Understanding thyroid function tests

Interpreting thyroid function tests is one of the things we are most commonly asked about. In November 2021 we held a ‘Meet the Experts’ webinar to shed some light on this complex topic.

In this fascinating session, we heard perspectives from both endocrinologists and a scientist. Our experts; Prof Krish Chatterjee, professor of endocrinology, Cambridge and Dr David Halsall, consultant clinical scientist, Cambridge and our chair Prof Carla Moran, consultant endocrinologist, Dublin also took the time to answer questions our audience had been grappling with.

These are some of the questions answered live by our experts during the webinar. 
Key: Prof Krish Chatterjee – (KC), Dr David Halsall – (DH), Prof Carla Moran (CM)

Should Thyroid Peroxidase Antibody (TPOAb) testing be repeated if they are positive? For example, does it mean anything if the levels go up or down?

I think the short answer is probably not. We recognise that there are grades of positivity. I have not overburdened you in my presentation with numbers. In a typical hypothyroidism case, our lab would categorise 1300 as very, very positive.

Then there is a mid-range and a low positive range. Those antibodies are actually imperfect markers of what is happening in the thyroid. It is not the antibodies that are destroying your thyroid tissue though. What is destroying it are the cells of the immune system and, of course, we cannot see into that. That is one of the reasons I would argue why repeatedly measuring that antibody is of little value. (KC)

Does Thyroid Stimulating Hormones (TSH) vary according to race or ethnicity? Does it change according to the time of day or the season?

The answer to both of those questions is yes.

I think the question regarding ethnicity may depend a little bit more on the iodine concentration in the area you live in. There is a well-described Circadian rhythm of thyroid hormones. They are slightly higher in the morning than in the afternoon. So, a TSH of 2.5 in the morning may become 2 mid-afternoon and then go back up again. There is also a seasonal variation in TSH. It is a hibernation hormone and the temperature will change it. Based on my discussion around the variability, I think there is not much to be gained by having increasingly sophisticated reference ranges for TSH. (DH)

Why does TSH sometimes stay persistently low? For example, in someone who has Graves’ disease whose T4 levels are now in range but their TSH remains suppressed?

This is an unusual phenomenon. The truth is we do not exactly know why the TSH stays chronically suppressed. I can give you two possibilities:

1. When we measure the thyroid hormones in the blood, it is a snapshot in time. It is not the T3 level throughout the 24-hour period. So, it is possible that in that Graves’ disease patient the snapshot measurement of T3 is ok but over a 24-hour period the thyroid gland is producing just a little too much T3. And this is what accounts for the persistently suppressed TSH.

2. Another explanation, for which there is also good evidence, is that the receptor to which TSH receptor antibodies bind is, strangely enough, also expressed on the TSH-producing cells of the pituitary. So, there is a suggestion that the Graves’ antibody cells – the Thyroid Stimulating Hormone Receptor Antibodies (TSHR Ab, also known as TRAb) – is what binds to the pituitary and shuts off the TSH for a long time. I think Prof Moran and I would agree that when we see this in clinical practice we observe this as a phenomenon that when we treat a patient with Graves’ disease, the TSH can remain suppressed for months. As things get better, it then flips. (KC)

If someone is on T3 and their T3 is high and TSH is suppressed, are symptoms such as palpitations related to the low TSH or to the raised T3? 

My take on this is to think about this in terms of the feedback axis. When it comes to suppressing the TSH, the pituitary gland is sensing a combination of the T4 and the T3 in the blood. So it senses the T3 in the blood directly because that gets straight to the cells and is the active hormone. The pituitary cells also sense the T4 because that gets taken up and converted by the deiodinases* to produce extra T3 inside the cells which you cannot measure. Together this suppresses the TSH.

So, for me, the arbiter is that the TSH is suppressed. If this is truly suppressed, I rely on a body of evidence that shows in the healthy population, individuals who have a chronically suppressed TSH are at greater risk of low bone density and cardiac problems in the future.

If you were to extrapolate from that finding to patients on thyroid hormone replacement therapy – and there I do not distinguish between patients on T4 monotherapy and patients on T4/T3 combination therapy, then I would argue that, in the long-term, this may not be a good place to be.

T3 blood measurements in people on T3 is problematic because T3 is a very short-acting hormone. So we know the level in the blood is greatly influenced by the timing of the blood test in relationship to when the T3 was ingested. his is not the case with T4. (KC)
*Deiodinase is a peroxidase enzyme involved in the activation or deactivation of thyroid hormones.

What is the optimal way to take thyroid function tests from a patient’s point of view? Should they be done after fasting or at a particular time of day?

Depending on how exacting you want to be, I suppose having a nine o’clock blood test would give a degree of continuity to it but it is not that straightforward. I would not see it as a particularly big issue. TSH will change slightly but will not be greatly influenced by what time of day you have the test, whether you have eaten or any other factors. I don’t know what you think Prof Chatterjee? (DH)

No, I don’t think so. In one of the earlier slides in my presentation, I showed that TSH is a hormone that has what we call a very long half-life.** So a TSH measurement is not going to be influenced greatly by when you took the thyroxine in relationship to the blood test. In people taking T4/T3 combination therapy, I still look primarily at the TSH and then I look at the relationship between T4 and T3 in order to judge the balance between the amount of T4 and T3 that I prescribe. I don’t look at the absolute value of T4 and T3 in judging the balance of combination therapy, and particularly not T3, for the reasons I have talked about. (KC)
**The half-life of a medication is the time it takes for the amount of a medication’s
active substance to reduce by half in the body.

What can hypothyroid patients do who still have symptoms, despite their TSH being within the reference range?

I can only give you my opinion which is based on my personal approach to this. It is a contentious area where more research is needed. The first thing to say is not knowing where an individual’s set point is, I would titrate the dose of thyroxine upward to bring the TSH down to the lower end of the reference range.

I would not subscribe to a suppressed TSH for the reasons I have stated earlier because that carries health risks with it. However, keeping the TSH at the lower end may eliminate those residual symptoms.

If this does not, it is worth asking whether there are other causes of ill health and investigating thoroughly for that. With residual symptoms that are particularly in the neurocognitive domain, there may be evidence that T4/T3 combination therapy may have a role to play in alleviating that. However, I think formal clinical trials are needed in order to show that and to change global practice. (KC)

Can you comment or provide any advice to someone who is concerned about weight gain after being treated either by antithyroid drugs, radioiodine or surgery for thyrotoxicosis (excess thyroid hormone in your body)?

I think this is an interesting area for research and many patients may have their own views on this. When someone is thyrotoxic we know they generally lose weight. It is an oversimplification to suggest this weight loss is because the metabolism has sped up. What also happens is that the high thyroid hormone levels act on the appetite centres in the brain and they stimulate the appetite. So it is very well known that when you are thyrotoxic you have got both things going on. You can eat an awful lot more and yet you are burning off the energy and so you lose weight.

I think what happens when you correct that is the balance between the appetite and energy expenditure is out of sync so your resting energy expenditure normalises quite quickly but your brain, which has been fooled into overeating due to this increased appetite, takes longer to adjust. So, in some individuals, you may then get an overshoot where you are still consuming more energy but you are expending less.
This then leads to weight gain. As we all know, once you put weight on it can be very hard to shift. This applies to any individual, regardless of their thyroid status. (KC)

I agree. It is a real clinical problem and one that definitely needs more research as it understandably bothers patients quite a lot. (CM)

Is there any research going on in Cambridge into autoimmune hypothyroidism (Hashimoto’s thyroiditis)? Are there any new treatments coming through on this?

No, we are not researching Hashimoto’s thyroiditis. I say that because historically we have explored other areas like rare genetic causes of thyroid over- or underactivity from birth, which is my colleague Dr Nadia Schoenmakers’ specialism, through to adult life.

As Prof Moran has said, one of our other enduring passions, which is an equally important area, is investigating why the measurement methods sometimes get tripped up. Because I do believe this is an equally important area in day-to-day practice. As Dr Halsall has said, and our hospital is not unique in this, ten million thyroid function tests are performed every year. If even a tiny proportion of those is erroneous there is an awful lot of time and energy that people can waste going down those blind alleys. We still think we can make a valuable contribution by sifting through some of these bear traps. (KC)

We sometimes see patients on thyroxine whose T4 is a little bit higher and their T3 is a little bit lower.
Do you think this means they have a problem converting T4 to T3 or is it a thyroxine effect?

I think I would go back to Prof Chatterjee’s initial discussion around this. I would take TSH as being the best marker here. And the T3/T4 ratio, I am not saying there is no benefit of changing T3 to T4. I am just saying, at the moment, our measurements of it cannot help direct that sort of therapy.

In simple hypothyroidism, you would not want TSH to be too far away from the reference range. If you want to change the reference ratio of T3 to T4, then yes maybe it works but there is nothing we can do by measuring those two hormones at this stage which would say you should alter the ratio of T3 to T4.

It is a very common finding in people on T4 that the T4 runs slightly higher than it would in people not on T4 therapy. Currently, I don’t think there is a therapeutic intervention in that group of patients. (DH)