Subclinical hyperthyroidism is a constellation of biochemical findings :

• Low serum TSH concentrations (<0.5 mU/mL) but…• Normal serum free thyroxine (T4) and triiodothyronine (T3)

concentrations

The term is essentially a biochemical definition

• Hyperthyroid symptoms are often times non-specific

• may be present in patients with subclinical disease

• Symptoms may be absent in those with overt disease, especially the elderly

The causes of subclinical hyperthyroidism are identical to the causes of overt hyperthyroidism

Like overt hyperthyroidism, subclinical hyperthyroidism can be persistent or transient

As many as 10 million people in the United States are taking thyroid hormone.

All are at risk for subclinical hyperthyroidism

whether intentional or unintentional.

As many as 25 percent have a suppressed TSH value

The vast majority of these patients have hypothyroidism and…

◦ subclinical hyperthyroidism is not the goal of therapy.

Subclinical hyperthyroidism is the goal of thyroid hormone therapy in patients with certain conditions:

◦ Well differentiated thyroid carcinomas where the goal is to suppress TSH to a level often times to as low as 0.1 mU/mL

◦ In these patients, the benefits of TSH suppression are thought to outweigh the risks of subclinical hyperthyroidism

Schlote B, Schaaf L, Schmidt R, et al. Mental and physical state in subclinical hyperthyroidism: investigations in a normal working population. Biol Psychiatry 1992; 32:48.

De Whalley P. Do abnormal thyroid stimulating hormone level values result in treatment changes? A study of patients on thyroxine in one general practice. Br J Gen Pract 1995; 45:93.

Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160:526.

Autonomously functioning thyroid adenomas and multinodular goiters

◦ The most common cause of endogenous subclinical hyperthyroidism.

Among patients over age 55, hyperthyroidism due to multinodular goiters was subclinical in 57 percent of patients

Díez JJ. Hyperthyroidism in patients older than 55 years: an analysis of the etiology and management. Gerontology 2003; 49:316

Rieu M, Bekka S, Sambor B, et al. Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non-toxic nodular goitre. Clin Endocrinol (Oxf) 1993; 39:67.

Graves' disease is much more rare as only 6 percent of patients present subclinically

May be seen in early Graves' disease, prior to the onset of more overt hyperthyroidism

More often patients will present with overt hyperthyroidism with suppressed TSH and elevated FT4/Ft3

Subclinical hyperthyroidism also occurs in patients with thyroiditis, often times seen in the recovery phase

Charkes ND. The many causes of subclinical hyperthyroidism. Thyroid 1996; 6:391

Pregnant women (especially in the first trimester)

Women with either Hyperemesis gravidarum or trophoblastic disease

◦ High serum chorionic gonadotropin concentrations lead to the biochemical presentation of subclinical hyperthyroidism

The prevalence of subclinical hyperthyroidism in the community varies between 0.7 and 12.4 percent.

◦ variability is due to differences in the definition of low serum TSH values and in the patient populations studied.

In the US, the NHANES data, which excluded subjects with known thyroid disease, reported 0.7 percent of 16,533 people had subclinical hyperthyroidism

More common in:◦ Females◦ Smokers◦ Elderly

Conflicting data regarding the frequency of progression from subclinical to overt hyperthyroidism

Progression appears to be related to the degree of subclinical hyperthyroidism and the underlying cause.

In a population-based study, 2024 adults with at least two suppressed (<0.4 mU/L) serum TSH levels measured four months apart with normal free or total T4 and total T3 were identified .

◦ 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 were:◦ 2 years 0.6%◦ 5 years 0.7%◦ 7 years 0.5%

◦ Twice as common in patients with serum TSH <0.1 mU/L compared to those with TSH between 0.1 and 0.4 mU/L.

The skeleton and the cardiovascular system are the major target tissues adversely affected by subclinical hyperthyroidism

Thyroid hormone directly stimulates bone resorption, and overt hyperthyroidism is associated with

Increased bone resorption

Low bone density

Increase in fracture

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

◦ Likely that similar duration of subclinical hyperthyroidism would have similar effects on the skeleton, but to a less severe degree.

Atrial fibrillation 

◦ The frequency of atrial fibrillation is increased in patients with subclinical hyperthyroidism

Risk is dependent on severity of disease

In a prospective cohort study of approximately 2000 adults over age 60 years (without atrial fibrillation) followed for 10 years, the risk of atrial fibrillation varied with the baseline serum TSH concentration

Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249.

TSH and free T4 concentrations may be associated with atrial fibrillation risk in biochemically euthyroid individuals.

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

Heeringa J, Hoogendoorn EH, van der Deure WM, et al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam study. Arch Intern Med 2008; 168:2219

Questionable evidence in respect to increased mortality and subclinical hyperthyroidism

In a meta-analysis of five population-based studies

the risk for all-cause and cardiovascular mortality was not significant

Ochs N, Auer R, Bauer DC, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med 2008; 148:832.

In contrast, another meta-analysis showed a significantly increased risk of all-cause mortality:

Excess mortality after diagnosis of subclinical hyperthyroidism depended upon age, with an increase beyond the age of 60 years.

Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B. Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies. Eur J Endocrinol 2008; 159:329.

In patients with endogenous subclinical hyperthyroidism, quality of life scores for both the physical and mental health components appear to be lower than in euthyroid control subjects

The low scores were due to symptoms related to thyroid hormone excess (palpitations, nervousness, tremor, and sweating).

Biondi B, Palmieri EA, Fazio S, et al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 2000; 85:4701.

 The negative feedback between serum T4 and T3 and TSH concentrations is a log-linear one.

◦ Even small increases in serum T4 and T3 concentrations suppress TSH secretion

TSH is the most sensitive indicator of thyroid hormone activity

◦ Initial screening test for thyroid disease is the serum TSH

If the serum TSH concentration is below normal, the TSH measurement should be repeated along with a serum free T4 and T3 to make the diagnosis of hyperthyroidism/ subclinical hyperthyroidism.

Other causes other than subclinical hyperthyroidism that can lead to suppressed TSH with normal FT4/FT3

◦ Central hypothyroidism ◦ Nonthyroidal illness ◦ Recovery from hyperthyroidism ◦ Pregnancy 

In patients not taking thyroid replacement who have persistently subnormal TSH values the next step in diagnosis is radioactive iodine uptake and scan to help determine the etiology of subclinical hyperthyroidism

Common Causes:

◦ Graves disease

◦ Toxic multinodular goiter

◦ Toxic adenoma

L-thyroxine suppressive therapy

Painful subacute thyroiditis

Painless [silent] lymphocytic thyroiditis◦ Post partum◦ sporadic

Iodine-induced thyrotoxicosis◦ Radiographic contrast media◦ Amiodarone

Thyroglobulin Ab

Thyroid peroxidase Ab

Thyroid-stimulating immunoglobulins

Observe

Patients on thyroid replacement:◦ Patients receiving thyroid replacement therapy

who have TSH concentrations below normal should have their dose adjusted to maintain a normal serum TSH concentration

Endogenous subclinical hyperthyroidism 

◦ Potential benefits of treatment include improvement in certain cardiovascular parameters and in bone mineral density.

◦ No studies evaluating the long-term benefits of correcting subclinical hyperthyroidism

Patients at high risk for complications — ◦ In patients at high risk for skeletal or cardiac complications

(>65 years of age), or those with risk factors for cardiac arrhythmias

TSH <0.1 mU/mL, treat the underlying cause of subclinical hyperthyroidism.

If the serum TSH is 0.1 to 0.5 mU/L treatment if there is underlying cardiovascular disease or if the bone density is low.

Consider treatment if a thyroid radionuclide scan shows one or more focal areas of high uptake (ie, evidence of autonomy).

Patients at low risk for complications 

◦ TSH value is <0.1 mU/mLtreat the underlying cause of subclinical hyperthyroidism if the patient has symptoms 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/mL, observation alone is appropriate with TSH, free T4, and freeT3 every six months.

Factor TSH (<0.1 mU/L)

TSH (0.1–0.5 mU/L)

Age>65 Yes Consider treating

Age<65 with comorbidities

Heart disease Yes Consider treating

Osteoporosis Yes Consider treating

Menopausal Consider treating

No

Symptoms Yes Consider treating

Age<65, asymptomatic

Consider treating

No

Defined biochemically as a normal T4 in the presence of an elevated serum TSH concentration.

Some patients with subclinical hypothyroidism may have vague, non-specific symptoms suggestive of hypothyroidism, but attempts to identify patients clinically have not been successful

Can only be diagnosed on the basis of laboratory test results.

In population-based studies, the prevalence of subclinical hypothyroidism ranges from 4 to 15 percent

The prevalence rises with age, is higher in females than males, and is lower in blacks than in whites

The causes of subclinical hypothyroidism are the same as those of overt hypothyroidism

Major Cause: ◦ Autoimmune Hashimoto's

thyroiditis ◦ high serum concentrations

of antithyroid peroxidase antibodies

Other major causes include◦ Treatment for hyperthyroidism

prior ablative or antithyroid drug therapy

◦ External radiation therapy

◦ Inadequate T4 replacement

◦ Drugs impairing thyroid function.

Although subclinical hypothyroidism is a common disorder, the value of screening for it at a routine examination when there is no relevant complaint or finding is controversial.

The diagnosis is based upon biochemical testing alone.

◦ Defined as a normal serum free T4 and an elevated TSH

◦ It may occur in the presence or absence of mild symptoms of hypothyroidism.

◦ Most patients have serum TSH levels <10 mU/L and are asymptomatic

Initial screening test for thyroid disease is TSH.

If TSH is elevated, the TSH should be repeated along with a serum free T4

Because TSH can be transiently elevated, a measurement should be repeated after one to three months to confirm the diagnosis.

In circumstances where there is a strong indication for T4 therapy, such as pregnancy or infertility, T4 replacement should be initiated if the serum TSH is elevated

An elevated TSH is defined as a TSH above the upper limit of the normal reference range, which is typically 4 to 5 mU/L

Considerable controversy over the appropriate upper limit of normal for serum TSH.

◦ AACE has suggested that the true upper limit is only 2.5 or 3 mU/L in healthy individuals without thyroid disease,

◦ Others argue that the serum TSH distribution shifts towards higher values with age, independent of the presence of antithyroid antibodies

In this case, the upper limit of normal could be as high as 6 to 8 mU/L in healthy octogenarians.

Recovery from nonthyroidal illness

Following the hyperthyroid phase of thyroiditis, where mild hypothyroidism is usually, but not always, transient.

Assay variability ◦ presence of heterophilic antibodies that

can interfere with TSH

Untreated adrenal insufficiency.

Central hypothyroidism, where up to 25 percent of patients have a mildly elevated serum TSH and a low or low-normal free T4

Progression to overt hypothyroidism  ◦ substantial proportion of patients eventually

develop overt hypothyroidism. In prospective studies with nearly 10 to 20 years of

follow-up, the cumulative incidence of overt hypothyroidism ranges from 33 to 55 percent

◦ Risk of progression initial TSH > 12 presence of TPO antibodies

Cardiovascular disease ◦ Conflicting data (likely related to differences in the

patient populations and study designs)

◦ Some but not all, observational studies report an increased risk of coronary heart disease in subjects with subclinical hypothyroidism.

A meta-analysis of seven prospective cohort studies (25,977 participants, 2020 with subclinical hypothyroidism) showed a significant trend of increased risk of coronary events at higher serum TSH concentrations .

◦ Compared with euthyroid subjects, participants with TSH ≥10 mU/L had a significant increase in CHD events 38.4 versus 20.3 events/1000 person years

◦ Minimal TSH elevations (4.5 to 6.9 mU/L) were not associated with an increased risk

◦ The risk estimates did not differ according to age, gender, or presence of preexisting CVD

Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010; 304:1365.

Some studies show an association between elevated TSH and total and LDL cholesterol concentrations

Associated with an increase in a number of other cardiovascular risk factors and surrogate cardiovascular endpoints◦ markers of inflammation◦ vascular reactivity◦ endothelial function◦ carotid intima media thickness

 Some studies have shown an increased risk of cardiovascular and/or all-cause mortality.

Meta-analysis showed the risk of cardiovascular mortality, but not all-cause mortality, increased with TSH concentrations ≥10 mU/L

In contrast, minimal elevations of TSH (4.5 to 6.9 mU/L) were not associated with cardiovascular or all-cause mortality.

Several reports suggest that subclinical hypothyroidism is associated with neuropsychiatric diseases

Other studies have failed to demonstrate an association of subclinical hypothyroidism with depression, anxiety, or cognitive dysfunction

Undetected subclinical hypothyroidism in pregnancy is a risk factor for miscarriage and low birth weight babies, and possibly poor developmental outcome in the offspring.

One might argue that treatment should be started to prevent progression to overt hypothyroidism, particularly in patients with serum TSH values ≥10

Patients with TSH values between 4.5 and 10 remains controversial, as randomized trials have not shown a consistent benefit with treatment.

Cardiovascular disease◦ T4 replacement has been shown to improve a number of

cardiovascular risk factors and surrogate cardiovascular endpoints and lipid parameters

◦ No substantial data demonstrating its ability to decrease cardiovascular events has been lacking

◦ In addition, the risk of adverse cardiovascular effects associated with overtreatment once thyroxine is administered is unknown.

◦ Clinical trials are needed

Candidates for T4 replacement 

◦ Almost all experts recommend treatment when TSH >10 Endocrine Society, American Thyroid Association,

and the American Association of Clinical Endocrinologists

◦ Treatment of asymptomatic patients with TSH values between 4.5 and 10 remains controversial

Lack of data to show either benefit or harm of T4 treatment in patients with TSH values between 4.5 and 10 mU/L.

The consensus group did not recommend routine treatment for such patients◦ Recommended monitoring TSH levels every 6 to 12

months

Others have recommended treatment for patients with TSH values in this range:◦ Unrecognized symptoms may improve◦ Correction of abnormal serum lipid concentrations may be

cardioprotective◦ Little risk associated with monitored T4 replacement

Treat non-elderly patients with serum TSH values of 4.5 to 10 with high titers of antithyroid peroxidase antibodies

Rationale: ◦ Very high likelihood of progression to overt

hypothyroidism

◦ Safe if followed: Start with the lowest dose necessary to normalize TSH,

typically 25 to 50 mcg daily Monitor frequently, targeting TSH between .5-2.5

In those older than 70◦ Do not treat elderly patients with TSH between

4.5 and 8

Overtreatment in this group is common, occurring in as many as 41 percent of

May result in adverse cardiac arrhythmias

Initiate therapy in pregnant women whose TSH values are above trimester-specific normal reference range with normal free T4

In women with subclinical hypothyroidism who wish to become pregnant or have ovulatory dysfunction and infertility