in patients with TSH values of 4 to 6 mIU/L.20 The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.18

Natural course of subclinical hypothyroidism
Figure 1. Natural course of subclinical hypothyroidism (TSH = thyroid-stimulating hormone, T4 = free thyroxine).
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.20,21 In one study, the risk of developing overt hypothyroidism in those with subclinical hypothyroidism increased from 1% to 4% with doubling of the TSH.21 Other risk factors for progression to hypothyroidism include female sex, older age, goiter, neck irradiation or radioactive iodine exposure, and high iodine intake.18,22

Figure 1 shows the natural history of subclinical hypothyroidism.1

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.23

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.24

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.25

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.26

The American Academy of Family Physicians recommends screening after age 60.18

The American College of Physicians recommends screening patients over age 50 who have symptoms.18

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.24

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.13

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.13

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.29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.31 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.

 

 

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

Adverse effects of subclinical hypothyroidism and the role for levothyroxine
Subclinical hypothyroidism has been associated with adverse metabolic, cardiovascular, neuromuscular, and cognitive effects and has been shown to have a detrimental impact on quality of life. However, studies of levothyroxine therapy in subclinical hypothyroidism have yielded mixed results.16 Subclinical hypothyroidism affects many biologic systems, and levothyroxine may have a role (Table 2).32–117

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

Factors favoring levothyroxine therapy in subclinical hypothyroidism
There is some evidence to support levothyroxine treatment in nonpregnant patients with overt hypothyroidism (TSH > 10 mIU/L) or in patients with TSH 5 to 10 mIU/L with symptoms or hyperlipidemia and in younger patients at risk of cardiovascular disease.118 Table 3 describes various patient factors that should be considered during clinical evaluation and decisions about levothyroxine treatment in subclinical hypothyroidism.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
Figure 2. Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
The strongest evidence in favor of treating subclinical hypothyroidism is in patients with TSH levels higher than 10 mIU/L.2 Thyroid dysfunction with this degree of TSH elevation has been associated with adverse cardiometabolic, neuromuscular, cognitive, and psychiatric effects as described above, and has been shown to improve with levothyroxine therapy.

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122

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 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 HYPOTHYROIDISM 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

Causes of elevated thyroid-stimulating hormone
Other causes include suboptimal treatment of hypothyroidism due to other reasons such as thyroidectomy, radioactive iodine treatment, external radiation, infiltrative diseases (eg, amyloidosis, sarcoidosis, hemochromatosis), and drugs (eg, iodinated contrast, amiodarone, lithium, tyrosine kinase inhibitors) (Table 1).1,2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, 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.

 

 

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.17 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,18 although it has been reported to resolve spontaneously in half of cases within 2 years,19 typically in patients with TSH values of 4 to 6 mIU/L.20 The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.18

Natural course of subclinical hypothyroidism
Figure 1. Natural course of subclinical hypothyroidism (TSH = thyroid-stimulating hormone, T4 = free thyroxine).
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.20,21 In one study, the risk of developing overt hypothyroidism in those with subclinical hypothyroidism increased from 1% to 4% with doubling of the TSH.21 Other risk factors for progression to hypothyroidism include female sex, older age, goiter, neck irradiation or radioactive iodine exposure, and high iodine intake.18,22

Figure 1 shows the natural history of subclinical hypothyroidism.1

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.23

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.24

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.25

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.26

The American Academy of Family Physicians recommends screening after age 60.18

The American College of Physicians recommends screening patients over age 50 who have symptoms.18

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.24

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.13

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.13

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.29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.31 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.

 

 

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

Adverse effects of subclinical hypothyroidism and the role for levothyroxine
Subclinical hypothyroidism has been associated with adverse metabolic, cardiovascular, neuromuscular, and cognitive effects and has been shown to have a detrimental impact on quality of life. However, studies of levothyroxine therapy in subclinical hypothyroidism have yielded mixed results.16 Subclinical hypothyroidism affects many biologic systems, and levothyroxine may have a role (Table 2).32–117

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

Factors favoring levothyroxine therapy in subclinical hypothyroidism
There is some evidence to support levothyroxine treatment in nonpregnant patients with overt hypothyroidism (TSH > 10 mIU/L) or in patients with TSH 5 to 10 mIU/L with symptoms or hyperlipidemia and in younger patients at risk of cardiovascular disease.118 Table 3 describes various patient factors that should be considered during clinical evaluation and decisions about levothyroxine treatment in subclinical hypothyroidism.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
Figure 2. Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
The strongest evidence in favor of treating subclinical hypothyroidism is in patients with TSH levels higher than 10 mIU/L.2 Thyroid dysfunction with this degree of TSH elevation has been associated with adverse cardiometabolic, neuromuscular, cognitive, and psychiatric effects as described above, and has been shown to improve with levothyroxine therapy.

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122

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Cleveland Clinic Journal of Medicine - 86(2)
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Cleveland Clinic Journal of Medicine - 86(2)
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101-110
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101-110
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Cleveland Clinic Journal of Medicine
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Cleveland Clinic Journal of Medicine
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Subclinical hypothyroidism: When to treat
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Subclinical hypothyroidism: When to treat
Legacy Keywords
subclinical hypothyroidism, thyroid gland, hypothyroid, thyroid-stimulating hormone, TSH, thyrotropin, thyroxine, T4, pituitary, Hashimoto thyroiditis, antiperoxidase antibodies, thyroid antibodies, Christian Nasr, Sidra Azim
Legacy Keywords
subclinical hypothyroidism, thyroid gland, hypothyroid, thyroid-stimulating hormone, TSH, thyrotropin, thyroxine, T4, pituitary, Hashimoto thyroiditis, antiperoxidase antibodies, thyroid antibodies, Christian Nasr, Sidra Azim
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KEY POINTS

  • From 4% to 20% of adults have subclinical hypothyroidism, with a higher prevalence in women, older people, and those with thyroid autoimmunity.
  • Subclinical hypothyroidism can progress to overt hypothyroidism, especially if antithyroid antibodies are present, and has been associated with adverse metabolic, cardiovascular, reproductive, maternal-fetal, neuromuscular, and cognitive abnormalities and lower quality of life.
  • Some studies have suggested that levothyroxine therapy is beneficial, but others have not, possibly owing to variability in study designs, sample sizes, and patient populations.
  • Further trials are needed to clearly demonstrate the clinical impact of subclinical hypothyroidism and the effect of levothyroxine therapy.
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