Information About Thyroid Biomarkers

Today we’re going to cover the thyroid biomarkers. This will include the thyroid-stimulating hormone, also known as TSH. We’re also going to look at T3 and T4, both free and total in each case. We’ll also cover reverse T3 and investigate a new ratio, being the free/reverse T3 ratio. Also, we’re going to look at a few older markers, too, including the free thyroid index called T7. Then, we’ll move on to T3 uptake and move on to two of the most essential antibodies. Finally, we’ll investigate antithyroglobulin antibodies, thyroid peroxidase, and anti-TPO. 

In terms of TSH, it’s useful for many different reasons. First, we can use it for both the determination of hypothyroidism as well as the potential differentiation of it. It’s also effective for both hyperactive thyroid and the certainly more pathological variant of hyperthyroidism. It is, in fact, one of the more sensitive possible tests involved in blood chemistry screening when looking for primary hypothyroidism, but not as much for thyroid conversion syndrome, which we’re going to cover later in our hyperthyroid section. In cases where TSH is normal, but there’s a clinical picture suggesting hypothyroidism, it’s advisable to investigate different factors, including conversions and the like. Regarding anterior pituitary hypothalamic function, a mildly different TSH shift is usually to be expected. 

In the end, the objective is to ascertain the specific reason for a thyroid-related issue. Here, the potential condition in play is the actual thyroid gland. It’s not always other systems. As a component of your broader thyroid screening panel, you should include TSH and possibly even a handful of different thyroid biomarkers which we’re going to cover. However, for our conversation about TSH, I’d like to talk a bit about what normal TSH levels should be. Some of you might be shocked to discover that historically speaking, the higher TSH range used to be 1 up to 9. However, it’s now actually down to 4.5, which means most American labs now use a typical TSH reference range that goes from 0.4 up to 4.5.  

At this time, notable experts are suggesting the upper range be lowered down to 3, if not 2, or even lower. That’s much closer to what a handful of functional practitioners are advocating for, although in the end, many of them prefer 3 as the upper range. Again, most American labs run their typical TSH range from 0.4 up to 4.5; however, analysis done by many researchers suggest that even this range of reference isn’t especially useful. You can expect a 1.5 mean TSH level for those individuals who lack thyroid antibodies present or are not diagnosed with thyroid disease. Reviews conducted of many published findings regarding TSH levels shows that a reading higher than 2 might indicate negative health issues that are associated with a lack of thyroid hormone output. One study highlighted that individuals that have TSH levels greater than 2 also have higher odds over the next two decades of developing the overt hypothyroid disease. Other studies point out that TSH values above 1.9 are indicative of abnormal pathologies within the thyroid; in particular, these can be autoimmune attacks targeting the actual thyroid gland, and these can lead to a substantial impairment. One disturbing study pointed out how TSH values greater than 4 mean a higher risk of heart disease is prevalent, even when other established factors were corrected for. When you take all this into account, it means that the optimal physiological TSH value is probably in the range of 1.3 up to 3. Utilizing other thyroid tests with this range gives us the power to analyze the thyroid better than ever before. 

That means that the optimal range for thyroids, thanks to functional practitioners, is from 1.3 up to 3. The next logical question is what this means at a clinical level. Given how high TSH levels are often related to primary hypothyroidism, it really implies that any issues are with the actual thyroid gland. In such circumstances, TSH levels are going to be raised. Hypothyroidism is a very common condition, and unfortunately, also frequently one that escapes diagnosis. What we’re focusing on right now is the relationship of TSH to primary hypothyroidism. Low levels here could indicate anything from hyperactive thyroid up to hyperthyroidism. Levels might also be low as a result of secondary hypothyroidism, an anterior pituitary dysfunction, as well as in the case of tertiary hypothyroidism, a hypothalamic dysfunction. We cover those in our hypothyroidism section. You might even witness low TSH levels in a case we have termed heavy metal body burden. The hormone that the thyroid releases is T4, and it’s primarily bound to binding proteins like the thyroxine-binding globulin, also known as TBG. Only approximately 0.03 up to 0.05 of this is in a free form, which is why we measure both free and total, which is free and bound. At what times should you be mindful of this test? It’s frequently used to specifically rule out both hypothyroidism and hyperthyroidism both. This can happen because the hormone gets secreted directly out of the gland in such conditions, which are primarily glandular in nature. T4 is also useful in possibly detecting and/or ruling out things like autoimmune thyroiditis, primary hypothyroidism, hyperthyroid states, and Hashimoto’s and Graves’ diseases. 

It’s also helpful in maintaining proper thyroid hormone dosage levels when treating hypothyroidism. In terms of reference ranges, a common United States lab range might go from 4.5 up to 12 mcg for each deciliter. An optimal range that you want to see is anywhere from 6 up to 11.9 mcg/deciliter. You can also do a measurement of free unbound T4, which is measured in nanograms per deciliter. Functional practitioners prefer seeing from 1 up to 1.5 nanograms in each deciliter. The question now is when you’d witness elevated levels of total or free T4? 

You’ll witness elevated T4 levels in cases of hyperthyroidism, hyperactive thyroid, and patients currently on thyroxine medication or supplementation. That might be Armour Thyroid, Synthroid, or other kinds of thyroid drugs and/or supplementation. These can result in elevated total and free levels. Low levels are more likely to be witnessed in iodine deficiency, primary hypothyroidism, and secondary hypothyroidism. Our article on hypothyroidism has more information regarding all three of these. 

Moving on to T3, keep in mind that this is a thyroid molecule that has an iodine molecule removed via tyrosyl residues. That means that ‘T3’ is letting us know that only three iodines are present. T3 is widely considered to be one of the more metabolically active members of the thyroid hormone family. Estimates suggest that it is roughly four or five times more active when metabolically compared to T4. 

The thyroid produces some of it, but most of it, usually 80 up to 85 percent, is made outside of the thyroid. This happens mostly by peripheral tissues like the kidneys and liver converting T4. T3 is an enzyme-dependent on selenium known as five-prime deiodinase. 

When should you test for this? When you’re trying to diagnose thyroid disorders. Clinical values for total T3 in lab testing in the United States range anywhere from 76 up to 181 nanograms for each deciliter. The optimal range for functional practitioners for total T3 is a bit narrower, from 90 up to 168 nanograms for each deciliter. In metric, it’s 1.4 up to 2.6 nanomoles for each liter. Free T3 levels in the United States are measured using two distinct units. 

One is picograms per deciliter, and the other is nanograms per deciliter. Based on what lab you use; you’ll discover that these values are going to be different by as much of a factor of 100. Some labs use the nanograms per deciliter. If your lab gives you picograms per deciliter, then you just divide the number by 100 to get nanograms per deciliter. The standard range for most labs is anywhere from 2.3 up to 4.2 nanograms for each deciliter. The optimal range for functional practitioners is tighter, running from 3 up to 3.25 nanograms for each deciliter, which of course, is 300 up to 235 picograms for each deciliter. 

So, what comes from all of this? As with T4, elevated T3 levels might be present of both hyperthyroidism and hyperactive thyroid. Higher total and free T3 levels can happen in certain instances of iodine insufficiency. Low T3 levels are witnessed in primary hypothyroidism. In a condition known as thyroid conversion syndrome, T4 can be normal even when T3 is very low. This can also happen in the event of Euthyroid sick syndrome, which looks very similar but has a different kind of pathophysiology. That’s covered in our hypothyroid article. You might also see cases of total and free T3, both being specifically low in selenium, to the point of deficiency. Remember that the enzyme five-prime deiodinase is selenium-dependent and crucial for iodine removal, for the five prime spots in the first tyrosyl ring. If there is a selenium deficiency, that enzyme might not be fully functional. 

Reverse T3 is a metabolically, inactive thyroid hormone. As with T3, the thyroid makes small amounts on its own. However, approximately 95 percent of reverse T3 production comes from T4 peripheral conversion. Five prime deiodinases aren’t the enzyme responsible in this case. It would be five deiodinases since the iodine is being removed from the second tyrosyl residue instead of the first. At this time, it’s not assumed that this one is selenium dependent. 

At what times would you do a reverse T3? It’s useful if you want to figure out the reason behind a low free or total T3, as witnessed in thyroid conversion syndrome. Reverse T ranges for standard labs are typically from 8 up to 25 nanograms for each deciliter. Functional practitioners, on the other hand, prefer an optimum range of 10 up to 25 nanograms for each deciliter. In metric, that is 0.15 up to 0.38 nanomoles in each liter. 

So, what factors or known to related to higher levels of reverse T3? For starters, it’s highly correlated to diabetes, interleukin six, interferon two, tissue necrosis factor-alpha, and elevated levels of cytokine. Fasting can result in elevated T3 levels, as can an increase in free radicals, heavy metals, oxidative stress, and increased catecholamines. In some cases, it can be prolonged stress or illness, and it can also be noradrenaline, adrenaline, epinephrine, and norepinephrine. Stress might be one of the more crucial factors. Decreases in reverse T3 aren’t considered clinically significant. In terms of T3 uptake, the name can be misleading, since it has nothing at all to do with T3 levels. Rather, it’s a somewhat roundabout way of measuring unsaturated binding sites on the various thyroxine-binding proteins, of which there are three. They are thyroid-binding globulin, albumin, and transthyretin. This test is best only ordered as a component of a thyroid panel that includes T4. In a short while, you’ll also see how it’s useful in calculating a free thyroxine index. T3 uptake is contingent upon how many binding sites there are on a thyroxine-binding protein. Unlike albumin or transthyretin, TBG only has one binding site for both T3 or T4, meaning that any changes in the volume of thyroid-binding proteins and any related binding sites will impact T3 uptake. TBG abnormalities can be drug-induced, congenital, or even the result of illnesses not related to the thyroid, such as kidney or liver disease. Any circumstances which result in a decrease of TBGs mean that T3 uptake goes up, and the reverse also holds true. When should you be mindful of this test? It needs to happen as a component of a total thyroid panel, but if there isn’t any T4, then it’s not useful. By itself, it’s also not helpful. However, this test can rule out lab errors as a potential cause behind a T4 increase. If T3 and T4 update levels are both increased, then that can confirm a genuine T4 increase. 

A typical lab range for T3 uptake is from 22 up to 35 percent. T3 uptake is, of course, a percentage, and functional practitioners should consider 27 up to 35 percent as an optimal range. Things that can elevate it would include thyroid hormone replacement, hyperthyroidism, and hyperactive thyroid. In contrast, low levels might be witnessed in iodine deficiency, selenium deficiency, and hypothyroidism. 

Free thyroxine index is the next Thyroid Biomarkers I want to cover. It’s alternatively known as T7 or just FTI. Many blood tests involve this calculated measurement. The reason why the FTI and T3 uptake tests are on panels is that it used to be harder to measure the specific T3 and T4 levels, particularly of the free variants. Modern measurement techniques are far more sensitive, simpler, and more cost-effective. However, it’s still useful to know about such tests and be mindful of them. 

The FTI determines the volume of available active thyroid hormone. This calculated measurement comes from the multiplication of total T4 with the T3 uptake, meaning it was a means of estimating the amount of available free T4. It’s widely considered reliable for indicating thyroid condition when there are presently abnormalities with the plasma protein binding. The clinical lab range is the same as the optimal range for once, which is 1.7 up to 4.6. You might witness this being low in cases of hypothyroidism, but high in both hyperthyroidism and hyperactive thyroid. 

Our next Thyroid Biomarkers to cover is the free T3/reverse T3 ratio. This ratio is useful in seeing what’s going on down at the tissue level since it is useful in ascertaining the efficiency of thyroid conversion of T4 into free or active T3. Use it as a calculation to see when active thyroid conversion is happening or not. 

There are some requirements. Free T3 must be in picograms per deciliter, which is in the hundreds. So, if you have picograms per milliliter as your value, you just multiply it by a hundred. Reverse T3 must be listed in nanograms for each deciliter, the normal US unit. 

Are you curious why you would ever use this? The answer is ascertaining whether there are complications with T4 to T3 thyroid hormone conversion. A great number of practitioners agree that it’s good to see ratios higher than 20. On the other hand, if there are elevated levels of free T3, but why would this happen? In many cases, patients might be taking T3 supplementation, which can result in false free T3 elevations. When that happens, the ratio might look a lot better than it is. 

Quite a few practitioners of functional wellness prefer seeing a ratio over 20. If both the reverse and free T3 values are in optimal status, then the ratio might help you get a feel for what’s going on down at the actual tissue level. At least that’s the case when the ratio is over 2, although 10 to 20 is better, and of course, being over 20 is best. Still, high levels aren’t always truly relevant. However, low levels can be a signal of there being thyroid conversion syndrome present. 

Regarding thyroid antibodies, we’re going to go over the two primary ones. One is the antithyroglobulin antibody, and the other is anti-TPO, otherwise known as thyroid peroxidase

Let’s start off with thyroid peroxidase first. Thyroid cells have this enzyme, and its role is attaching iodine molecules to tyrosyl resides. This makes T4, or thyroxine. Thyroid peroxidase antibody testing is a means of measuring the volume of bloodstream antibodies known to be attacking TPO enzymes located in thyroid cells. An elevated level of anti-TPO is commonly found in autoimmune thyroiditis conditions like Hashimoto’s. This is something we review in an article about hyperthyroid autoimmune thyroiditis. Now, for some background on the antithyroglobulin antibody. Thyroglobulin is a certain protein that thyroid gland follicular cells produce. This means that this protein is a precursor for T4, and even T3 to some degree. Thyroglobulin’s tyrosine residues undergo combination with iodine before the protein is eventually cleaved right into singular tyrosine residues. 

It’s thyroid peroxidase enzymes that go into action, putting iodine onto tyrosine residues. Every molecule of thyroglobulin protein has a normal range of 100 up to 120 tyrosine residues. Yet, eventually, a tiny percentage of these come into play. Some suggest that only about 20 of these tyrosine residues get iodinated by thyroid peroxidase inside the thyroid follicle. Keep in mind that every thyroid hormone molecule is, in fact, two different tyrosine residues, so there is some math involved at this point. For every molecule of thyroglobulin, we only wind up with 20 tyrosine residues. When those two are joined to come up with thyroxine, the result is that each molecule of thyroglobulin winds up, providing approximately 10 thyroid hormone molecules. Eventually, thyroglobulin antibodies are immune cells, and as such, they attack the thyroid’s thyroglobulin. 

At what time should you be mindful of all this? The answer is any time that you suspect there might be autoimmune thyroiditis going on. You need to run both these when there are any abnormalities of the thyroid suspected. This is even more true when there are elevated TSH levels. Doing this will be useful in differentiating between many different autoimmune conditions. You can differentiate between things like subacute thyroiditis versus Graves’ or Hashimoto’s disease. These are strongly rooted in antibody titers, which we reviewed in our article covering hyperthyroid and autoimmune thyroiditis. In our Quest values here, we can see from 0 up to 9 IUs/mL, with an optimal range of 0 up to 6. 

In terms of antithyroglobulin antibodies, the optimal and standard ranges are both zero to one. There are times that you might see elevated levels of anti-TPO antibodies. Three of them are thyroid cancer, Graves’ disease, and the early and late stages of Hashimoto’s thyroiditis. In these cases, low findings aren’t considered to be clinically relevant.