Laboratory Testing for the Diagnosis and Management of Thyroid Disorders

Laboratory testing for the diagnosis and management of thyroid disorders [PODCAST TRANSCRIPT]

Welcome to the Healthier World with Quest Diagnostics podcast. Our goal is to prompt action from insight as we keep you up to date on current clinical and diagnostic topics in cardiovascular, metabolic, endocrine, and wellness medicine.  

When I think about the clinical reasons I've chosen to screen thyroid function in a patient, the list is pretty lengthy. The thyroid may be small, but it sure is mighty as the hormones that are produced play a critical role in many bodily functions. Because of the thyroid’s vast number of roles within the body when there's dysfunction signs and symptoms can be nonspecific and nondiagnostic with severity ranging from minimal to life-threatening. 

Thyroid dysfunction that remains undiagnosed and untreated can contribute to numerous physiologic and metabolic consequences. Making timely diagnosis and management of these conditions crucial. I'm Sarah Walsh, physician assistant by training and educator at heart and one of Quest Diagnostics, clinical specialists within the cardiovascular metabolic, endocrine, and wellness clinical segment. Today, I'm joined by Dr Sanjay Dixit board certified endocrinologist, and one of Quest Diagnostics medical directors. Join us as we walked through the fundamentals of the thyroid and touch on thyroid function, test selection, and test interpretation. We'll also review a guideline supported algorithm that provides a step-by-step method to assess thyroid dysfunction in adults. Welcome Dr Dixit. Thank you so much for joining me today.  

Thanks Sarah, it's good to be here again. 

For listeners and want to start with saying thyroid dysfunction or thyroid disorders may mean different things to different individuals. So I want to be clear that when I say thyroid dysfunction or disorders throughout our time today, we are focusing specifically on hypothyroidism and hyperthyroidism. Also for context, we will be talking about the non-pregnant adult patient. As pregnant and pediatric populations may have differing recommendations. Okay. The stage is set. Let's jump into it. Dr Dixit, how common are these specific conditions in the US? 

These are very common medical conditions, it's something that's seen in every primary care and endocrinology office. About 12 percent of the US population will develop a thyroid condition, and it's estimated that 20 million Americans have some form of thyroid disease. In fact, up to 60 percent of those, with thyroid disease are unaware. Statistically, women have thyroid disease more than men, and older individuals have this more than younger individuals. It seems to occur most frequently in women over age 60. The most important thing is that undiagnosed thyroid disease can put patients at risk for other medical conditions, such as cardiovascular disease and infertility. 

I know there can be a pretty lengthy list of signs and symptoms when talking about hypo or hyperthyroidism, but can we briefly touch on some of the common clinical features a provider may see? 

Absolutely, Sarah. I used to explain to my patients when I was in practice that hypothyroidism and hyperthyroidism, think of it like a seesaw or the yin and the yang, Hypothyroidism typical symptoms are a depressed mood, perhaps weight gain, cold intolerance, constipation. Think of hyperthyroidism as 180 degrees away from hypothyroidism. So feeling revved up all the time, symptoms like anxiety, heat intolerance, loose stools, tachycardia, and increased appetite would be typical symptoms of hyperthyroidism.

Okay. Great. So hypothyroidism that under active thyroid gland, you're seeing things like weight gain, cold tolerance, fatigue, constipation. Hyperthyroidism so that overactive thyroid gland, you're seeing weight loss. Increased heart rate, increased appetite, more frequent bowel movements. But when thinking about all those signs and symptoms, you listed off things like fatigue, weight gain, constipation. There can be a whole plethora of differentials that come to mind there. With the spectrum of potential signs and symptoms, this is not a clinical diagnosis correct? 

That's absolutely correct, Sarah. The symptoms are things to take into consideration. So a perfectly healthy person without any complaints should not have thyroid function tests checked. However, any of those symptoms can prompt a provider to test the thyroid. Lab testing plays a large role in supporting the diagnosis of hypo or hyperthyroidism. It is the objective evidence that a provider needs for the diagnosis.

When you're talking about indications for testing thyroid function, all the signs and symptoms you mentioned would likely prompt a provider to screen thyroid function. But what about things like medical history or family history? Are there any other populations that we should be aware of that may be suitable for assessing thyroid function without any reported symptoms? 

Sarah, I think it's important to state initially that the United States Preventive Services Task Force doesn't recommend universal screening for asymptomatic adults with thyroid function tests. There are individuals, however, in which a provider may consider testing. Perhaps individuals with a strong family or personal history of thyroid disorders, patients with atrial fibrillation, cardiovascular disease, hypercalcemia, folks with autoimmune diseases such as rheumatoid arthritis, Type 1 diabetes or lupus, as there is an association between folks who have thyroid disease from an autoimmune cause and those other autoimmune disorders that I just talked about, and certain medications can cause thyroid dysfunction, medications, such as amiodarone, lithium and chemotherapy, specifically the immune checkpoint inhibitors. 

That's helpful to highlight. Obviously, we have our signs and symptoms clinically that providers can be looking for. But also helpful to note that there are those higher risk populations that you highlighted. So individuals with specific medical conditions such as, you know, things like a afib, cardiovascular disease, autoimmune conditions, and medications that can put individuals at higher risk for thyroid dysfunction. There are a lot of different laboratory tests available to evaluate the thyroid. What is the current guidance from the major health organizations regarding thyroid testing? Where do we start when we're evaluating a non-pregnant adult patient for thyroid dysfunction?  

Sarah, the starting point is always going to be the TSH. It's the preferred test, it has a clinical sensitivity of 98% and a specificity of about 92%. However, there are many providers that will add a free T four to the TSH or a TSH with reflex to free T4. Let me explain that, that test will reflex to a free T4 only if the TSH is abnormal. Why is this important? It'll facilitate a quicker differential diagnosis and it will likely improve patient satisfaction because they will not have to be redrawn for another test.

Awesome. So we have a patient, we suspect thyroid dysfunction in, or a high risk individual for thyroid dysfunction. We are starting with the TSH and for many providers that could be a TSH plus a free T4 to expedite that differential diagnosis. And really, depending on the results of the TSH, that's going to determine what additional labs are needed, correct? 

That's absolutely correct. 

To make this as easy as possible for our listeners to follow along. Let's start with next steps when you find the TSH is elevated. So you have a patient that comes back with an elevated TSH. What are we doing from here?  

If the TSH is elevated, the provider would be suspecting hypothyroidism, but additional information is needed. It would be recommended to check a free T4, and if the free T4 is low, this is compatible with a diagnosis of primary hypothyroidism. This means there's an abnormality of thyroid hormone production driven by the thyroid gland itself. However, if the free T4 is elevated as well, the results are compatible with a more complex diagnosis, medical conditions that are rare, such as a TSH secreting pituitary adenoma, or thyroid hormone resistance. And for those patients with a high TSH and a high free T4, the provider could consider checking a free T4 with a different methodology but a referral to an endocrinologist is also warranted.

So just as a recap. TSH is elevated. We run a free T4. If that free T4 is low, those results are compatible with primary hypothyroidism. If the TSH is elevated and the free T4 is also elevated, that's going to be compatible with a more complex diagnosis, likely, you know, being referred out of primary care to endocrinology.  

A couple of follow up questions I have after that answer. I know when we're talking about the evaluation of hormones from a laboratory perspective, in general, you can assess both free and total levels of certain hormones. Free meaning it evaluates the amount of hormone, not bound to a protein and total evaluating the amount of both bound and unbound hormone. Why are we evaluating a free T4 here and not a total T4?

Free T4 measures the actual thyroid hormone that is not bound to protein. And that's the amount of hormone that can actually enter and affect the target tissues. A free T4 more accurately reflects functioning of the thyroid gland compared to total T4 and it's the preferred measurement for the general population. 

Thanks for that clarification. Now my second follow-up question. You mentioned an individual with an elevated TSH and an elevated free T4. You could consider checking free T4 using a different methodology. Can you expand a little bit on that?

Free T4 is typically measured by immunoassay, Sarah, but there are certain scenarios where in which the binding proteins may be abnormal, and the free T4 immunoassay doesn't match the clinical picture. So evaluating free T4 by a methodology called equilibrium dialysis can provide more accurate free T4 measurements that are unaffected by variations in binding protein levels. Again, I should state that in general the immunoassay free T4 is fine for the general population and equilibrium dialysis free T4 should really be reserved for special circumstances. 

All right now for curve ball. A patient has an elevated TSH, but a normal or in range, free T4. What are the current recommendations here? What should providers be considering?

Good question. This is a condition called subclinical hypothyroidism, where you have an elevated TSH, but normal levels of free T4. In such a case, it may be beneficial to evaluate for a specific thyroid antibody called thyroid peroxidase antibody. As I said earlier, many cases of hypothyroidism are due to autoimmune disease. If the TPO is elevated, this would indicate autoimmune dependent subclinical hypothyroidism. It may be useful to predict progression from subclinical to overt disease. And it might influence whether a provider would start treatment or just wait and recheck several weeks later. 

All right. So we've covered when TSH is elevated. Now let's jump into next steps when a provider finds that the TSH in a patient is low. What should providers be considering ordering here from a laboratory perspective? 

Sarah, when a patient has a low TSH, just as we talked about in the scenario, when a patient has a high TSH, the next step is testing that person with a free T4. When the TSH is low and the free T4 value is high, this result is compatible with primary hyperthyroidism. However, if the free T4 value is low, this is compatible with the diagnosis of central or secondary hypothyroidism. And in this case, a provider could consider investigating other pituitary hormones and referring to an endocrinologist. 

So when the TSH is low and the free T4 is elevated. That's going to be consistent with primary hyperthyroidism. And when the TSH is low and the free T4 is low. Again, that's going to be another scenario that is likely being referred out of primary care to endocrinology. Now for the patient that has the low TSH and elevated free T4, do we stop there from a laboratory evaluation perspective or are there additional testing recommendations in this scenario? 

There are additional tests that are recommended, Sarah, to identify autoimmune causes for the hyperthyroidism, Graves disease being the typical example. So, in this case, thyroid stimulating immunoglobulin, TSI, and thyroid peroxidase antibodies, TPO antibodies should be considered. Those individuals with high TSI and TPO results are compatible with the diagnosis of Graves disease in most cases. 

If the patient has normal values of TSI and TPO, generally the patient would not have an autoimmune related case of hyperthyroidism. The provider should consider other forms, like iodine induced drug related hyperthyroidism, the classic example being amiodarone, or a toxic nodule or toxic multinodular goiter. For those patients that have a normal TSI and a high TPO, those are individuals that would undergo imaging, either with a thyroid scan and or a thyroid ultrasound. In addition, these patients should be referred to an endocrinologist for further assessment and treatment.

All right. So adding the TSI and TPO to the patient that has TSH that's low and a free T4 that's elevated. Its purpose is really to determine and identify the cause of the hyperthyroidism. I'm sure you know where I'm going next. What about the patient with low TSH and normal or in range free T4? What are the recommendations here? 

This is where a total T3 assessment can help distinguishing subclinical hyperthyroidism versus T3 toxicosis. If the total T3 is high, the results are compatible with the diagnosis of T3 toxicosis. However, if the total T3 is in range, other disorders such as subclinical hyperthyroidism, recovery from hyperthyroidism, or even non thyroidal illness, also called euthyroid sick syndrome, should be considered. 

You mentioned total T3 evaluation here. But when we were talking about T4, it's recommended to measure free T4. Why are we measuring total T3 and not free T3 here? 

It's a good question, Sarah. There are multiple types of T3 assessments, including total T3 and free T3. But total T3 is really considered a more robust and better validated test than free T3. 

Okay, that makes sense. You know, each hormone may have a preferred option, whether that's free versus total. And for T3, total T3 is that preferred measurement. We've touched on the starting point of assessing thyroid dysfunction, utilizing TSH, how and where to incorporate free T4 and total T3 but I'm assuming we've only scratched the surface here. As far as testing, available to evaluate thyroid function. Right? 

That's right, Sarah. What we chose to focus on today during this podcast is the guideline recommended testing. And really hit the baseline of what can be done within a primary care provider's office or a women's health office. But of course, Quest offers additional thyroid testing, which should include antibodies, thyroglobulin panels, and many others, because every provider is going to differ on their comfort level with thyroid testing and the scope of testing that they want to use.

When I was practicing in a primary care setting, I had training regarding the utilization of T4, T3, TPO, TSI, and felt comfortable ordering these labs. But as I talked to more and more providers, I get the feeling that this isn't always the case in primary care and women's health. As an endocrinologist, I'd love to hear your opinion, how do you feel about primary care providers ordering beyond a TSH? 

Well, in practice, it was fairly common to have a patient wait months to see either myself or one of my partners so I am an advocate for primary care providers checking additional thyroid testing to help facilitate diagnosis and to expedite referrals to endocrinologists. This algorithm developed by Quest was developed with primary care providers in mind. As an example, for someone with a high TSH, the addition of a free T4 could identify subclinical disease and prompt testing for thyroid antibodies or streamline the diagnosis of hypothyroidism and actually have the patient started on treatment without the need to see a specialist. So you've saved the patient time and additional expense. However, for somebody that is suspected to have central or secondary disease. Again, based on the results of a TSH and FreeT4 that patient is being directed to the endocrinologist more efficiently.

With one of our previous podcasts that you and I recorded on PCOS we touched on the cardiometabolic connection with that common endocrine disorder. Is there a similar impact here? Do thyroid disorders impact cardio-metabolic health or risk in a patient? 

Definitely, an excess or deficiency of thyroid hormone can start or even worsen cardiovascular disease. Thyroid disorders are associated with dyslipidemia, heart failure, hypertension, atrial fibrillation, et cetera.

Thank you for highlighting some of those crucial interconnections we can see here between cardiometabolic conditions and common endocrine disorders. So very similar to PCOS, thyroid disorders have an impact on cardiometabolic health. You mentioned the algorithm developed by Quest for the diagnosis and management of thyroid disorders a few questions back. Can you speak a little bit more to this and let our listeners know where they can access this? 

Yes, our team of medical experts have developed diagnostic algorithms that can simplify the path to diagnosis. They align medical society guidelines with our comprehensive endocrine test menu. So we've included the link to the algorithm in this podcast description but the algorithm can also be found as a link within our test directory under the test we discussed today, like TSH, free T4, and total T3.

I also want to highlight, there are additional resources linked in the podcast description, Quest Diagnostics, clinical focus for the diagnosis and management of thyroid disorders. This specifically highlights available tests, test selection, test interpretation, and reviews, drugs, and nutrients that can affect thyroid function test. There's also a link to quest diagnostics clinical education center that has a plethora of webinars, publications, podcasts, presentations for providers to explore. All right. We've covered a lot today. Let's hear your final takeaways for our listeners.  

Absolutely, Sarah. First, thyroid dysfunction is common. However, the symptoms are nonspecific. So we need objective evidence to confirm the diagnosis of hypo or hyperthyroidism. And that's where the lab testing comes in. Checking a TSH along with a free T4 can facilitate diagnosis of both hypo and hyperthyroidism. There are autoimmune causes for both hypo and hyperthyroidism. that can be evaluated with tests such as TSI and TPO antibodies. And lastly, thyroid dysfunction can cause a whole host of cardiometabolic problems such as hyperlipidemia and atrial fibrillation. 

Well, thank you so much, Dr Dixit for joining me and sharing your time and expertise.  

Thanks, Sarah. It was great to be here again. 

That's it for this episode of Healthier World with Quest Diagnostics. We hope you enjoyed the recording. Please follow us on your favorite podcast app and be sure to visit our channel for more available podcasts. Also check out the additional resources section linked in the podcast description. For the latest information on our educational webinars, podcasts, scientific publications, and conference presentations, visit the Quest Diagnostics Clinical Education Center website. Thanks again for joining us as we've worked together to create a healthier world, one life at a time.