The Journal of Clinical Endocrinology & Metabolism 2005; 90(12):6403–6409
Annewieke W. van den Beld, Theo J. Visser, Richard A. Feelders, Diederick E. Grobbee, and Steven W. J. Lamberts Department of Internal Medicine , University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
This study of 403 men investigated the association between TSH, T4, free T4, T3, TBG and reverse T3 (rT3) and parameters of physical functioning. This study demonstrates that TSH and/or T4 levels are poor indicators of tissue thyroid levels and thus, in a large percentage of patients, cannot be used to determine whether a person is euthyroid (normal thyroid levels) at the tissue level. In fact, T4 levels had a negative correlation with tissue thyroid levels (higher T4 levels were associated with decreased peripheral conversion of T4, low T3 levels and high rT3). This study demonstrates that rT3 inversely correlates with physical performance scores and that the T3/rT3 ratio is currently the best indicator of tissue levels of thyroid.
This study showed that increased T4 and RT3 levels and decreased T3 levels are associated with hypothyroidism at the tissue level with diminished physicial functioning and the presence of a catabolic state (breakdown of the body). This study adds to the mounting evidence that giving T4 preparations such as Synthroid and Levoxyl are inadequate for restoring tissue euthyroidism and that a normal TSH cannot be relied upon as as an indication of euthyroidism, as it has a very low sensitivity and specificity for hypothyroidism. This poor sensitivity and specificity is further decreased with the presence of one or more systemic illnesses, including diabetes, heart disease, hypertension, systemic inflammation, asthma, CFS, fibromyalgia, rheumatoid arthritis, lupus, insulin resistance, obesity, chronic stress and almost any other systemic illness.
Low T3 syndrome, with low T3 and high reverse T3, is almost always missed when using standard thyroid function tests, as the T3 level is often in the low normal range and reverse T3 is the high normal range, again making the T3/rT3 ratio the most useful marker for tissue hypothyroidism and as a marker of diminished cellular functioning. The authors of this study conclude, “Subjects with low T3 and high reverse T3 had the lowest PPS [PPS is a scoring system that takes into account normal activities of daily living and is a measure of physical and mental functioning]…Furthermore, subjects with high reverse T3 concentrations had worse physical performance scores and lower grip strength. These high rT3 levels were accompanied by high FT4 levels (within the normal range)…These changes in thyroid hormone concentrations may be explained by a decrease in peripheral thyroid hormone metabolism… Increasing rT3 levels could then represent a catabolic state, eventually proceeding an overt low T3 syndrome.”
This study demonstrates that TSH and T4 levels are poor measures of tissue thyroid levels, TSH and T4 levels should not be relied upon to determine the tissue thyroid levels and that the best estimate of the tissue thyroid effect is the rT3 level and the T3/rT3 ratio
Reverse T3 (rT3)
Thyroid hormones are essential in maintaining and regulating the body’s metabolism. Triiodthyronine (T3) is the most active of the thyroid hormones. Approximately 85% of circulating T3 is produced by monodeiodination of thyroxine (T4) in tissues such as liver, muscle and kidney. Selenium and zinc are required for this process.
Reverse T3 (rT3) is an inactive form of T3 that is produced in the body particularly during periods of stress. rT3 differs from T3 in that the missing deiodinated iodine is from the inner ring of the thyroxine molecule compared with outer ring on T3. rT3 is measured by a blood test.
Under normal conditions T4 will convert to both T3 and rT3 continually and the body eliminates rT3 quickly.
Under certain conditions, more rT3 is produced and the desirable conversion of T4 to T3 decreases. This occurs during fasting, starvation, illness such as liver disease and during times of increased stress.
This becomes a vicious cycle as rT3 competes with T3 as a substrate for the 5-deiodinase enzyme. This inhibits the conversion of T4 to T3, with more T4 being converted to more rT3.
An increased production of rT3 is often seen in patients with disorders such as fibromyalgia, chronic fatigue sydrome (CFS), Wilson's Thyroid Syndrome and stress. Measurement of rT3 is also valuable in identifying sick euthyroid syndrome where active T3 is within normal range and rT3 is elevated.
T4 (thyroxine) and T3 (triiodothyronine) are important thyroid hormones. Yet, even with normal levels of T3 and T4, it’s possible to still have the symptoms of hypothyroidism, which may be due to excessive production of rT3 in the body. Reverse T3 competes with T3 at important binding sites, which is a problem because rT3 is inactive and therefore not as beneficial as T3.
It’s normal for your body to produce some rT3. In fact, the liver constantly converts T4 to rT3 to get rid of excessive amounts of T4. Normally, about 40 percent of T4 is converted to T3 and 60 percent is converted to rT3.2
However, the production of rT3 can rise after emotional or physical stress, after you get the flu, after surgery, car accidents or any acute injury, diabetes, aging or even being on drugs like beta blockers and amiodarone. If you’re under chronic stress and your adrenal glands are producing too much cortisol, your production of rT3 may skyrocket.
When looking at thyroid test results, it’s not necessarily the levels of reverse T3 alone that are important—although if rT3 is high that’s a signal something is wrong. But it’s really the ratio between rT3 and free T3 that tells the full story. To calculate the ratio, divide the free T3 by the reverse T3 (free T3 ÷ rT3). Holistic providers often suggest tha the ratio should be 20 or larger. Anything lower indicates potential cause for concern.
It’s also important to test for free T3 and free T4 rather than total T3 and total T4. This is because total T3 and total T4 doesn’t tell you how much of the T3 and T4 are doing their proper jobs in the body. In other words, total T3 and total T4 can’t show you whether your body is using these two thyroid hormones effectively.
Lastly, your doctor may also want to do an ultrasound on your thyroid, especially if it’s enlarged. In addition, if there is concern of autoimmune thyroid disease, ordering a thyroid peroxidase antibody and anti-thyroglobulin antibody level is a common next step.
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