Thyroid Testing: An overview

The thyroid. It's an endocrine gland in your neck, meaning that it produces chemicals that can have long-term effects on many bodily functions around the body, such as increased or decreased metabolism.

They thyroid: nature's bowtie

Generally, when a doctor suspects some kind of thyroid issues, they order up a thyroid function order set. Sometimes this just means a TSH. If that TSH is abnormal, other tests will be ordered.

Get to Know the Thyroid Tests

TSH (Thyroid Stimulating Hormone)

TSH testing is the cornerstone for evaluating thyroid function, but it can be misunderstood without proper clinical context. A slightly elevated TSH does not always mean a patient requires thyroid hormone replacement. Subclinical hypothyroidism, where TSH is elevated but free T4 levels are normal and the patient is asymptomatic, often requires a nuanced decision regarding treatment. Similarly, transient TSH elevations can occur during illness, following recovery from a non-thyroidal illness ("euthyroid sick syndrome"), or even due to laboratory variability. Overinterpretation can lead to lifelong, unnecessary thyroid hormone therapy.

TSH does not come from the thyroid gland. It is produced in the pituitary gland (located in the brain).

T4 and Free T4 Testing

T4, or thyroxine, is one of the primary hormones produced by the thyroid gland. It circulates in the bloodstream in two forms: bound to proteins and unbound, or "free." Total T4 measures both the bound and unbound hormone, while Free T4 specifically measures the small fraction that is unbound and biologically active. Understanding the distinction between these two forms is critical because only Free T4 is available to enter cells and exert metabolic effects.

Total T4 testing provides an overview of the body's total thyroxine content but can be misleading if there are abnormalities in the proteins that bind thyroid hormones, such as thyroxine-binding globulin (TBG). Changes in TBG levels can occur due to pregnancy, estrogen therapy, liver disease, or nephrotic syndrome, thus altering Total T4 levels without truly reflecting thyroid function.

Free T4 testing has become the preferred method for assessing thyroid hormone status because it directly measures the active hormone without interference from protein-binding abnormalities. It is particularly useful in diagnosing and monitoring primary hypothyroidism and hyperthyroidism. Low Free T4 levels in the presence of an elevated thyroid-stimulating hormone (TSH) indicate hypothyroidism, while elevated Free T4 levels with a suppressed TSH suggest hyperthyroidism.

In clinical practice, Free T4 is often ordered alongside TSH for a more accurate picture of thyroid function. However, interpreting T4 and Free T4 levels requires context, including medication use, critical illness, and lab-specific reference ranges. Conditions like non-thyroidal illness syndrome, certain medications like corticosteroids, and severe systemic disease can alter Free T4 without indicating true thyroid dysfunction, underscoring the importance of correlating laboratory findings with clinical presentation.

T3 Testing

Triiodothyronine (T3) is a potent thyroid hormone that plays a vital role in regulating the body's metabolism. Although it exists in smaller quantities compared to thyroxine (T4), T3 is significantly more active at the cellular level. T3 circulates in two forms: bound to proteins and free. Total T3 testing measures both the protein-bound and free fractions, while Free T3 testing isolates the biologically active, unbound hormone.

T3 testing is typically not the first-line test for evaluating general thyroid function. Instead, it is most valuable when hyperthyroidism is suspected but the T4 level is normal. Some patients, particularly those with early or mild Graves’ disease, may exhibit elevated T3 levels while their T4 remains within the normal range, a condition known as "T3 toxicosis." In such cases, measuring T3 helps to avoid missing a diagnosis that T4 and TSH alone might not reveal.

Interpretation of T3 levels must be approached carefully. Factors such as malnutrition, liver disease, and critical illness can lower Total T3 levels without indicating true hypothyroidism, a phenomenon known as "euthyroid sick syndrome." Furthermore, alterations in thyroid hormone-binding proteins can skew Total T3 results, making Free T3 a more reliable marker in certain clinical contexts.

Routine use of T3 testing in the evaluation of hypothyroidism is generally not recommended, as T3 levels can remain within normal limits even when T4 and TSH are clearly abnormal. For patients being treated with thyroid hormone replacement, T3 testing is sometimes used to fine-tune therapy, especially when symptoms persist despite normalized TSH and T4.

Overall, T3 testing serves as a focused tool in specific diagnostic scenarios, particularly for detecting subtle forms of hyperthyroidism, but it must always be interpreted in conjunction with TSH, T4, and clinical findings for the results to be meaningful.

Thyroid (note: not to scale)

Conditions Associated with High Thyroid Function

High thyroid function, often referred to as thyrotoxicosis, can arise from a variety of diseases and physiologic states. The overproduction or release of thyroid hormones—T3 and T4—can result in symptoms such as weight loss, tachycardia, heat intolerance, anxiety, and tremors. However, not all causes of thyrotoxicosis stem from primary overactivity of the thyroid gland itself. Understanding the various etiologies is crucial for appropriate diagnosis and management. Here goes:

Graves’ Disease

Graves’ disease is the most common cause of hyperthyroidism. It is an autoimmune condition in which thyroid-stimulating immunoglobulins (TSIs) bind to and activate the TSH receptor, leading to uncontrolled production of thyroid hormones. Clinical features often include diffuse goiter, ophthalmopathy (such as exophthalmos), and pretibial myxedema.

Toxic Multinodular Goiter

In toxic multinodular goiter, multiple autonomous thyroid nodules produce excess thyroid hormone independently of TSH regulation. This condition is more prevalent in older adults and in regions where iodine deficiency is or was historically common.

Toxic Adenoma

A toxic adenoma is a single hyperfunctioning nodule within the thyroid that produces excess thyroid hormone. These nodules often suppress the rest of the thyroid gland's activity, leading to an isolated source of hyperthyroidism.

Thyroiditis (Subacute, Silent, and Postpartum)

Inflammatory processes can damage thyroid follicles, causing the unregulated release of preformed thyroid hormones into the circulation. Subacute (de Quervain’s) thyroiditis typically follows a viral illness and presents with a tender, painful thyroid gland. Silent thyroiditis and postpartum thyroiditis are painless variants and are thought to be autoimmune in nature. In these cases, hyperthyroidism is often transient and can be followed by a hypothyroid phase.

Excessive Iodine Intake (Jod-Basedow Phenomenon)

Excess iodine can trigger hyperthyroidism, especially in individuals with underlying nodular thyroid disease or latent Graves’ disease. This phenomenon is often observed after exposure to iodine-rich contrast agents or medications like amiodarone.

Exogenous Thyroid Hormone Intake

Taking excessive doses of thyroid hormone, either intentionally (as in factitious thyrotoxicosis) or unintentionally (due to dosing errors), can lead to biochemical and clinical hyperthyroidism. Laboratory findings in such cases often show suppressed TSH with elevated T3 and T4, but imaging studies reveal low thyroid uptake because the gland itself is not overproducing hormone.

Struma Ovarii

Struma ovarii is a rare form of ovarian teratoma composed predominantly of thyroid tissue, which can produce thyroid hormones and lead to hyperthyroidism. Diagnosis typically requires high suspicion and imaging, as the thyroid gland in the neck is not responsible for hormone overproduction in this case.

TSH-Secreting Pituitary Adenoma

In rare cases, a pituitary adenoma secreting excessive TSH can cause secondary hyperthyroidism. Laboratory findings include elevated TSH in the presence of elevated free T4 and T3, a combination not typically seen in primary thyroid disorders.

Hydatidiform Mole or Choriocarcinoma

Some forms of gestational trophoblastic disease, such as hydatidiform mole and choriocarcinoma, produce high levels of human chorionic gonadotropin (hCG). Because hCG can weakly stimulate the TSH receptor, these conditions can occasionally cause hyperthyroidism.

Familial Non-Autoimmune Hyperthyroidism

This is a very rare, inherited condition where activating mutations of the TSH receptor cause constitutive stimulation of the thyroid gland, leading to persistent hyperthyroidism without autoimmune involvement.

See the resemblance?

Conditions Associated with Low Thyroid Function

Low thyroid function, or hypothyroidism, is a clinical state characterized by deficient production or action of thyroid hormones. The deficiency leads to a general slowing of metabolic processes, and patients often present with fatigue, weight gain, cold intolerance, bradycardia, constipation, and depression. Just like hyperthyroidism, hypothyroidism can arise from diverse causes affecting different levels of the thyroid axis, including the thyroid gland itself, the pituitary gland, and the hypothalamus. Here goes:

Hashimoto’s Thyroiditis

Hashimoto’s thyroiditis is the most common cause of primary hypothyroidism in iodine-sufficient regions. It is an autoimmune condition where antibodies such as anti-thyroid peroxidase (TPO) and anti-thyroglobulin antibodies gradually destroy thyroid tissue, leading to progressive loss of thyroid function. Over time, patients may transition from an early phase of normal or slightly elevated TSH to overt hypothyroidism.

Iatrogenic Hypothyroidism

Medical interventions are a frequent cause of hypothyroidism. Thyroidectomy, whether partial or total, almost always results in hypothyroidism if sufficient thyroid tissue is removed. Similarly, radioactive iodine (RAI) therapy for hyperthyroidism or thyroid cancer can ablate thyroid tissue and lead to permanent hypothyroidism. External radiation therapy to the head and neck for non-thyroid cancers can also damage the thyroid.

Medications Inducing Hypothyroidism

Certain medications are well known to interfere with thyroid hormone production. Amiodarone, a highly iodine-rich antiarrhythmic drug, can block thyroid hormone synthesis. Lithium, used for mood stabilization, can impair thyroid hormone release. Other agents such as interferon-alpha and tyrosine kinase inhibitors may also lead to hypothyroidism.

Congenital Hypothyroidism

Congenital hypothyroidism occurs when newborns are born without a fully developed thyroid gland (thyroid agenesis or dysgenesis) or have defects in thyroid hormone production (dyshormonogenesis). Early diagnosis and treatment are critical to prevent irreversible intellectual disability and developmental delays, which is why newborn screening programs universally test for TSH or T4 levels.

Secondary Hypothyroidism (Pituitary Dysfunction)

In secondary hypothyroidism, the thyroid gland itself is healthy but fails to receive adequate stimulation due to pituitary dysfunction. Tumors such as pituitary adenomas, surgical damage, radiation, or infiltrative diseases affecting the pituitary can impair TSH production, leading to reduced thyroid hormone levels. Unlike primary hypothyroidism, TSH is low or inappropriately normal rather than elevated.

Tertiary Hypothyroidism (Hypothalamic Dysfunction)

Tertiary hypothyroidism is even rarer and results from hypothalamic dysfunction where there is insufficient production of thyrotropin-releasing hormone (TRH). This leads to downstream decreases in TSH and thyroid hormone. Causes include hypothalamic tumors, trauma, or congenital defects.

Severe Iodine Deficiency

Although rare in developed countries due to iodized salt, iodine deficiency remains a leading cause of hypothyroidism worldwide. Iodine is essential for the synthesis of thyroid hormones, and insufficient intake leads to reduced hormone production, often accompanied by goiter formation as the gland attempts to compensate.

Postpartum Thyroiditis

In some women, autoimmune thyroid dysfunction can occur after delivery. Postpartum thyroiditis often follows a biphasic course with an initial thyrotoxic phase, followed by hypothyroidism. While some patients return to euthyroid status, others develop permanent hypothyroidism.

Silent or Painless Thyroiditis

Silent thyroiditis is a form of autoimmune thyroid inflammation that can also result in transient hypothyroidism following an initial hyperthyroid phase. Many patients recover full thyroid function, but a subset may progress to permanent hypothyroidism.

Infiltrative Diseases

Conditions such as sarcoidosis, amyloidosis, and hemochromatosis can infiltrate and damage thyroid tissue or the pituitary gland, resulting in hypothyroidism. Although rare, these causes should be considered, especially when hypothyroidism is part of a broader pattern of systemic disease.

Resistance to Thyroid Hormone

Resistance to thyroid hormone is a rare genetic condition in which the body's tissues are less sensitive to the effects of thyroid hormones. This paradoxically can present with elevated thyroid hormone levels and non-suppressed TSH but clinical features that resemble hypothyroidism in some cases.