Subclinical Hyperthyroidism: Definition, Symptoms, Causes, Diagnosis and Treatment

The prevalence of SH is approximately 1%, although it tends to be more common in areas with relative iodine deficiency.

Subclinical hyperthyroidism (SH) is defined biochemically by a low (or undetectable) level of thyroid stimulating hormone (TSH) with a normal serum free T4 and normal total serum T3 levels due to thyroid disease or excessive exogenous administration of thyroid hormone.

In comparison, overt hyperthyroidism occurs when the TSH level is low (or undetectable) and the level of free T4 and / or the total level of T3 is high.

It is important to distinguish between SH and overt hyperthyroidism because they can be handled differently in most cases.


Patients with SH are often asymptomatic.

When there are symptoms, they are similar to symptoms in patients with overt hyperthyroidism , although they are generally milder.

With the exception of one study, subclinical hyperthyroidism is associated with relevant signs and symptoms of excess thyroid hormone and with deterioration in quality of life.

With different types of questionnaires formulated to investigate the psychophysical effects of thyroid hormone, it was found that patients with subclinical hyperthyroidism, whether exogenous or endogenous, had a higher prevalence of palpitations, tremors, heat intolerance, sweating, nervousness, anxiety, feeling of discomfort, fear, hostility and inability to concentrate, etc.

It should be noted that, in a retrospective study, an almost three-fold increased risk of dementia and Alzheimer’s disease was found in patients with subclinical hyperthyroidism.

The excess of thyroid hormone causes a wide spectrum of cardiovascular changes, which arise from the direct and indirect effects on the cardiovascular system and the effects mediated by neurohormonal activation.

The cardiovascular risk of subclinical hyperthyroidism is related to short-term effects due to the electrophysiological effects of thyroid hormones and the long-term effects resulting from increased left ventricular mass and increased cardiac workload.

In most studies, patients with subclinical hyperthyroidism, either exogenous or endogenous, have a higher heart rate and a higher prevalence of supraventricular arrhythmias, as assessed by Holter electrocardiographic 24-hour monitoring.

In individuals with a shorter PR interval on the standard electrocardiogram , due to the presence of two functionally distinct atrioventricular ganglionic pathways, subclinical hyperthyroidism can precipitate a reentrant atrioventricular nodal tachycardia.

Manifest hyperthyroidism is an important risk factor for osteoporosis and fractures.

Thyroid hormones accelerate the rate of bone remodeling, which leads to a negative calcium balance and a net bone loss that accelerates the development of osteoporosis and, therefore, increases bone vulnerability to trauma.

If subclinical hyperthyroidism significantly affects bone metabolism and increases the risk of fractures, it remains a controversial issue.

Serum concentrations of several markers of synthesis and bone resorption, ie, osteocalcin and telopeptide type I, and crosslinking of pyridinoline in urine and hydroxyproline, are increased in patients with subclinical hyperthyroidism and negatively correlated with serum TSH levels.

In several cross-sectional studies, bone mineral density decreased in multiple sites in pre and postmenopausal women with hyperthyroidism.


Subclinical hyperthyroidism may be caused by exogenous or endogenous factors and may be transient or persistent.

Adverse effects on tissues are similar, whatever the cause of subclinical hyperthyroidism and depend mainly on the duration of the disease.

Exogenous SH occurs when a patient consumes excessive thyroid hormone, either intentionally or not.

Some cases include patients taking thyroid hormone as a replacement, some may simply be taking too much or have been prescribed a higher dose of thyroid hormone than necessary and require an adjustment.

The exogenous form of subclinical hyperthyroidism is generally related to TSH suppressive therapy with L-thyroxine for a single thyroid nodule, multinodular goiter, or differentiated thyroid carcinoma.

In addition, TSH can be suppressed involuntarily during hormone replacement therapy in approximately 20% of patients with hypothyroidism .

The endogenous form is usually related to the same causes as overt thyrotoxicosis, namely, Graves’ disease, thyroid adenoma that functions autonomously and multinodular goiter.

The last two causes are particularly frequent in the elderly, especially in areas with iodine deficiency.

Subclinical hyperthyroidism caused by nodular disease tends to be persistent, whereas SH generated by Graves’ disease may be transient or persistent.

It is important to recognize that subnormal TSH levels in serum do not always reflect the presence of subclinical hyperthyroidism.

Abnormal serum TSH may occur in patients with pituitary or hypothalamic insufficiency, or nonthyroidal pathological conditions, or as a consequence of the administration of glucocorticoids , dopamine or amiodarone .


In addition, the TSH concentration may be below the normal range in some elderly patients as a result of decreased age-related thyroid hormone clearance.

In any case, a careful physical examination, a detailed medical history and the pattern of thyroid hormones can help diagnose these conditions.

The main laboratory tests necessary for the diagnosis of subclinical hyperthyroidism (SH) are tests of thyroid function, specifically TSH, free T4 and total or free T3.

Subclinical hyperthyroidism is associated with low (or suppressed) TSH with normal free T4 and normal total T3.

Laboratory studies must be repeated to confirm the diagnosis.

Once the diagnosis has been confirmed, the etiology of the patient should be determined.

Thyroid antibodies can help distinguish Graves’ disease from other causes of SH.

The most specific antibody for Graves’ disease is thyroid-stimulating immunoglobulin (ETI), which can be measured in most reference laboratories.

In patients with suspected thyroiditis, it may be useful to obtain antibodies with thyroid peroxidase and levels of thyroglobulin antibodies, since they are often positive in cases of thyroiditis.

However, they are also usually positive in patients with Graves’ disease.

In addition to laboratory studies, imaging tests are useful in determining the etiology of this condition.

Obtaining a thyroid ultrasound offers information about the general structure and characteristics of the thyroid gland.

In patients with Graves disease or thyroiditis, the thyroid gland is usually enlarged and heterogeneous in appearance.

In patients with multinodular goiter and / or solitary autonomous nodule, thyroid ultrasound can characterize the number and size of the nodules.

Even more specific than a thyroid ultrasound is the uptake of radioactive iodine from 4 to 6 and 24 hours and the exploration of the thyroid gland.

The results of the examination can be very useful to elucidate the etiology of the patient’s disease.

If 24-hour uptake and scanning show diffuse uptake throughout the thyroid gland and elevated uptake, then the likely diagnosis is Graves’ disease.

If the capture and scanning show ” hot nodules ” or specific areas of increased uptake, then this would fit with a diagnosis of multinodular goiter or a solitary nodule of autonomous functioning.

Finally, if the uptake and scanning show a decrease in uptake in the thyroid, then the probable diagnosis is thyroiditis or excess ingestion of exogenous thyroid hormone.

Subclinical hyperthyroidism may have specific effects on the cardiovascular system and on bone metabolism.

Therefore, other tests that may be useful in deciding how to treat a particular patient with SH would include an evaluation of bone mineral density and cardiovascular.

Several studies have identified an association between SH and atrial fibrillation.

Patients with subclinical hyperthyroidism have a 2.8-5 times higher risk of developing atrial fibrillation; This risk is higher in patients older than 60 years and in patients with completely suppressed TSH levels (undetectable).

The relationship is not so clear between this condition and other types of cardiovascular diseases.

In patients with a history of atrial arrhythmias or underlying heart disease and in patients older than 60 years, it would be reasonable to consider a cardiac evaluation.

This evaluation could include any or all of the following: electrocardiogram, ambulatory holter monitor and echocardiogram.

The findings of this evaluation would help distinguish which patients are more likely to benefit from the treatment.


The first step in the treatment of subclinical hyperthyroidism (SH) is to repeat thyroid function tests (TSH, free T4 and total T3) in perhaps 2 to 4 weeks to determine if SH is persistent.

Once it has been established that subclinical hyperthyroidism is persistent, patients should be evaluated individually to determine treatment.

Not all patients with the disease require treatment.

The decision is based on several factors, including the level of TSH, the age of the patient and coexisting conditions.

In most cases, the normal range of TSH is approximately 0.4-4.5 mUI / L.

A low TSH level is between 0.1-0.4 mUI / L and a suppressed TSH level is one below 0.1 mUI / L.

When determining treatment for SH, it is important to know if the patient’s TSH is low or suppressed.

Patients with TSH levels below 0.1 mIU / L are more likely to have complications due to SH, such as atrial fibrillation, bone loss, and conversion to overt hyperthyroidism.

Therefore, in certain groups of patients with TSH below 0.1 mIU / L, the treatment should be considered firmly.

These groups include patients 60 years of age or older, patients who have or are at risk for osteoporosis or heart disease, and patients with symptoms of hyperthyroidism.

In patients with TSH levels between 0.1-0.4 mIU / L, the link between the disease and the complications listed above is less clear. Therefore, treatment is not recommended in these patients.

However, if patients are 60 years of age or older, have heart disease or symptoms of hyperthyroidism, treatment may be considered.

The decision to treat subclinical hyperthyroidism should be individualized and made only after a full discussion with the patient.

Even if patients were not treated for SH, their thyroid function tests should be monitored periodically to verify resolution or conversion to overt hyperthyroidism.

In addition, they should avoid high doses of iodine, such as exposure to intravenous radiocontrast material, as this could aggravate their hyperthyroidism. The treatment varies according to the etiology of the disease.

In patients with subclinical hyperthyroidism generated by subacute or postpartum thyroiditis, treatment with antithyroid drugs is contraindicated since excessive serum levels of thyroid hormone result from the release of the stored hormone and do not increase synthesis.

However, if the patient is symptomatic, beta-blockers can be started and adjusted to the smallest dose needed to control the symptoms.

In patients who have a condition that is caused by Graves’ disease, treatment options include thionamides or radioiodine.

There are two easily available thionamides: methimazole and propylthiouracil (PTU).

Because PTU has been associated with rare but fatal cases of hepatotoxicity (especially in children and pregnant women), methimazole is the first line of thionamide for use in patients with hyperthyroidism (except in pregnant patients during the first trimester).

In treatment, low doses of methimazole are usually sufficient.

Possible side effects of methimazole include neutropenia , abnormal liver enzymes (cholestatic hepatitis) and rash.

Methimazole should not be used in the first trimester of pregnancy.

If used during the first trimester of pregnancy, large doses of methimazole can cause skin aplasia and esophageal atresia or choanae.

Therefore, PTU is the preferred thionamide for patients in their first trimester of pregnancy.

However, pregnant patients rarely need treatment with thionamides.

Once patients with SH begin therapy with thionamide, their laboratory studies (eg, complete blood count [CBC], complete metabolic profile, FT4, TT3 or FT3 and TSH) should be routinely monitored to evaluate changes in thyroid function tests and possible side effects.

After the patient becomes euthyroid, it would be reasonable to decrease or discontinue treatment with thionamides to assess whether the SH has resolved.

The measurement of thyroid antibodies and thyroid stimulating immunoglobulins may also be useful in predicting remission.

The other therapeutic option for patients with SH due to Graves’ disease is radioactive iodine therapy. It is more definitive than thionamide therapy.

The dose of radioactive iodine can be calculated from a 24-hour radioactive iodine uptake and an exploration of the thyroid gland.

Once the dose is administered, the patient can take between 2 and 3 months to become euthyroid.

In most cases, patients eventually become hypothyroid and require thyroid hormone supplements, so it is necessary to talk to the patient before therapy.

Patients who have the disease due to a nodular disease, either multinodular goiter or autonomous solitary nodule, are good candidates for radioactive iodine therapy.

Radioiodine therapy is preferred because nodular disease tends to be persistent, which makes definitive therapy beneficial.

In addition, the vast majority of patients with nodular goiter have a resolution of their hyperthyroidism after a dose of radioactive iodine therapy.

The possibility of thyroid cancer should be ruled out by a fine-needle aspiration biopsy of hypofunctioning nodules.

If the nodular thyroid is very large, definitive thyroid surgery remains an option.

As mentioned above, pregnant patients have different normal reference ranges for TSH depending on the trimester.

The reference ranges must be provided by individual laboratories.

If they are not provided, then it is reasonable to use the following:

  • Reference range of the first trimester for TSH: 0.1-2.5 mIU / L.
  • Second Trimester Reference Range for TSH: 0.2-3.0 mIU / L.
  • Reference range of the third quarter for TSH: 0.3-3.0 mIU / L.

In addition, pregnant patients also tend to have a slightly elevated or high normal T4 index and total T3 levels due to physiological changes.

Because of these alterations in thyroid function tests, it is unusual for pregnant patients to be diagnosed with this disease.

If you have laboratory and clinical findings suggestive of SH and symptoms of SH, then it is reasonable to begin treatment with low doses of beta-blockers.

Again, not all patients with subclinical hyperthyroidism require treatment.

The decision to treat and how to treat is a choice that must be made in collaboration with the patient.

Ultimately, the most important step in treatment is to monitor the transition to overt hyperthyroidism, which occurs in approximately 0.5-1% of cases.

In patients with overt hyperthyroidism, treatment is necessary.