TSH, Total T3, Total T4, Free T3, and Free T4: Diagnostic Markers and Clinical Significance

Authors: Payal Bhandari, M.D., Emilia Feria

Contributors: Hailey Chin, Vivi Chador, Amer Džanković



Thyroid-Stimulating Hormone (TSH) 


TSH (thyroid-stimulating hormone) is produced in the pituitary gland and signals to the thyroid to produce thyroid hormone T4 (thyroxine) and T3 (triiodothyronine), 95% of which is T4 and 5% is T3. The majority of T4 and T3 in the blood are bound to protein and must be converted to free T3 to enter cells and regulate a myriad of essential functions, ranging from energy production, fat metabolism, body temperature, muscle strength, digestion, skin, immune, mental and psychological health. When TSH levels are low, it can indicate overproduction of thyroid hormones (also called hyperthyroidism), and is associated with an overstimulated endocrine system. When TSH levels are high (also called hypothyroidism), it can indicate decreased production of thyroid hormones and is associated with an exhausted endocrine system and compromised immune and digestive systems. Over time, abnormal TSH levels can increase the risk of autoimmune diseases, diabetes, cancer, cardiovascular disease, chronic infections, and many other chronic diseases.



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.





Total T3 (Triiodothyronine)


TSH (thyroid-stimulating hormone) is produced in the pituitary gland and signals to the thyroid to produce thyroid hormone T4 (thyroxine) and T3 (triiodothyronine), 95% of which is T4 and 5% is T3. The majority of T4 and T3 in the blood are bound to protein and must be converted to free T3 to enter cells and regulate a myriad of essential functions, ranging from energy production, fat metabolism, body temperature, muscle strength, digestion, skin, immune, mental and psychological health. Abnormal Total T3 levels may indicate issues linked to conversion of T4 to T3 in the liver and abnormalities with proteins bound to T4. Hormonal drugs (e.g., estrogen, progesterone, testosterone), thyroid medications, steroids, and some cancer drugs can adversely affect total T3 levels. 



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.





Total T4 (Thyroxine)


TSH (thyroid-stimulating hormone) is produced in the pituitary gland and signals to the thyroid to produce thyroid hormone T4 (thyroxine) and T3 (triiodothyronine), 95% of which is T4 and 5% is T3. The majority of T4 and T3 in the blood are bound to protein and must be converted to free T3 to enter cells and regulate a myriad of essential functions, ranging from energy production, fat metabolism, body temperature, muscle strength, digestion, skin, immune, mental and psychological health. T4 and TSH levels often move inversely: when one rises, the other falls. For example, low T4 levels often cause TSH levels to rise and signal underproduction of thyroid hormones (also called hypothyroidism). High T4 levels often cause TSH to drop and signifies overproduction of thyroid hormone (also called hyperthyroidism). Hormonal drugs (e.g., estrogen, progesterone, testosterone), thyroid medications, steroids, and some cancer drugs can adversely affect total T4 levels. 



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.





Free T3 (Triiodothyronine)


TSH (thyroid-stimulating hormone) is produced in the pituitary gland and signals to the thyroid to produce thyroid hormone T4 (thyroxine) and T3 (triiodothyronine), 95% of which is T4 and 5% is T3. The majority of T4 and T3 in the blood are bound to protein and must be converted to free T3 to enter cells and regulate a myriad of essential functions, ranging from energy production, fat metabolism, body temperature, muscle strength, digestion, skin, immune, mental and psychological health. Abnormal Free T3 levels can indicate issues linked to conversion of T4 to T3 and abnormalities with proteins bound to T3.  Hormonal drugs (e.g., estrogen, progesterone, testosterone), thyroid medications, steroids, and some cancer drugs can adversely affect Free T3 levels. 



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.





Free T4 (Thyroxine)


TSH (thyroid-stimulating hormone) is produced in the pituitary gland and signals to the thyroid to produce thyroid hormone T4 (thyroxine) and T3 (triiodothyronine), 95% of which is T4 and 5% is T3. The majority of T4 and T3 in the blood are bound to protein and must be converted to free T3 to enter cells and regulate a myriad of essential functions, ranging from energy production, fat metabolism, body temperature, muscle strength, digestion, skin, immune, mental and psychological health. T4 and TSH levels often move inversely: when one rises, the other falls. For example, low T4 levels often cause TSH levels to rise and signal underproduction of thyroid hormones (also called hypothyroidism). High T4 levels often cause TSH to drop and signifies overproduction of thyroid hormone (also called hyperthyroidism). Abnormal free T4 levels may indicate issues linked to conversion of T4 to T3 in the liver and abnormalities with proteins bound to T4. Hormonal drugs (e.g., estrogen, progesterone, testosterone), thyroid medications, steroids, and some cancer drugs can adversely affect free T4 levels. 



Typical Adult Range


Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.




Key Insights


Thyroid hormones (TH) help regulate digestion, nutrient absorption, energy production, and essential body functions. Problems with TH levels can disrupt metabolism, leading to issues like insulin resistance, fat storage, muscle loss, inflammation, autoimmune diseases, mood changes, and organ damage.

A full thyroid test panel includes markers like TSH, T4, T3, and thyroid antibodies to assess thyroid function and diagnose related conditions. Here’s what key tests measure:

  • TSH: A pituitary hormone that controls thyroid hormone production.

  • Free T4 and Free T3: The active, unbound thyroid hormones in the blood.

  • Total T4 and Total T3: Both free and bound thyroid hormones.

Thyroid imbalances (e.g., high T3/T4 with low TSH in hyperthyroidism or the reverse in hypothyroidism) may not always show abnormal lab results. Subclinical thyroid issues can occur, especially with broad population ranges for normal levels.

Testing results depend on factors like age, genetics, and environment. Treatment may include medications or lifestyle changes to address the root cause. Left untreated, thyroid disorders can lead to high blood pressure, blood clots, tissue damage, and other complications. Regular monitoring is vital for overall health.


What is TSH?

Thyroid-stimulating hormone (TSH) is produced by the pituitary gland and helps control thyroid function. It consists of two parts, similar to other pituitary hormones. TSH stimulates the thyroid gland by binding to receptors on its cells. This triggers processes that help the thyroid grow, take in iodide, and release hormones like thyroxine (T4), triiodothyronine (T3), and calcitonin.


             

What are Thyroid Hormones?

Thyroid hormones, mainly thyroxine (T4) and triiodothyronine (T3), control metabolism and energy production, which are essential for the body’s functions. T4 is mostly inactive, but it gets converted into active T3, which helps cells use glucose and oxygen. This process releases heat, which is important for keeping the body warm.

T3 plays a key role in how the body digests food, absorbs nutrients, and removes waste. It also helps break down glucose, fat, and protein, affecting blood sugar, cholesterol, fat, weight, and energy use. T3 regulates body temperature and supports muscle and brain functions.

In the heart, T3 helps it respond to nerve signals and beat properly. It also promotes the growth of bones, skin, and red blood cells, while controlling bone strength and mineral levels. However, too much T3 can create harmful byproducts that damage healthy cells and DNA, leading to inflammation and problems with cell growth and repair. When thyroid function is off, it can cause a wide range of issues, like infertility, menstrual problems, sexual dysfunction, and disorders in various organs.


Thyroid Hormone Formation                      

Here’s a simpler, shorter version of the article:

Thyroid hormone production is controlled by a feedback loop. Thyroxine (T4) is converted into the active hormone triiodothyronine (T3) or the inactive reverse T3 (rT3). Dietary iodine is crucial for making thyroid hormones, with iodine making up 65% of T4 and 58% of T3. The process goes like this:

  1. Iodine from food is absorbed into the bloodstream and carried to the thyroid gland.

  2. The sodium-iodide symporter (NIS) helps iodine enter thyroid cells.

  3. An enzyme called thyroid peroxidase (TPO) turns iodine into an active form and bonds it with the amino acid tyrosine. This forms iodotyrosines (MIT and DIT), which combine to make T4 (90-95%) and T3 (5-10%).

  4. When there’s heat from inflammation, the liver makes proteins and enzymes, using glucose as energy and releasing thyroid hormones into the bloodstream.

  5. Most thyroid hormones bind to transporter proteins in the blood, while only a small amount is free.

  6. These hormones travel to organs where enzymes convert T4 to T3 or reverse T3.

  7. T3 works in the body and is eventually broken down or excreted, with waste removed through the kidneys or intestines.

 

Figure 1: Iodide from food is absorbed in the small intestine and enters the bloodstream. In the thyroid, it’s turned into iodine, which forms thyroid hormones (mainly T4, with some T3). High blood glucose and reactive oxygen species trigger the release of TRH from the hypothalamus, causing the pituitary to release TSH. TSH helps release T4 and T3 from the thyroid. T4 is converted into active T3 or inactive reverse T3 in the body. Iodine is then recycled or removed through urine, while thyroid hormones are excreted by the liver through stool or urine.


Regulation of TSH and Thyroid Hormones 

The hypothalamus-pituitary gland-adrenal gland (HPA) axis controls the secretion of thyroid hormones by a tightly regulated negative feedback loop. 


                             

Figure 2: The HPA axis controls thyroid hormone release. High T3 or T4 levels (hyperthyroidism) lower TRH and TSH, reducing thyroid hormone production. Low T3 or T4 levels (hypothyroidism) raise TRH and TSH, increasing thyroid hormone release. When thyroid hormones are low, the body converts more T4 to active T3 to generate heat. Neurons release somatostatin to turn T4 into inactive T3 (reverse T3). Calcitonin helps balance calcium levels but doesn’t affect thyroid hormone use.



The HPA axis and thyroid hormone production are controlled by two main factors:

  1. Iodine Supply: Too little or too much iodine affects thyroid hormone production. Low iodine increases TRH and TSH, causing thyroid growth (goiter) and hormone release. Too much iodine reduces thyroid hormone production by blocking necessary processes in the thyroid.

  2. Blood Glucose and Liver Health: The liver regulates metabolism and thyroid hormone production. If the liver is damaged, it disrupts energy use and hormone balance. High glucose levels lead to:

    • Increased glucose as the main energy source, producing less energy and more heat (ROS).

    • More stored fat and less fat breakdown, reducing energy supply.

    • Increased muscle breakdown for energy.

To support energy needs, glucose helps release thyroid hormones from the thyroid gland, but high blood glucose and fat levels cause inflammation. Over time, this can lead to insulin resistance, cell damage, and reduced thyroid hormone production. This results in imbalances in T4 and T3 levels.

High blood glucose triggers the release of somatostatin, which reduces TSH and thyroid hormone production. Somatostatin also slows digestion, reduces protein synthesis, and lowers the production of proteins needed for thyroid hormone function. The kidneys also lose important nutrients, further affecting hormone balance.         


                  

Figure 3: Blood glucose affects the production of several hormones, including thyroid-stimulating hormone, corticotropin, FSH, LH, growth hormone, oxytocin, ADH, and prolactin. All these hormones, except prolactin, help control glucose storage, its use for energy, and heat production in the body. Keeping these processes balanced is important for stable hormone levels and preventing excess heat.

          


Clinical Significance of Abnormal TSH and Thyroid Hormone Levels


Imbalanced thyroid hormone (TH) levels can affect energy use and increase heat production, especially during stress or illness. This heat (ROS) can damage cells, DNA, and disrupt metabolism, leading to inflammation. High glucose and inflammatory proteins can increase fat storage and harm organs.

Hormonal changes, such as pregnancy, menopause, or use of synthetic hormones, can worsen thyroid problems. Radiation treatment or thyroid surgery can also disrupt thyroid function. Chronic inflammation can affect many body systems, causing symptoms like:

  • Eye and brain swelling (bulging eyes, double vision, headaches)

  • Mood changes (anxiety, depression)

  • Thyroid enlargement (goiter)

  • Weight gain or loss

  • Irregular heart rate and blood pressure

  • Temperature sensitivity

  • Fatigue

  • Irregular periods, infertility, and sexual problems

  • Skin issues

  • Digestive problems (diarrhea/constipation)

  • Weak bones (osteoporosis)

  • Tumors and cancers in endocrine tissues and organs


Figure 4 8: Thyroid hormone imbalance affects the metabolism of glucose, fat, and proteins, and causes changes in hormone production. Gonadotrophs release hormones (LH and FSH) that control sex hormones, while lactotrophs produce prolactin, which regulates milk production, fat storage, insulin, and fluid balance. In hyperthyroidism, increased SHBG binds testosterone, lowering its effects. This raises LH, FSH, and oxytocin levels, boosting estrogen and progesterone, while reducing thyroid hormone. In hypothyroidism, this process reverses, lowering estrogen, progesterone, and thyroid hormones.

 


Hypothyroidism: High TSH and Low T3 and T4 Blood Levels

Hypothyroidism reduces thyroid hormone production and affects how the body uses it. There are three types:

  1. Primary Hypothyroidism: The thyroid gland is not producing enough hormones, but the pituitary gland releases high levels of TSH to try to compensate.

  2. Central Hypothyroidism: The problem starts in the hypothalamus or pituitary gland, affecting the signals to the thyroid.

  3. Peripheral Hypothyroidism: The issue is in other glands besides the thyroid.

The most common type is acquired primary hypothyroidism, which happens when chronic inflammation causes the immune system to attack the thyroid. There are two autoimmune thyroid diseases: Graves’ disease and Hashimoto’s thyroiditis.

Overt hypothyroidism is when thyroid hormone levels are low, and more T3 (the active form) is available to increase metabolism and free radicals. Subclinical hypothyroidism shows normal thyroid hormone levels but lower T3.

All types of hypothyroidism lead to poor fat and protein metabolism, causing fat to build up in arteries (leading to atherosclerosis), tissues (obesity), and organs like the liver and muscles. This buildup increases inflammation and cell damage, raising the risk of autoimmune diseases, infections, heart problems, and organ failure.


Hyperthyroidism: Low TSH and High T3 and T4 Blood Levels

There are three types of hyperthyroidism, all linked to low thyroid-stimulating hormone (TSH) and too much thyroid hormone:

  1. Overt Hyperthyroidism: The thyroid makes too much hormone, causing high T4 levels and increased iodine uptake.

  2. Thyrotoxicosis: Other tissues release thyroid hormones, causing low iodine uptake.

  3. Subclinical Hyperthyroidism: T3 and T4 levels are normal, but there may still be changes in thyroid activity.

In all cases, the body produces more heat (reactive oxygen species) due to increased T3 activity. Over time, this can lead to fat loss, muscle breakdown, low cholesterol, and eventually reduced thyroid hormone levels, causing hypothyroidism.


Prevalence and Statistics of Abnormal Thyroid Function Tests

Thyroid problems are common, especially in women during pregnancy, postpartum, menopause, and with age. Women are more likely to develop thyroid issues like hypothyroidism and hyperthyroidism, which can increase the risk of autoimmune diseases such as diabetes and arthritis.

Around 5 to 10 percent of women over 60 have thyroid problems and may need hormone treatment, but many experience signs of over- or under-treatment. About 4.6 percent of the U.S. population has hypothyroidism, and 9 percent have subclinical hypothyroidism, which rises to over 20 percent in women aged 75 and older. Hyperthyroidism affects 0.5 to 1.3 percent of people, more so in areas with low iodine.


Conclusion

A thyroid function panel (TSH, T4, T3) can help diagnose and guide treatment for many health conditions. Lab results should be understood in the context of a person’s age, gender, ethnicity, medications, and other health issues that affect thyroid hormone production and use. Treating thyroid problems often includes lifestyle changes, managing medication side effects, reducing stress, adjusting diet, and using medications and supplements. Proper treatment is important to prevent low energy, hormone imbalances, and damage to multiple organs.


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