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
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Subclinical hypothyroidism is defined by an elevated se- rum thyroid-stimulating hormone (TSH) level along with a normal free thyroxine (T4) level. Whether it should be treated remains controversial. Currently, the best practical approach is to base treatment decisions on the degree
of TSH elevation, thyroid autoimmunity, and associated comorbidities.
From 4% to 20% of adults have subclinical hypothyroid- ism, with a higher prevalence in women, older people, and those with thyroid autoimmunity.
Subclinical hypothyroidism can progress to overt hypo- thyroidism, especially if antithyroid antibodies are pres- ent, and has been associated with adverse metabolic, cardiovascular, reproductive, maternal-fetal, neuromuscu- lar, and cognitive abnormalities and lower quality of life.
Some studies have suggested that levothyroxine therapy is beneficial, but others have not, possibly owing to vari- ability in study designs, sample sizes, and patient popula- tions.
Further trials are needed to clearly demonstrate the clini- cal impact of subclinical hypothyroidism and the effect of levothyroxine therapy.
Dr. Nasr has disclosed teaching and speaking for Eisai, Genzyme/Sanofi, and Shire and member- ship on an advisory committee or review panel for Exelixis, Nevro, and Pfenex.
Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their ndings, and although most have found this condition to be associated with a variety of adverse outcomes, large ran- domized controlled trials are needed to clear- ly demonstrate its clinical impact in various age groups and the bene t 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 con- ditions.
■ HIGH TSH, NORMAL FREE T4 LEVELS
Subclinical hypothyroidism is de ned by ele- vated 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 cir- cadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated mea- surements 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, de ned as the 97.5th percentile, is approximately 4 or 5
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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 2 FEBRUARY 2019 101
Causes of elevated thyroid-stimulating hormone
Autoimmune (Hashimoto) thyroiditis
Suboptimal treatment of overt hypothyroidism
Radioactive iodine ablation
External beam radiation of head and neck
Infiltrative diseases of the thyroid (amyloidosis, sarcoidosis, hemochro- matosis, Riedel thyroiditis, scleroderma)
Drugs, eg, iodine contrast, amiodarone, lithium, tyrosine kinase inhibitors (sunitinib, sorafenib), interferon alpha, or immune response modulators (ipilimumab, alemtuzumab, pembrolizumab)
Iodine deficiency Excess iodine Thyroid dysgenesis
Recovery phase of euthyroid sick syndrome
Recovery phase of subacute, painless, or postpartum thyroiditis
Substances that interfere with TSH assays (heterophile antibodies, rheumatoid factor, biotin, macro-TSH or abnormal TSH isoforms)
Central hypothyroidism or hyperthyroidism Thyroid hormone resistance
Impaired renal function
Obesity Older age
Based on information in references 1, 2, and 16.
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 distri- bution of serum TSH levels in the healthy general population does not seem to be a typi- cal 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 anti- thyroid 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 diagno- sis 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 overtreat- ment.
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 octoge- narians.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 Interest- ingly, higher TSH in older people has been linked to lower mortality rates in some stud- ies.11
Authors of the NHANES III8 and Han- ford Thyroid Disease study12 have proposed a cutoff of 4.1 mIU/L for the upper limit of nor- mal for serum TSH in patients with negative antithyroid antibodies and normal ndings on thyroid ultrasonography.
■ SUBCLINICAL HYPOTHYROIDISM IS COMMON
In different studies, the prevalence of subclini- cal 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-suf cient areas, and it increases in iodine-de cient areas with iodine supplemen- tation.14 Genetics also plays a role, as subclini-
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AZIM AND NASR
cal hypothyroidism is more common in white people than in African Americans.8
A dif culty 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 ado- lescents, the elderly, and pregnant women.10,15
■ A VARIETY OF CAUSES
The most common cause of subclinical hy- pothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroid- itis,2 in which thyroid peroxidase antibodies are usually present.2,16
Other causes include suboptimal treat- ment of hypothyroidism due to other reasons such as thyroidectomy, radioactive iodine treatment, external radiation, in ltrative dis- eases (eg, amyloidosis, sarcoidosis, hemochro- matosis), and drugs (eg, iodinated contrast, amiodarone, lithium, tyrosine kinase inhibi- tors) (Table 1).1,2,16
Also important to rule out are false-posi- tive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); re- versible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resis- tance.
■ 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 hypo- thyroidism,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 35% over 10 to 20 years of follow-up.18
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 an- tibody.20,21 In one study, the risk of developing overt hypothyroidism in those with subclini-
Reverts to euthyroid state in up to 60% of cases over 5 years, depend- ing on serum TSH concentration and antithyroid antibody status.
Progresses to overt hypothyroid- ism in 1%–5% of cases per year, depending on serum TSH concentra- tion and antithyroid antibody status.
Reprinted from The Lancet; volume 379, Cooper DS, Biondi B. Subclinical thyroid disease, pages 1142–1154, copyright 2012, with permission from Elsevier.
Figure 1. Natural course of subclinical hypothyroidism (TSH = thyroid-stimulating hormone, T4 = free thyroxine).
cal hypothyroidism increased from 1% to 4% with doubling of the TSH.21 Other risk factors for progression to hypothyroidism include fe- male sex, older age, goiter, neck irradiation or radioactive iodine exposure, and high iodine intake.18,22
Figure 1 shows the natural history of sub- clinical hypothyroidism.1
■ GUIDELINES FOR SCREENING DIFFER
Guidelines differ on screening for thyroid dis- ease in the general population, owing to lack of large-scale randomized controlled trials show- ing treatment bene t in otherwise-healthy people with mildly elevated TSH values.
Various professional societies have adopted different criteria for aggressive case- nding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipid- emia, atrial brillation, unexplained weight loss, hyperprolactinemia, autoimmune disor- ders, and use of medications affecting thyroid function.23
The US Preventive Services Task Force
The upper limit of normal
for serum TSH is controversial
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Adverse effects of subclinical hypothyroidism and the role for levothyroxine
Adverse effect Evidence of adverse effect Role for treatment with levothyroxine
Metabolic syndrome, Associations observed, but cause and effect No evidence to support obesity, diabetes are unclear23,24
Dyslipidemia Relationships observed between thyroid-stim- Associated with improved lipid profiles2,34,44–46 ulating hormone (TSH) elevation and altered
Cardiovascular endothelial Increased risk of myocardial infarction, athero- Lessens cardiovascular risk and mortality in dysfunction sclerosis, aortic calcification,48 cardiovascular patients < 65 years
disease and mortality37; increased arterial stiff- ness and systemic vascular resistance45,53
Stroke Conflicting data: no association in patients Lessens cardiovascular risk and mortality in ≥ 65 years, but some association in those < 65 patients < 65 years
Psychiatric and cognitive Associated with worsened preexisting depres- May improve mood, anxiety, cognition in older dysfunction sion and bipolar disease; may affect cogni- patients35
Neuromuscular dysfunc- Associated with skeletal muscle dysfunction, Limited data on treatment; role is unclear75 tion, exercise intolerance exercise intolerance71
Bone health Associated with increased risk of hip fracture Too few clinical studies to define a role attributed to suppression of bone turnover by
Thyroid cancer Some data suggest elevated TSH is associated More studies needed to understand associa- with higher risk79–82 tion
Inconclusive evidence links subclinical hypothyroidism with infertility86; infertility rate is higher in women who also have positive thyroid peroxidase antibody than in women without autoimmunity87
Some studies have shown lower rates of miscarriage with levothyroxine when TSH
> 4.0 mIU/L86,91–92; insufficient data to support its use in patients with subclinical hypothyroid- ism and infertility; however, consider in euthy- roid patients with positive peroxidase antibody and recurrent miscarriage90
Pregnancy complications Associated with several pregnancy-related No recommendations; insufficient evidence to complications including preeclampsia, hyper- evaluate role of treatment
tension, placental abruption, and postpartum hemorrhage in some studies,26,96 but not in others; if present, screen for autoimmunity
Preterm delivery, pregnancy loss
Associated with high risk of miscarriage, preterm delivery, pregnancy loss at even mildly elevated TSH levels (2.5–5 mIU/L)99;104–107; risk is as high as 60% with TSH levels > 6 mIU/L
and higher with positive thyroid peroxidase antibody108–110
Improves maternal and fetal outcomes, includ- ing risk of low birth weight and low Apgar score, in women with subclinical hypothyroid- ism and TSH 2.5–10 mIU/L93,106; evidence less clear with TSH 2.5–4 mIU/L86; not recommended for the subgroup of pregnant patients with negative thyroid peroxidase antibody and TSH within pregnancy-specific range or < 4 mIU/L
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in 2014 found insuf cient evidence on the bene ts 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 dis- eases, neck irradiation, or medications affect- ing thyroid function.26
The American Academy of Family Phy- sicians recommends screening after age 60.18
The American College of Physicians rec- ommends screening patients over age 50 who have symptoms.18
Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case- nding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with sub- clinical hypothyroidism.24
■ CLINICAL PRESENTATION
About 70% of patients with subclinical hypo- thyroidism have no symptoms.13
Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid con- trols in 1 study, but other studies have been unable to replicate this nding.27,28
Other frequently reported symptoms in- clude dry skin, cognitive slowing, poor memo- ry, muscle weakness, cold intolerance, consti- pation, 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 bene t.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 explana- tion 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 dif cult to ascertain symp- tomatic 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 un- treated subclinical hypothyroidism may lead to increased morbidity and mortality.
■ ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY
Subclinical hypothyroidism has been associat- ed with adverse metabolic, cardiovascular, neu- romuscular, and cognitive effects and has been shown to have a detrimental impact on quality of life. However, studies of levothyroxine ther- apy in subclinical hypothyroidism have yielded mixed results.16 Subclinical hypothyroidism af- fects many biologic systems, and levothyroxine may have a role (Table 2).32–117
■ INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING
The management of subclinical hypothyroid- ism should be individualized on the basis of
The most common cause of subclinical hypothyroidism is Hashimoto (autoimmune) thyroiditis
AZIM AND NASR
Factors favoring levothyroxine therapy in subclinical hypothyroidism
Thyroid-stimulating hormone (TSH) level > 2 times the upper limit of normal or > 8 mIU/L
Progressive rise in TSH
Positive antithyroid antibodies Pregnancy or planning pregnancy Infertility or ovulatory dysfunction Childhood or adolescence Dyslipidemia
Established cardiovascular disease or risk factors for cardiovascular disease
Depression or bipolar disease
Therapeutic trial for clinical symptoms of hypothyroidism Patient preference
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Elevated thyroid-stimulating hormone (TSH) and normal free thyroxine (T4)
Recheck TSH and free T4 in 8–12 weeks and check thyroid peroxidase antibodies (TPO Ab)
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TPO Ab- negative
if symptomatic or as needed
TSH remains elevated
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TPO Ab- positive
Check thyroid function annually
TSH < 10 mIU/L and normal free T4
Symptoms of hypothyroidism absent
Symptoms of hypothyroidism present
Consider 6-month trial of treatment with goal TSH < 2.5 mIU/L
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TSH ≥ 10 mIU/L and normal free T4
Symptoms do not improve
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TSH > 4.5 to < 7 mIU/L
No treatment recommended, but can consider 6-month trial of treatment after shared decision- making
TSH ≥ 7 to < 10 mIU/L
Consider 6-month trial of treatment if age < 70 or cardiac risk factors or TPO Ab-positive
Age < 70
Recommend treatment, especially if cardiac risk factors or TPO Ab-positive
Age ≥ 70
Consider 6-month treatment trial, especially if low- normal T4 or TPO Ab-positive
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Based on information in reference 122.
Figure 2. Treatment algorithm for subclinical hypothyroidism in nonpregnant patients.
extent of thyroid dysfunction, comorbid con- ditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and bene ts of levothyroxine treatment and the patient’s goals.
There is some evidence to support levo- thyroxine 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 evalua- tion and decisions about levothyroxine treat-
ment in subclinical hypothyroidism.
The risks of treatment should be kept in mind and explained to the patient. Levothy- roxine has a narrow therapeutic range, caus- ing 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 be- cause foods and supplements interfere with its absorption.118,120 In addition, the cost of medi- cation, frequent biochemical monitoring, and possible need for titration can add to nancial burden.
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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 11.
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.
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
Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on the relationship between subclinical hypothy- roidism and ischemic heart disease: a metaanalysis. J Clin Endocrinol
AZIM AND NASR
When choosing the dose, one should con- sider 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 signi cant consequences. For these reasons, levothyroxine therapy is not thought to be bene cial 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 pa- tients with negative thyroid peroxidase anti- body and TSH within the pregnancy-speci c range or less than 4 mIU/L if the reference ranges are unavailable.
Keep in mind that, even at these TSH val- ues, there is risk of progression to overt hypo- thyroidism, especially in the presence of thy-
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 Endo- crinol 2011; 7(4):232–239. doi:10.1038/nrendo.2011.13
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roid peroxidase antibody, so patients in this group should be monitored closely.
If TSH is mildly elevated
The evidence to support levothyroxine thera- py 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 bene t of treating sub- clinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychi- atric outcomes have included patients with a wide range of TSH levels, and some of these studies were not strati ed on the basis of de- gree of TSH elevation.
The risk that subclinical hypothyroidism will progress to overt hypothyroidism in pa- tients 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
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 cardiometa- bolic, neuromuscular, cognitive, and psychi- atric 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 ■
7. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotro-
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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
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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
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ADDRESS: Christian Nasr, MD, Department of Endocrinology, Diabetes, and Metabolism, F20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; NASRC@ccf.org
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