Subclinical hyperthyroidism

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2016. | This topic last updated: Dec 30, 2014.

INTRODUCTION — The availability of sensitive assays for thyroid-stimulating hormone (TSH) resulted in the identification of patients who have low serum TSH concentrations (<0.5 mU/L) but normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations, a constellation of biochemical findings defined as subclinical hyperthyroidism. The term overt hyperthyroidism refers to patients with elevated levels of free T4, T3, or both, and a subnormal TSH concentration. Both subclinical and overt hyperthyroidism are biochemical definitions, since hyperthyroid symptoms are non-specific and may be present in patients with subclinical disease and absent in those with overt disease, especially older adults.

Subclinical hyperthyroidism will be discussed here. Overt hyperthyroidism is discussed separately. (See "Diagnosis of hyperthyroidism" and "Overview of the clinical manifestations of hyperthyroidism in adults".)

CAUSES — The causes of subclinical hyperthyroidism are the same as the causes of overt hyperthyroidism and, like overt hyperthyroidism, subclinical hyperthyroidism can be persistent or transient (table 1). (See "Disorders that cause hyperthyroidism".)

Exogenous subclinical hyperthyroidism — As many as 10 million people in the United States, and possibly as many as 200 million people worldwide, are taking thyroid hormone. All are at risk for subclinical hyperthyroidism, whether intentional or unintentional. Among patients taking thyroxine (T4), as many as 25 percent have low serum thyroid-stimulating hormone (TSH) values [1,2], and in one study, 5.8 percent were under 0.1 mU/L [3]. (See "Exogenous hyperthyroidism".)

Many of these patients have hypothyroidism, and in them subclinical hyperthyroidism is not the goal of thyroid hormone therapy. However, subclinical hyperthyroidism is the goal of thyroid hormone therapy in patients with thyroid cancer and in some patients with solitary thyroid nodules, multinodular or diffuse goiters, or a history of head and neck irradiation. In these patients, the benefits of TSH suppression are thought to outweigh the risks of subclinical hyperthyroidism. (See "Differentiated thyroid cancer: Overview of management", section on 'Thyroid hormone suppression' and "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter".)

Endogenous subclinical hyperthyroidism — Autonomously functioning thyroid adenomas and multinodular goiters are the most common causes of endogenous subclinical hyperthyroidism. Among patients over age 55 years, hyperthyroidism due to multinodular goiters was subclinical in 57 percent of patients, while hyperthyroidism due to Graves' disease was subclinical in only 6 percent of patients [4]. In another study, 22 percent of patients with multinodular goiter had subclinical hyperthyroidism, while 28 percent of those with subclinical hyperthyroidism had autonomous area(s) on thyroid imaging [5].

Subclinical hyperthyroidism also occurs in patients with thyroiditis [6], and it has been reported in 63 percent of euthyroid patients with Graves' ophthalmopathy (euthyroid Graves' disease) [7] and 4 percent of those with Graves' disease in remission [8]. It may also be seen in patients with early Graves' disease prior to the onset of more overt hyperthyroidism. In addition, pregnant women (especially in the first trimester) and those with hyperemesis gravidarum (or trophoblastic disease), who have high serum chorionic gonadotropin concentrations, may have subclinical hyperthyroidism. (See 'Pregnancy' below.)

EPIDEMIOLOGY AND NATURAL HISTORY — Several large studies have examined the prevalence of subclinical hyperthyroidism [9-15]. The results of these studies, primarily in subjects over age 55 to 60 years, can be summarized as follows:

●The prevalence of subclinical hyperthyroidism in the community varies between 0.7 and 12.4 percent. This variability is in part due to differences in the definition of low serum thyroid-stimulating hormone (TSH) values and in the patient populations studied. In the United States, the National Health and Nutrition Examination Survey (NHANES III), which excluded subjects with known thyroid disease, 0.7 percent of 16,533 people had subclinical hyperthyroidism (TSH <0.1 mU/L) [16].

 

●Subclinical hyperthyroidism is more common in areas of the world with mild to moderate iodine deficiency. In addition, subclinical thyroid dysfunction is more common in females, smokers, and older adults [16,17].

 

●When studied weeks to a year later, 40 to 60 percent of subjects with subclinical hyperthyroidism have normal values [10,12]. This is most likely to occur in subjects with only slightly subnormal serum TSH values (eg, between 0.1 and 0.5 mU/L) when first studied. In an analysis of a primary care network that included 422,242 persons without known thyroid disease, 52 percent who had a serum TSH concentration <0.35 mU/L at baseline had a normal TSH subsequently in the absence of treatment [18].

 

There are conflicting data regarding the frequency of progression from subclinical to overt hyperthyroidism [9,12,19-22]. Progression to overt hyperthyroidism appears to be related to the degree of subclinical hyperthyroidism and the underlying disease. As examples:

●In a population-based study from Scotland, 2024 adults with at least two suppressed (<0.4 mU/L) serum TSH levels measured four months apart with normal free or total thyroxine (T4) and total triiodothyronine (T3) were identified [22]. In the first year of observation, the overall progression rate from subclinical to overt hyperthyroidism was 6.1 percent. For patients with stable subclinical hyperthyroidism who did not progress after one year, progression rates at two, five, and seven years were 0.6, 0.7, and 0.5 percent, respectively. Although the proportion of patients who progressed to overt hyperthyroidism was small, progression was approximately twice as common in patients with serum TSH <0.1 mU/L compared with those with TSH between 0.1 and 0.4 mU/L.

 

●In a New Zealand study of 96 patients with endogenous subclinical thyrotoxicosis (TSH <0.25 mU/L), progression to overt hyperthyroidism occurred in 8 percent at one year, and increased to 26 percent at five years. At five years, overt hyperthyroidism was seen in 9, 21, and 61 percent of patients whose subclinical hyperthyroidism was due to Graves’ disease, nodular goiter, and autonomous nodules, respectively [19].

 

●In a Brazilian study of 48 women <65 years who had TSH ≤0.1 mU/L (confirmed by repeat measurement six to eight weeks later), 20 percent with nodular disease and 40 percent with Graves’ disease progressed from subclinical to overt hyperthyroidism over a two-year period [20]. In a separate study of women ≥60 years with only minimal thyrotoxicosis (TSH 0.1 to 0.4 mU/L), progression to overt hyperthyroidism was uncommon (approximately 1 percent yearly) [21].

 

●In a study from the United Kingdom, 20.3 percent of patients with subclinical hyperthyroidism and TSH <0.1 mU/L progressed to overt hyperthyroidism over an average of 32 months, compared with 6.8 percent of those with TSH 0.1 to 0.39 mU/L [23].

 

●In the Framingham study of adults >60 years with a TSH <0.1 mU/L, only 4.3 percent of patients progressed to overt hyperthyroidism after four years [9].

 

CLINICAL FINDINGS — The skeleton and the cardiovascular system are the major target tissues adversely affected by subclinical hyperthyroidism, although abnormalities in other systems have been reported (table 2).

Bone and mineral metabolism — Thyroid hormone directly stimulates bone resorption, and overt hyperthyroidism is associated with increased bone resorption (and to a lesser extent low bone formation), low bone density, and an increase in fracture [24]. The changes are greatest in cortical bone (wrist), least in trabecular bone (lumbar spine), and intermediate in mixed cortical-trabecular bone (hip).

In some, but not all, studies, subclinical hyperthyroidism is associated with low bone density in postmenopausal women. Whether subclinical hyperthyroidism increases fracture rate is debated, but there is no reason to doubt that similar durations of subclinical hyperthyroidism would have similar effects on the skeleton, but to a less severe degree. Any adverse effect of thyroxine (T4) on bone density is likely dose-dependent. This topic is reviewed separately. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)

Cardiovascular effects — Overt hyperthyroidism is associated with an increased risk of atrial fibrillation, heart failure, pulmonary hypertension, and angina (see "Cardiovascular effects of hyperthyroidism"). Patients with subclinical hyperthyroidism also have an increased risk of atrial fibrillation and, in addition, have more subtle cardiac findings, including increases in heart rate, cardiac contractility, and left ventricular mass [25,26].

Atrial fibrillation — In a meta-analysis of patient level data from five prospective cohort studies (8711 participants, 810 with endogenous subclinical hyperthyroidism), subclinical hyperthyroidism was associated with an increased risk of atrial fibrillation (hazard ratio [HR] 1.68, 95% CI 1.16-2.43) [27]. The risk was higher for thyroid-stimulating hormone (TSH) levels <0.1 mU/L compared with 0.1 to 0.44 mU/L (HRs 2.54 versus 1.63).

The cumulative incidence of atrial fibrillation in patients with subclinical hyperthyroidism is illustrated by the findings of a prospective cohort study of approximately 2000 adults over age 60 years (without atrial fibrillation) followed for 10 years [15]. For subjects with serum TSH values <0.1 mU/L, 0.1 to 0.4 mU/L, or within the normal range, the cumulative incidence of atrial fibrillation was 28, 16, and 11 percent, respectively (figure 1) [15].

In biochemically euthyroid individuals, both serum TSH and free T4 concentrations may also be associated with atrial fibrillation risk. In a population-based study of 1426 subjects, euthyroid individuals with a TSH in the lowest quartile had a higher risk of atrial fibrillation than those in the highest quartile [28]. Similar findings were noted in another population-based study of 5519 euthyroid (normal serum TSH and free T4) older subjects [29]. Higher serum free T4 concentrations (within the normal range) were independently associated with atrial fibrillation [29].

Guidelines for the management of atrial fibrillation in patients with hyperthyroidism are discussed separately. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Hyperthyroidism'.)

Coronary heart disease events, heart failure, and other cardiac parameters — In the meta-analysis described above (22,437 participants, 718 with endogenous subclinical hyperthyroidism), the risk of coronary heart disease events was higher in patients with endogenous subclinical hyperthyroidism (HR 1.21, 95% CI 0.99-1.46) [27]. Similar findings were reported in a population based study from Scotland, which was not included in the meta-analysis [30]. Endogenous subclinical hyperthyroidism was associated with an increased risk of nonfatal cardiovascular disease (HR 1.39, 95% CI 1.22-1.58) [30]. 

 

• Subclinical hyperthyroidism is also associated with an increased risk of heart failure [31-33]. In a cohort of men and women aged 70 to 82 years with a history of vascular disease (5316 participants, 71 with subclinical hyperthyroidism, five taking levothyroxine), the risk of heart failure over 3.2 years of follow-up was higher compared with euthyroid controls (HR 2.93, 95% CI 1.37-6.24) [31], and in a pooled analysis of individual data from six prospective cohort studies (25,390 participants, 648 with subclinical hyperthyroidism), patients with TSH levels <0.10 mU/L had a higher risk of heart failure than euthyroid controls (16 events in 154 participants [10.4 percent] versus 1762 events in 22,674 [7.8 percent], HR 1.94, 95% CI 1.01-3.72) [32]. The risk persisted (HR 1.8, 95% CI 1.04-3.13) when those using thyroid hormone were excluded from the analysis. 

 

Subclinical hyperthyroidism has several other effects on cardiac function, all similar to but less severe and less frequent than those in overt hyperthyroidism. These include sinus tachycardia, atrial premature beats, increase in left ventricular mass index, increase in cardiac contractility, impaired endothelial function, reduced exercise tolerance, reduced heart rate variability, and an increase in markers of coagulation [25,26,34-37]. The presence of cardiovascular findings is variable, likely due to the degree of TSH suppression, the underlying disease, and individual sensitivity to thyroid hormone excess.

The degree of TSH suppression that predicts adverse cardiovascular effects is unknown. However, in one small study of exogenous subclinical hyperthyroidism, cardiovascular parameters that were abnormal at higher doses became normal when the dose of levothyroxinewas adjusted so that the TSH measured approximately 0.1 mU/L [38].

Mortality — Although subclinical hyperthyroidism has been associated with several cardiovascular risk factors, it is unknown whether there is an increase in mortality. In a meta-analysis of five population-based studies examining the association between subclinical hyperthyroidism (TSH less than 0.3 to 0.5 mU/L) and cardiovascular and all-cause mortality, the risk for all-cause and cardiovascular mortality was not significant (relative risks [RRs] 1.12, 95% CI 0.89-1.42 and 1.19, 95% CI 0.81-1.76, respectively) [39]. In contrast, another meta-analysis showed a significantly increased risk of all-cause mortality (HR 1.41, 95% CI 1.12-1.79) [40]. In a mathematical model designed a priori to explore mortality risk, the excess mortality after diagnosis of subclinical hyperthyroidism depended upon age, with an increase beyond the age of 60 years. However, in a subsequent population-based study, subclinical hyperthyroidism was associated with reduced survival only in individuals <age 65 years [41].

The meta-analyses included patients with both exogenous and endogenous subclinical hyperthyroidism. Serum triiodothyronine (T3) levels are higher in patients with endogenous than exogenous subclinical hyperthyroidism, and this may confer a higher mortality risk [25]. In the meta-analysis of 10 prospective cohort studies described above (52,674 participants, 2188 with endogenous subclinical hyperthyroidism) that included only patients with endogenous subclinical hyperthyroidism, there was an increased risk of both total (HR 1.24, 95% CI 1.06-1.46) and cardiovascular (HR 1.29, 95% CI 1.02-1.62) mortality in patients with endogenous subclinical hyperthyroidism [27]. The risk of cardiovascular mortality was higher for TSH levels <0.1 mU/L compared with levels between 0.1 and 0.44 mU/L (HRs 1.84 versus 1.24).

In a study evaluating only patients with exogenous subclinical hyperthyroidism, there was an increased risk of cardiovascular or overall mortality only in patients with fully suppressed TSH levels [42]. In this cohort study of 17,684 patients (mean age 61.6 years) taking T4 replacement therapy, TSH levels were fully suppressed (<0.03 mU/L) or low (0.04 to 0.4 mU/L) in 6 and 21 percent of patients, respectively. Compared to patients with normal TSH, patients with suppressed TSH concentrations (<0.03 mU/L) had increased cardiovascular morbidity and mortality (adjusted HR 1.37, 95% CI 1.17-1.60), whereas those who had serum TSH levels between 0.04 and 0.4 mU/L had a smaller increase in risk that was not significant (adjusted HR 1.10 [95% CI 0.99-1.23]).

Overall, the increased risk of mortality from subclinical hyperthyroidism appears to be small but increases with the degree of TSH suppression.

Dementia — Although data are conflicting, subclinical hyperthyroidism may also be associated with an increased risk of dementia [30,43-45]. As examples:

●In a prospective cohort study of 1864 participants (mean age of 71 years and TSH of 0.1 to 10 mU/L), followed for a mean of 12.7 years, women (but not men) whose TSH was in the lowest tertile had a 2.39 increased risk of developing Alzheimer disease compared with the middle tertile [44].

 

●Similar results were seen in a population-based study of 1171 subjects in which subclinical hyperthyroidism (TSH <0.46 mU/L) was associated with cognitive dysfunction (HR 2.26, 95% CI 1.32-3.91) [45].

 

●In a population-based study from Scotland (n = 2004), persistent endogenous subclinical hyperthyroidism (TSH <0.4 mU/L) was associated with an increased risk of dementia (adjusted HR 1.79, 95% CI 1.28-2.51) [30].

 

●In a prospective population study from Korea, 54 out of 313 patients who showed decline in cognitive function had lower TSH levels within the normal reference range compared with individuals whose cognitive function was stable or improved [46].

 

In contrast, cross-sectional studies of primary care patients in England [47], thyroid cancer patients in Korea [48], and women taking T4-suppressive therapy in the United States [49] failed to demonstrate an association of subclinical hyperthyroidism with cognitive function.

Quality of life — In patients with exogenous subclinical hyperthyroidism, disturbances in sleep and decreases in some physical components have been reported with [49] or without [47,50-52] significant effect on mood or mental health. As examples:

●In hypothyroid patients randomly assigned to the usual dose of T4 (euthyroid group) versus higher dose T4 (subclinical hyperthyroid group), the SF-36 physical component and general healthy subscale were slightly worse in the subclinical hyperthyroid group [52]. In contrast, mental health, mood, and motor learning were improved.

 

●In a six-month randomized trial of T4 titrated to establish continuation of TSH suppression versus normalization of TSH in 24 patients with a history of differentiated thyroid carcinoma, there were no significant changes in any SF-36 components in either group [51].

 

On the other hand, in a non-blinded study in which subjects were given a T4 dose that was 50 mcg greater or less than their optimal dose (based on TRH stimulated TSH testing), patients on the higher dose had improved "well being" using a visual analog scale compared with baseline [53].

In patients with endogenous subclinical hyperthyroidism, scores for both the physical and mental health components appear to be lower than in euthyroid control subjects [54]. The low scores were due to symptoms related to thyroid hormone excess (palpitations, nervousness, tremor, and sweating).

Thus, quality of life may be impaired in some patients with subclinical hyperthyroidism, particularly those with endogenous subclinical hyperthyroidism [25]. The variability in findings is likely related to differences in patient populations, duration of subclinical hyperthyroidism, and degree of TSH suppression.

DIAGNOSIS — The negative feedback relationship between serum thyroxine (T4) and triiodothyronine (T3) and thyroid-stimulating hormone (TSH) concentrations is a log-linear one. Thus, even small increases in serum T4 and T3 concentrations (whether caused by exogenous thyroid hormone therapy or endogenous thyroid hormone secretion) suppress TSH secretion [53]. There is general agreement that measurement of serum TSH is the most sensitive indicator of thyroid hormone activity in its target tissues (in the absence of pituitary or hypothalamic disease). In most circumstances, the initial screening test for thyroid disease is the serum TSH. (See "Laboratory assessment of thyroid function".)

If the serum TSH concentration is below normal (<0.5 mU/L in many laboratories), the TSH measurement should be repeated along with a serum free T4 and T3 to make the diagnosis of subclinical hyperthyroidism. The diagnosis of subclinical hyperthyroidism is based upon the combination of a low serum TSH concentration and normal serum free T4 and T3 concentrations. It may occur in the presence or absence of mild symptoms of hyperthyroidism. Because the serum TSH concentration can be transiently reduced, a serum TSH measurement, along with a free T4 and T3, should be repeated after one to three months to confirm the diagnosis.

Other causes of low TSH concentrations should be excluded. There are three causes of the combination of low serum TSH and normal free T4 and T3 concentrations other than subclinical hyperthyroidism:

●Central hypothyroidism – Some patients with central hypothyroidism have low serum TSH and normal (but usually low or low-normal) free T4 and T3 concentrations. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Central hypothyroidism", section on 'TSH low'.)

 

●Nonthyroidal illness – Euthyroid patients with nonthyroidal illness, especially those receiving high-dose glucocorticoids or dopamine, may have low serum TSH and low-normal free T4 and T3 concentrations. (See "Thyroid function in nonthyroidal illness".)

 

●Recovery from hyperthyroidism – Serum TSH concentrations may remain low for up to several months after normalization of serum T4 and T3 concentrations in patients treated for hyperthyroidism or recovering from hyperthyroidism caused by thyroiditis.

 

When the diagnosis of subclinical hyperthyroidism is uncertain, measurement of 24-hour thyroid radioiodine uptake or thyroid radionuclide imaging may be helpful. A high or relatively high 24-hour uptake (relative to the low serum TSH value) or a focal area of increased radionuclide uptake supports the diagnosis of subclinical hyperthyroidism. (See 'Evaluation' below.)

Pregnancy — The diagnosis of true subclinical or overt hyperthyroidism during pregnancy may be difficult because of the changes in thyroid function that occur during normal pregnancy. Transient subclinical hyperthyroidism in the first trimester of pregnancy is considered a normal physiologic finding. True subclinical hyperthyroidism may occur, but it is not typically associated with adverse outcomes during pregnancy [55] and does not require therapy. Furthermore, in pregnant women with overt hyperthyroidism, the goal of therapy is to maintain serum free T4 concentrations in the high-normal range and serum TSH concentrations in the low-normal or suppressed range (ie, to maintain persistent but minimal mild hyperthyroidism). (See "Overview of thyroid disease in pregnancy", section on 'hCG and thyroid function' and "Hyperthyroidism during pregnancy: Treatment".)

EVALUATION — Patients with subclinical hyperthyroidism should be questioned about symptoms of hyperthyroidism (eg, tremor, palpitations, heat intolerance), in addition to a past history of thyroid disease, exposure to iodine-containing radiographic contrast media or herbal products containing iodine, and use of medications that may suppress thyroid-stimulating hormone (TSH) (thyroxine [T4], high-dose glucocorticoids). Women of childbearing age should be questioned about the possibility of pregnancy. All patients should be examined for the presence of thyroid gland enlargement and/or nodularity.

In patients not taking T4 who have persistently subnormal TSH values and in whom we are considering treatment, we obtain a radioactive iodine uptake and scan to help determine the etiology of subclinical hyperthyroidism (table 1). Women of childbearing age should have a negative pregnancy test prior to undergoing radioactive iodine scanning.

If the scan shows one or more focal areas of increased uptake, this could account for the low serum TSH. If there are focal areas of increased uptake, a thyroid ultrasound would then be useful in delineating the presence of discrete nodules. In patients with low or no uptake on radioiodine scan, the etiology of subclinical hyperthyroidism may be thyroiditis or recent iodine exposure (table 1).

In postmenopausal women or other patients at risk for osteoporosis, a bone densitometry study may be useful in making a decision to treat subclinical hyperthyroidism or to monitor. (See "Osteoporotic fracture risk assessment" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)

MANAGEMENT

Patients on T4 for the treatment of hypothyroidism — Both low bone density and atrial fibrillation can result in substantial morbidity in older patients and, therefore, subclinical hyperthyroidism should be avoided. Patients receiving thyroid replacement therapy who have thyroid-stimulating hormone (TSH) concentrations below normal should have their dose adjusted to maintain a normal serum TSH concentration (approximately 0.5 to 5.0 mU/L). (See "Treatment of hypothyroidism", section on 'Goals of therapy' and "Treatment of hypothyroidism", section on 'Older patients or those with coronary heart disease'.)

Patients on suppressive levothyroxine therapy — Subclinical hyperthyroidism is unavoidable when thyroid hormone is given to suppress TSH secretion in an attempt to prevent or reduce goiter growth or prevent recurrence of thyroid cancer, since it is the goal of therapy. However, the adverse effects of suppressive therapy can be minimized by treatment with the lowest dose of thyroxine (T4) necessary to meet the desired goal [38,56].

In patients with thyroid cancer, subclinical hyperthyroidism is the goal of thyroid hormone therapy. In these patients, the benefits of TSH suppression are thought to outweigh the risks of subclinical hyperthyroidism. This topic is reviewed elsewhere. (See "Differentiated thyroid cancer: Overview of management", section on 'Thyroid hormone suppression'.)

Candidates for suppressive therapy and goal TSH levels in patients with benign thyroid disease are also reviewed in detail separately. (See "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter".)

Postmenopausal women taking suppressive doses of thyroid hormone should receive calcium and vitamin D supplementation if needed, and consideration should be given to instituting antiresorptive therapy to prevent bone loss. Drug options for prevention of osteoporosis are reviewed elsewhere. (See "Bone disease with hyperthyroidism and thyroid hormone therapy" and "Prevention of osteoporosis" and "Calcium and vitamin D supplementation in osteoporosis".)

Endogenous subclinical hyperthyroidism — There are few data to guide clinical decisions regarding the treatment of patients with endogenous subclinical hyperthyroidism. In some patients the values are normal on retesting weeks or months later, so that intervention should not be considered unless persistently low TSH values are documented [10,12].

Potential benefits of treatment include improvement in certain cardiovascular parameters and in bone mineral density. However, there are no studies evaluating the long-term benefits of correcting subclinical hyperthyroidism, particularly studies with clinically important endpoints, such as cardiovascular disease and fracture. As an example, in a prospective but uncontrolled study of patients with subclinical hyperthyroidism, antithyroid drugs reduced heart rate, atrial and ventricular premature beats, left ventricular mass index, interventricular septal thickness, and left ventricular posterior wall thickness [57]. Similar improvements in hemodynamic parameters were seen in another study following radioiodine therapy [58].

In two other non-randomized studies, postmenopausal women with nodular goiter and subclinical hyperthyroidism treated with antithyroid drugs or radioiodine for two years had higher bone density than similar women who were not treated [59,60].

Thus, in some patients with subclinical hyperthyroidism, normalization of TSH results in improvement in surrogate outcomes. Long-term clinical trials are required to determine if correcting subclinical hyperthyroidism improves cardiovascular or skeletal outcomes. In the absence of data to guide selection of patients with endogenous subclinical hyperthyroidism for therapy, we base our decision to treat on clinical risk for complications of subclinical hyperthyroidism and the degree of TSH suppression.

Patients at high risk for complications — In patients at high risk for skeletal or cardiac complications (eg, older patients >65 years of age, patients with risk factors for cardiac arrhythmias, and postmenopausal women with or at risk for osteoporosis), we use the following approach:

●If the serum TSH value is <0.1 mU/L, we treat the underlying cause of subclinical hyperthyroidism.

 

●If the serum TSH is 0.1 to 0.5 mU/L, we suggest treatment if there is underlying cardiovascular disease or if the bone density is low. We are also more likely to consider treatment if a thyroid radionuclide scan shows one or more focal areas of high uptake (ie, evidence of autonomy). Subclinical hyperthyroidism due to autonomous nodule(s) is more likely to progress to overt hyperthyroidism than is subclinical hyperthyroidism due to Graves' disease. We suggest observation if the bone density is normal and the thyroid scan fails to show a focal area of high uptake. We might also consider observation if a patient is on a beta-adrenergic antagonist drug for other reasons. In observed patients, we measure TSH, free T4, and triiodothyronine (T3) every six months.

 

Patients at low risk for complications — In patients at low risk for complications of hyperthyroidism (young individuals, premenopausal women), we use the following approach:

●If the serum TSH value is <0.1 mU/L, we treat the underlying cause of subclinical hyperthyroidism if the patient has symptoms suggestive of hyperthyroidism and/or if a thyroid radionuclide scan shows one or more focal areas of increased uptake.

 

●If the TSH is between 0.1 to 0.5 mU/L, observation alone is appropriate. We measure TSH, free T4, and T3 every six months.

 

These recommendations are consistent with those of a clinical consensus group (comprised of representatives from The Endocrine Society, the American Thyroid Association [ATA], and the American Association of Clinical Endocrinologists [AACE]) [61].

Treatment options — The treatment options for patients with subclinical hyperthyroidism are the same as those for overt hyperthyroidism and depend upon the underlying etiology. Beta-adrenergic antagonist drugs are useful to control symptoms of adrenergic overactivity (eg, palpitations, tremor). (See "Beta blockers in the treatment of hyperthyroidism".)

In patients with Graves’ disease or nodular thyroid disease with autonomy, treatment options include thionamides, radioiodine, or surgery. The treatment of these conditions is reviewed separately. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment" and "Treatment of toxic adenoma and toxic multinodular goiter" and "Radioiodine in the treatment of hyperthyroidism".)

In patients with low or no uptake on radioiodine scan, the etiology of subclinical hyperthyroidism may be thyroiditis or exogenous thyroid hormone intake (table 1). Most patients with thyroiditis require no treatment since thyroid dysfunction is rarely severe and is transient. However, thyroid tests should be monitored, initially every four to eight weeks, until normalization. Symptomatic patients may benefit from beta-adrenergic antagonists. (See "Painless thyroiditis".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.) 

●Basics topics (see "Patient information: Hyperthyroidism (overactive thyroid) (The Basics)")

 

●Beyond the Basics topics (see "Patient information: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient information: Antithyroid drugs (Beyond the Basics)")

 

SUMMARY AND RECOMMENDATIONS

●Subclinical hyperthyroidism is defined biochemically by a low serum thyroid-stimulating hormone (TSH) concentration but normal serum free thyroxine (T4) and triiodothyronine (T3) concentrations. Patients with subclinical hyperthyroidism typically have few or no symptoms of hyperthyroidism. (See 'Diagnosis' above.)

 

●The most common causes of subclinical hyperthyroidism are treatment with T4 (exogenous) and autonomously functioning thyroid adenomas and multinodular goiters (endogenous) (table 1). (See 'Causes' above.)

 

●Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and, primarily in postmenopausal women, a decrease in bone mineral density. (See 'Clinical findings' above.)

 

●Patients receiving thyroid replacement therapy for the treatment of hypothyroidism and who have TSH concentrations below normal should have their dose adjusted to maintain a normal serum TSH concentration (approximately 0.5 to 5.0 mU/L). (See 'Patients on T4 for the treatment of hypothyroidism' above.)

 

●For patients with thyroid cancer and in some patients with benign nodular thyroid disease, subclinical hyperthyroidism is the goal of thyroid hormone therapy. In these patients, the benefits of TSH suppression are thought to outweigh the risks of subclinical hyperthyroidism. (See 'Patients on suppressive levothyroxine therapy' above.)

 

●For patients with endogenous subclinical hyperthyroidism at high risk for cardiac or skeletal complications (ie, older adults) and who have a TSH concentration less than 0.1 mU/L, we recommend treatment of the underlying cause of subclinical hyperthyroidism (Grade 1C).

For similar patients who have TSH values between 0.1 and 0.5 mU/L, we suggest treatment if the bone density is low and/or if the radionuclide scan shows one or more focal areas of increased uptake (Grade 2C). If bone density is normal and the thyroid scan fails to show a focal area of high uptake, we typically observe patients. In observed patients, we measure TSH, free T4, and T3 every six months. (See 'Patients at high risk for complications' above.)

 

●For patients with endogenous subclinical hyperthyroidism at low risk for cardiac or skeletal complications (young individuals, premenopausal women) and TSH values less than 0.1 mU/L, we suggest treatment if the radionuclide scan shows one or more focal areas of increased uptake (Grade 2C). For low risk patients who have a TSH value between 0.1 and 0.5 mU/L, we suggest observation (Grade 2C). We measure TSH, free T4, and T3 every six months. (See 'Patients at low risk for complications' above.)

 

●The treatment options for patients with subclinical hyperthyroidism are the same as those for overt hyperthyroidism and depend upon the underlying etiology. (See 'Treatment options' above.)

 

 

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