Reverse T3 and T3 Uptake: Diagnostic Markers and Clinical Significance

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

Contributors: Hailey Chin, Vivi Chador, Amer Džanković



Reverse 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). The majority of T4 must be converted to T3 so it can 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. Reverse T3 is a thyroid hormone which blocks the conversion of T4 to T3. Elevated levels of reverse T3 can indicate thyroid dysfunction and other serious diseases associated with insufficient blood oxygenation.



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.





T3 Uptake (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 must be converted to free T3 so it can 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. T3 uptake estimates how much T3 is in the blood and available to enter cells. Abnormally low T3 uptake levels can indicate underproduction of thyroid hormones, poor conversion of T4 to T3 in the liver, abnormalities with proteins bound to T3, and minimal availability of Free T3 to enter cells. Abnormally high T3 uptake levels can indicate an increased demand for free T3 by cells linked to an organ dysfunction unrelated to the endocrine system. Over time, abnormal T3 uptake levels increase the risk for autoimmune diseases, diabetes, cancer, cardiovascular disease, and kidney failure. 



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 help with digestion, energy production, and other vital functions. The most active hormone is T3, while reverse T3 (rT3) controls T3 levels but has little activity.

A test called T3 uptake measures how much T3 binds to a protein (TBG) and how well it enters cells for energy. Doctors use thyroid tests, including TSH, T4, T3, rT3, and T3 uptake, to assess thyroid health. Results depend on factors like age, gender, medications, and symptoms.

  • High rT3: May mean less T3 is produced, but more T3 enters cells.

  • Low rT3: May mean more T3 is produced, but less enters cells.

Thyroid problems can cause weight gain, high blood sugar, mood issues, and faster aging. Treatment may involve medications and lifestyle changes. Regular testing helps prevent serious health issues and keeps your thyroid healthy.


What are Reverse T3 (rT3) and T3 Uptake Tests? 


Reverse T3 (rT3) and T3 uptake tests are part of a group of thyroid tests used to diagnose and manage thyroid and other health problems.

rT3 is a version of the thyroid hormone T3, but it doesn’t have any major biological function. It’s made when the thyroid hormone T4 is processed in a way that prevents it from becoming active T3. Since T3 is the most active thyroid hormone, the rT3 test helps measure how much T3 the thyroid is producing.

The T3 uptake test shows how much thyroid hormone in the blood is free (not attached to proteins) and available for use. Most T4, an inactive hormone, is turned into T3 by an enzyme and nutrients. T3 then attaches to receptors in organs like the liver, brain, and muscles, helping cells absorb oxygen and glucose. This process provides energy and supports important body functions, such as maintaining body temperature.

             


Triiodothyronine (T3)’s Role in the Body

From before birth through every stage of life, the thyroid hormone T3 (triiodothyronine) plays a key role in telling organs how to function. T3 helps control digestion, breaking down food into nutrients and energy while managing waste removal. It regulates blood sugar, fat, and protein levels, energy use, body temperature, and metabolism.

T3 also affects the heart, helping it respond to nerve signals and beat properly. In the brain, T3 supports nerve growth, connections, and protective coatings around nerves. It also helps build and break down bone, keeping bones strong and healthy.

T3 is involved in making skin cells, red blood cells, and hormones from other glands. It produces reactive oxygen species (ROS), a type of energy that supports cell growth and repair. But too much ROS can harm cells, disrupt metabolism, and damage DNA. T3 helps balance ROS to control inflammation and keep the body’s organs working properly.

In the reproductive system, T3 supports uterine cell growth and ovarian functions. When thyroid hormones are out of balance, it can lead to infertility, organ disorders, autoimmune diseases, and even cancer.

 

The Formation of the Thyroid Hormones T4, T3, and Reverse T3                      

Thyroid hormones, T4 (inactive) and T3 (active), are made in the thyroid gland and regulated by a feedback loop. Reverse T3 (rT3) is another inactive form of T4. Iodine, found in food, is essential for making these hormones. T4 contains 65% iodine by weight, and T3 contains 58%.

Steps in Thyroid Hormone Production:

  1. Iodine Absorption and Transport:
    Iodine from food is absorbed in the small intestine, enters the bloodstream as iodide, and moves to the thyroid gland.

  2. Iodide Uptake:
    A protein called NIS moves iodide into thyroid cells.

  3. Hormone Formation:
    An enzyme, thyroid peroxidase (TPO), uses iodide to form iodine, which attaches to the protein thyroglobulin (Tg). This creates T4 (90–95%) and T3 (5–10%).

  4. Hormone Release:
    During inflammation or repair, the liver makes transporter proteins that help release thyroid hormones into the bloodstream.

  5. Hormone Transport:
    About 99% of T4 and T3 bind to transport proteins like thyroid-binding globulin (TBG). Only 1% remains free and active.

  6. Hormone Activation and Conversion:
    In organs, enzymes convert T4 to T3 (active) or rT3 (inactive):

    • DIO1: Converts T4 to T3 in the liver, kidneys, and muscles.

    • DIO2: Converts T4 to T3 in the brain, pituitary gland, and fat tissue.

    • DIO3: Converts T4 to rT3 in the placenta, brain, and skin to lower metabolic activity.

  7. Hormone Breakdown and Excretion:
    After use, T3 is broken down. Iodide is either stored in the thyroid or excreted in urine. TBG carries hormone remnants to the liver, where they’re made water-soluble and excreted in stool or urine.

 

Figure 1: Iodide from food is absorbed in the small intestine and enters the blood. The thyroid pulls in iodide and turns it into iodine, which combines with a protein to make thyroid hormones: mostly T4 and some T3. The brain controls this process. When needed, it signals the thyroid to release more hormones. T4 is mostly inactive until it’s converted to active T3 or inactive reverse T3 in the body. Active T3 helps control metabolism. Unused iodine is recycled or removed from the body through urine or stool.


Regulation of Reverse T3 and T3 Uptake Blood Levels                                        

The hypothalamic-pituitary gland-adrenal gland (HPA) axis controls the secretion of thyroid hormones and T3 uptake by a tightly regulated negative feedback loop.

                                   

Figure 2: The HPA axis controls thyroid hormone release. High levels of T3 or T4 (hyperthyroidism) lower TRH and TSH production, which reduces thyroid hormone release. Low T4 levels also decrease reverse T3 (rT3) production. More thyroid-binding globulin (TBG) binds with hormones, allowing more free T3 to enter the body, which shows as a high T3 uptake.



Low T3 or T4 levels (hypothyroidism) cause higher TRH and TSH production, breaking down thyroglobulin (Tg) and releasing more thyroid hormones. The thyroid stores less iodine and hormones. When thyroid hormones bind to TBG, less free T3 can enter tissues, shown by low T3 uptake in the blood. The liver, kidneys, muscles, brain, and brown fat convert more T4 to active T3, producing heat (ROS). Neurons release somatostatin to reduce heat and lower T3 activity, shown by high rT3 levels.

Two main factors control thyroid function:

  1. Iodine Supply: Too much or too little iodine affects hormone production. Low iodine increases TRH and TSH, causing the thyroid to enlarge and release more hormones. High iodine reduces hormone production by blocking necessary reactions in the thyroid.

  2. Blood Glucose and Liver Function: The liver regulates metabolism and thyroid hormones. Liver damage disrupts energy use and hormone production. With liver damage, the body uses glucose for energy, breaking down less fat and producing less heat (ROS). Muscle also breaks down more protein.

Glucose binds to Tg in the thyroid, releasing thyroid hormones into the bloodstream to regulate energy. However, high blood sugar, fat, and inflammation can cause insulin resistance, damaging cells and reducing thyroid function. Chronic inflammation can worsen thyroid issues and lead to conditions like atherosclerosis.

Somatostatin from the hypothalamus slows TSH and hormone production, limiting thyroid hormone release and storage. It also reduces stomach acid and enzyme secretion, slowing digestion and nutrient absorption, which affects thyroid hormone production. The kidneys also release proteins and nutrients in urine, further impacting thyroid function.


                                   

                    


Figure 3: Blood glucose helps produce thyroid and other hormones. The pituitary gland makes hormones like corticotropin, growth hormone, and prolactin (PRL). These hormones, except PRL, trigger other glands to release thyroid hormones and break down stored glucose. This boosts energy and supports body functions by increasing glucose and oxygen in the body.


Clinical Significance of Abnormal Reverse T3 and T3 Uptake Blood Levels


Abnormal rT3 and T3 uptake blood levels can signal thyroid problems that affect energy use and increase free radicals (ROS), especially during stress or illness. ROS can damage cells, DNA, and metabolism, harming organs and gut health. Extra heat from ROS raises blood sugar and inflammation, which harms the body. Since thyroid hormone production relies on organs like the digestive system, pancreas, and brain, thyroid issues can be caused by problems in these areas. Hormonal changes from pregnancy, menopause, or treatments like radiation can worsen thyroid problems. Long-term inflammation can cause symptoms like:

  • Eye issues (bulging eyes, double vision, pain)

  • Enlarged thyroid (goiter)

  • Weight changes

  • Irregular heart rate and blood pressure

  • Temperature intolerance

  • Fatigue

  • Menstrual and reproductive issues, including infertility

  • Skin problems

  • Digestive issues (diarrhea, constipation)

  • Brittle bones

  • Tumors or cancers

Thyroid problems can lead to a wide range of health issues.


                

Figure 4 10: Thyroid hormones affect how the body processes glucose, fat, and proteins, and they also trigger thyroid-stimulating antibodies that change hormone production. Gonadotrophs release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which help produce sex hormones like estrogen, testosterone, and progesterone. Lactotrophs release prolactin, which influences milk production, fat storage, insulin, and fluid balance. Oxytocin, also from lactotrophs, affects fertility, mood, and bonding. In hyperthyroidism, SHBG increases, reducing testosterone levels and leading to higher LH, FSH, and oxytocin, but lower prolactin. This raises estrogen and progesterone levels but reduces thyroid hormone production. In hypothyroidism, increased GnRH causes the pituitary to reduce LH, FSH, and oxytocin, while prolactin rises, lowering estrogen and progesterone and reducing thyroid hormone release.


Hypothyroidism: Low Reverse T3 (rT3) and High T3 Uptake Blood Levels

Hypothyroidism lowers thyroid hormone production, affects protein binding in the blood, and reduces free T3 in tissues. This is seen in low rT3 and high T3 uptake levels in blood tests.

There are three types:

  1. Primary Hypothyroidism: Problem starts in the thyroid with high TSH but low thyroid hormone.

  2. Central Hypothyroidism: Problem in the hypothalamus or pituitary gland stops thyroid stimulation.

  3. Peripheral Hypothyroidism: Other endocrine glands cause thyroid issues.

The most common form is acquired primary hypothyroidism, caused by inflammation that misdirects white blood cells and affects thyroid hormone production. This includes Graves’ disease and Hashimoto’s thyroiditis.

In overt primary hypothyroidism, low free T4 and low hormone binding increase free T3, speeding up metabolism and creating ROS, which damages cells. It also lowers T4 conversion to inactive T3.

In subclinical hypothyroidism, T4 levels are normal, but more T4 turns into rT3, raising rT3 levels.

All forms reduce fat and protein metabolism, cause excess fat in blood vessels (atherosclerosis), fat tissues (obesity), and organs. This leads to inflammation, cell damage, and increases the risk of autoimmune diseases, infections, and organ failure.


Hyperthyroidism: High Reverse T3 (rT3) and Low T3 Uptake Blood Levels

There are three types of hyperthyroidism, all linked to low TSH and high or normal thyroid hormone levels. One type involves thyroid hormones binding to a protein (TBG), lowering active T3. Another type causes T4 to turn into reverse T3, which builds up.

Overt hyperthyroidism occurs when the thyroid overproduces hormones, raising iodine uptake. Thyrotoxicosis happens when other tissues release hormones, lowering iodine uptake. Subclinical hyperthyroidism has normal T3 and T4 levels but varying reverse T3 and T3 uptake. All types increase T3 use in tissues, raising heat. Long-term hyperthyroidism can lead to fat loss, muscle breakdown, lower cholesterol, and eventually hypothyroidism.


Prevalence and Statistics of Abnormal Thyroid Function Tests

Thyroid problems are common, especially in women during pregnancy, after childbirth, and menopause. Women are more likely to develop thyroid issues like hypothyroidism and hyperthyroidism, which can also lead to autoimmune diseases like diabetes, arthritis, lupus, and cancers.

About 5 to 10 percent of women over 60 in the U.S. have thyroid problems and take synthetic hormones, but many still have imbalances. The National Health and Nutrition Examination Survey found 4.6 percent of people have hypothyroidism, with 0.4 percent severe and 9 percent mild. In women over 75, more than 20 percent are affected. In Europe, hypothyroidism affects 226 people per 100,000 annually. Hyperthyroidism affects 0.5 to 0.8 percent in Europe and 1.3 percent in the U.S., with higher rates in white people and areas with low iodine.


Conclusion

New research shows that T3 uptake and reverse T3 can be useful for diagnosing thyroid problems and guiding treatment for various health issues. When looking at lab results, it’s important to consider a person’s full medical history, including age, gender, ethnicity, medications, and other health conditions that may affect thyroid hormone levels and function. Treating thyroid issues usually involves lifestyle changes, managing side effects from medications, reducing stress, changing the diet, using medications, and taking supplements. Proper thyroid management is crucial to prevent other health problems related to low energy and hormonal imbalances.



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