[Music] today I will be discussing thyroid function tests the learning objectives will be first to be able to describe the general structure and function of the hormones involved in thyroid gland regulation second to be able to diagram the relationship between the thyroid hormones next to use thyroid function tests to diagnose the four General categories of thyroidal illness and last to list non-thyroidal conditions which can affect tfts tfts can be a confusing topic for a number of reasons their interpretation superficially seems like it should be incredibly easy and for the majority of patients it is however a significant minority of tfts don't conform to what logic suggests for reasons I'll discuss also the biosynthesis of thyroid hormone is unusually complex but as most of the synthetic steps are of minimal clinical relevance I'll be covering only the most important aspects finally even the terminology surrounding tfts is confusing while the term thyroid hormone generally refers to one of two specific and nearly identical compounds there are nevertheless a total of 4 hormones involved in the process I'll briefly review each the first is thyrotropin releasing hormone or TR TR is a tripeptide amide which essentially means it's composed of three amino acids it's formed in the hypothalamus and travels to the anterior pituitary via the hypothalamic hypothal portal system the primary effect of TR is to stimulate release in the pituitary of the next hormone in the pathway TSH another effect of TR which won't be discussed further in this particular video is to stimulate secretion of prolactin now TSH known forly as thyroid stimulating hormone as well as thyrotropin is a glycoprotein it has a number of different specific effects all of which are focused on increasing the physiologic actions of thyroid hormone these are to increase the release of preformed thyroid hormone to increase the rate of thyroid hormone formation and to increase the size and number of thyroid cells which produce that hormone next let me talk about the true thyroid hormones that is those hormones which are actually synthesized and released by the thyroid gland they are almost universally called T3 and T4 though formally are triiodothyronine and thyroxine as mentioned a minute ago the biosynthesis of T3 and T4 is very complicated but requires tyrosine and iodine the tyrosine used for thyroid hormone is actually stored as a glycoprotein called thyroglobulin each molecule of which has about 70 molecules of tyrosine and the thyroid hormone is actually synthesized while still attached to the larger thyro globulin and remain so until it is secreted the thyroid gland is relatively unique among endocrine organs in its ability to store large amounts of pre-formed hormone this can become relevant in diseases such as Hashimoto thyroiditis and autoimmune mediated destruction of the thyroid gland which can transiently result in hyper thyroidism due to abrupt release of hormone in normal physiologic conditions in response to TSH the thyroid secretes predominantly T4 along with a small amount of T3 the ratio of T4 to T3 is about 90% to 10% after they're released over 99% of the thyroid hormones are bound to plasma proteins in the circulation the predominant one is called thyroxine binding globulin or tbg some is also bound to albumin as well as a protein called transthyretin so named because it's responsible for the transport of thyroxine and retinol only the tiny free Unbound form of thyroid hormone is physiologically active the effect of protein binding is clinically important because changes in the concentration of thyroxine binding globulin can affect the concentration of Unbound hormone for example in steroid use and in curosis less of thyroxin binding globulin is produced resulting in a higher proportion of free hormones the opposite effect occurs during pregnancy in which the liver produces higher than normal amounts of thyroxin binding globulin now despite the fact that the thyroid secretes much more T4 than T3 the biological activity of T3 is much greater than T4 the peripheral tissues convert some of the relatively inactive T4 to the relatively active T3 as well as some to the completely inactive reverse T3 also known as rt3 in fact some recommend considering T4 more of an inactive pro hormone and T3 really the only proper thyroid hormone what do T3 and T4 do they have the greatest diversity of actions of any hormone their primary effects are first to increase the basil metabolic rate which results in increased heat generation and oxygen consumption second they sort of rev up metabolism specifically increasing gluconeogenesis glycolysis glucose absorption from the GI tract lipolysis and protein turnover next they stimulate bone maturation and growth and their last major effect under normal physiologic conditions is to increase cardiac output by increasing both the heart rate and contractility you may have noticed that many of the physiological effects of the thyroid hormones are similar to those from the activation of the sympathetic nervous system and there may be interactions between the two which are not yet understood explaining why beta blockers are a commonly employed a treatment for some manifestations of hyperthyroidism I'll now move on to discuss how thyroid hormones are regulated which will partly be a visual representation of what was just covered it begins in the brain at the hypothalamus where TR is released into the hypophysial portal system to be delivered directly to the anterior pituitary where it stimulates TSH release and TSH released into the systemic circulation travels to the thyroid where it stimulates among other things the formation of predominantly T4 from thyroid globuline and iodine T4 travels in the bloodstream largely bound to thyroxine binding globulin and when it reaches certain peripheral tissues it's converted to T3 by an enzyme more accurately a collection of very similar enzymes called deiodinases which as their name implies can add or remove an iodine Atom from a molecule there actually a number of different names for these enzymes in medical textbooks and in the literature one of the more common alternate names is five Prime iodase now not all of the T4 gets converted to T3 as some also gets converted into the molecule reverse T3 which as I said before is inactive both active T3 and reverse T3 only differ in which of the four iodine atoms were removed by the enzyme normally there's about a one to1 ratio of T3 to reverse T3 that it's produced however pregnancy fasting hepatic and renal failure and beta blockers all result in preferential conversion to reverse T3 thus decreasing the amount of active hormone there are a number of important negative feedback mechanisms in this pathway first the thyroid hormones themselves exert negative feedback on the hypothalamus and pituitary to reduce secretion of TR and TSH respectively so for example if TSH starts to get too high this leads to higher levels of T3 and T4 which leads to Greater inhibition of TSH thus the system can keep TSH and thyroid hormones within a specific window in addition to hormonal negative feedback there are a few others as well for example both physiologic and emotional stress can inhibit TR and TSH which is a likely contributor to the U thyroid 6 syndrome to be discussed in a few minutes in addition exposure to coold temperature appears to inhibit TR though the clinical significance of this in humans appears to be low the final point to bring up with this diagram concerns the two possible effects of an acute iodine load on the actions of the thyroid the first possible effect is called the wolf chof effect which is a reduction in thyroid hormone levels seen after an acute iodine load which presumably evolved as a mean to prevent hyperthyroidism in response to being suddenly provided a high amount of substrate this effect explains both the hypothyroidism seen by some patients after starting the iodine containing anti- rythmic medication amiodarone as well as the use of highd do iodine after nuclear emergencies as it will prevent uptake of radioactive iodine from the atmosphere the second possible effect of an acute iodine load is called the yode bastal effect which is stimulation of the thyroid gland's production of hormone unlike the wolf chof effect which can be seen in patients with completely normal thyroids the yode bastal effect is only observed in patients with pre-existing thyroid pathology a typical scenario occurs when the patient with a goer and hypothyroidism from chronic iodine deficiency moves to an area where iodine is abundant in the diet it can also be seen in patients with a multi-nodular goiter or Graves disease who has started on am oone if you feel confused by these two seemingly contradictory effects don't worry you're not alone luckily with the exception of amoon use these effects come up pretty uncommonly in routine clinical practice okay well now I'm finally going to get to discuss what you've probably been waiting for the actual thyroid function tests or tfts tfts are complicated due to the variety of substances that can be measured and the variety of specific assays that different Labs can use the only three tests which are commonly checked are TSH free T4 and to a lesser extent free T3 we typically only order T3 when we are specifically concerned about hyper thyroidism because it will be more sensitive based on our current understanding of thyroid disease and current lab technology TSH free T4 plus or minus fre T3 are more or less the only choices within the domain of thyroid function tests that you will ever need to order or interpret unless you become an endoc chronologist in which case there are a few more that may come up from time to time some of these other tests which are uh sometimes commercially available for clinical purposes and sometimes used only for research uh include the following total T4 and T3 and something called the T3 resin uptake together these tests could be used to estimate free T4 and free T3 via a calculation called the free T4 T3 index luckily with the relatively recent wide availability of free T4 and T3 tests these others are no longer necessary another rarely ordered test is the reverse T3 it was once invogue as a means to distinguish true thyroid disease from TFT abnormalities caused by non-thyroidal illness although physiologically this use seems to make sense its usefulness has not panned out and it's now phenomenally rare for a conventional doctor to check one having said that reverse T3 has become very popular among doctors and other providers working more on the fringes of medicine where they often Market it as the critical hormone your own doctor won't tell you about as if endocrinologists somehow make more money by intentionally not diagnosing thyroid disease next is TR I honest honestly don't know if the fact it's so rarely ordered is because it's not available not validated for clinical use generally not helpful or all three there's also thyroxine binding globulin which I've never seen ordered on a patient and last is thyroid globulin which actually has a very important though uncommon role in following differentiated thyroid cancer since thyroid globulin is only produced by thyroid folicular cells having detectable levels in the serum is indicative of residual thyroid tissue being present thus if a patient has had the thyroid gland removed entirely as part of the treatment of thyroid cancer but still has detectable thyroid globulin it is suggestive of recurrent or metastatic disease so if TSH freet T4 and freet T3 are the only tests which are typically used to diagnose thyroid pathology and free T4 and T3 typically Trend together it should be pretty easy to interpret tfts well here's a basic summary the most common scenario is for TSH to be high and thyroid hormones to be low that occurs in primary hypothyroidism meaning there is something wrong with the thyroid gland itself if the gland is diseased and not producing the hormone there's less negative feedback on the hypothalamus and pituitary leading to the secondary increase in TSH a less common combination is a low sh and high hormones as seen with primary hyper thyroidism including the situation of excess exogenous thyroid replacement much much rare combinations include low TSH and low free T4 and T3 which is referred to as Central hypothyroidism which the problem may be in the pituitary or theoretically the hypothalamus and last is something called secondary hyperthyroidism in which there is a TSH producing tumor somewhere so interpretation of tfts doesn't seem so bad does it four combinations four General Diagnostic categories unfortunately in a significant minority of patients it can be substantially more challenging on account of the effect of non-thyroidal conditions on tfts tfts can be affected by non-thyroidal conditions for a variety of reasons there could be transient acquired pituitary dysfunction and critical illness an alteration the level of thyroid bonding globulin an increase in circulating free fatty acids which displace thyroid hormone from thyroxine binding globulin decreased peripheral conversion of T4 to T3 and an altered ratio of T3 to rt3 the net consequence of these potential effects may be some combination of low TSH either low or high free T4 low free T3 and high rt3 the abnormal tfts due to non-thyroidal illness is often referred to as either U thyroid SI syndrome or sick U thyroid syndrome common causes of euthyroid six syndrome include pregnancy any clinical illness liver disease renal disease malnutrition and various medications let's relook at how to interpret tfts keeping in mind you thyroid 6 syndrome as well as a few other diagnoses and this time let's have a column and row for a normal TSH and normal thyroid hormones first the obvious now the most common scenario other than everything being normal is still high TSH and low T4 plusus T3 which is consistent with just primary hypothyroidism there isn't really anything else that commonly causes that P pattern in the event that TSH is low and T4 and T3 are high that's still consistent with primary hyperthyroidism but it's also consistent with u thyroid 6 syndrome particularly if the free T4 is high but freet T3 is low if everything is low it can be due to either Central hypothyroidism as before as well as you thyroid 6 syndrome if everything is high it can still be due to secondary hyperthyroidism from a TSH produc ucing tumor it can also be due to a very rare inherited disorder of thyroid hormone transport or hormone metabolism now if the thyroid hormones are normal but TSH is not we have a category of thyroid disease called subclinical hyper thyroidism or subclinical hypothyroidism I'm not a huge fan of the terms since usually subclinical means without symptoms but in this case the diagnosis is essentially based just on lab tests I suppose the patient is presumably not symptomatic if thyroid hormone is in the normal range since that's the final mediator of thyroid function but the term still feels a little misused to me in addition a low TSH with normal T4 and T3 can also be from U thyroid 6 syndrome a high TSH with normal T4 and T3 can occur during the recovery phase of you thyroid 6 syndrome a normal TSH with low T4 and T3 can be from you thyroid 6 syndrome and a normal TSH with high T4 and T3 is sometimes seen in acute psychiatric illness and various drugs most notably amiodarone can cause almost any pattern of TFT abnormalities so as you can see interpretation of tfts can become far more complicated if a patient's results don't fall neatly into one of the four classic patterns previously shown when it comes to ordering tfts the selection of tests is very straightforward remember unless you are testing for something highly unusual only worry about TSH freet T4 and free T3 if you have a low suspicion for a thyroid disease and the patient is acutely ill consider deferring tfts until the patient's better it can be very difficult to sort out you thyroid 6 Syndrome from True thyroid pathology in acutely ill patients if the patient is not acutely ill check the TSH by itself first if it's normal consider yourself done with no further testing if it's high check a fre T4 to distinguish hypothyroidism from subclinical hypothyroidism if it's low check a fre T4 and freet T3 if the freet T3 is elevated it's consistent with hyperthyroidism if it's normal the patient likely has subclinical hyperthyroidism if there is high suspicion for hypothyroidism check a TSH and free T4 and if there is a high suspicion for hyper thyroidism check a TSH free T4 and free T3 you could ask if we always check a T3 when hyperthyroidism is suspected why in the world do we bother with a T4 at all that's a good question I don't really have a good answer for it I don't think I've ever seen a T3 ordered without a T4 but I'm not positive a T4 is actually always necessary I'm going to end the video with a discussion of three more tests which aren't technically thyroid function tests though they are logically included with this topic these are the anti-thyroid antibodies the first two of these antibodies are anti-thyroglobulin antibody an anti-thyroid peroxidase antibody thyroid peroxidase is an enzy enzyme involved in the synthesis of thyroid hormone at least one of these is seen in almost all cases of Hashimoto's thyroiditis the most common ideology of hypothyroidism the last category of antibody is anti-tsh receptor antibody of which there are three subtypes stimulating blocking or neutral Graves disease a common cause of hyperthyroidism is due to stimulating anti-tsh receptor anti body while various anti-tsh receptor antibodies can be seen in different stages of Hashimoto measurement of these antibodies is not always needed for making the associated diagnosis if the history and exam strongly favor a particular diagnosis already however if the history or exam is inconsistent with a common ideology of either hypo or hyperthyroidism or if there is concern about confounding U thyroid 6 syndrome in a critically own patient with symptoms or signs consistent with thyroid disease checking antibodies can be helpful that concludes this video on thyroid function tests and their interpretation if you found it interesting or useful please remember to like and share it