Thyroid

Why TSH is the first-line test, and what that actually rests on

TSH is not made by the thyroid. It is thyroid stimulating hormone, released by the pituitary gland in the brain and it is a message to the thyroid. The pituitary tracks how much thyroid hormone is circulating and adjusts the instruction accordingly. When the thyroid is producing less, the pituitary pushes harder and TSH goes up. This inversion catches almost everybody out the first time they see it.

So why is TSH so sensitive? It is not just because the pituitary is watching closely. The relationship between the two is not linear. It is roughly logarithmic so a small fall in free T4 results in a large, multiplied rise in TSH. The axis amplifies the signal before you ever draw the blood, which is why a change too small to see in free T4 shows up clearly in TSH. That amplification is the core of the case for using TSH as the first test, and it is a property of the system rather than of the assay. It holds as long as the pituitary itself is working, since a pituitary problem can leave TSH normal or low while thyroid hormone is genuinely low.

There is a second thing about TSH that matters more than the reference range. Each person has their own set point. A person's free T4 and TSH oscillate within a band much narrower than the published population range, and where that band sits is mostly inherited. The published range has to be wide because it has to cover everybody's narrow band at once.

Two things come from this. Firstly, a result sitting inside the range is not automatically normal for the person it came from. Secondly, a series of measurements on the same person carries far more useful information than one measurement compared against a population.

The machinery that turns T4 into T3

The thyroid mostly makes T4, which is a prohormone so it has to be converted before it can exert its effects. Most of the T3 in your blood was not made by the thyroid at all. It was made from T4 elsewhere.

That conversion is done by three enzymes called the iodothyronine deiodinases, and they are the real control layer in this system.

Type 1 deiodinase sits mainly in liver and kidney. It contributes to the T3 circulating in blood, and it clears reverse T3.

Type 2 deiodinase sits in brain, pituitary, brown fat and skeletal muscle. It is a local activator which converts T4 into T3 inside the tissue that needs it. Not all of that T3 stays put, and in people with normal thyroid function type 2 is thought to supply more of the T3 in the blood than type 1 does.

Type 3 deiodinase is the off switch. It cuts T4 on the other ring, producing reverse T3, and it inactivates T3 as well. Reverse T3 is not a separate hormone with its own job. It is what you get when the same molecule is cut in the wrong place, and it has no thyroid activity of its own.

Metabolism does genuinely slow when this enzyme is active. Type 3 deiodinase is doing 2 things at once: destroying active T3, and diverting T4 into reverse T3 instead of T3. Less accelerator, and more of something that is essentially useless.

The result of all of these enzymes is local control, and it changes how you read the whole panel. A tissue can raise or lower its own thyroid hormone level mostly independently of what is in the blood, by changing how much of each enzyme it makes. Type 2 activity rises when thyroid hormone falls, which protects the tissue's own T3 while blood levels are dropping. So blood levels and tissue levels are not the same thing, and a blood test measures the first.

This is also what the argument about free T3 is really about. The pituitary runs on type 2, generating its own T3 from T4 locally and adapting as it does so. TSH therefore reports the pituitary's view of thyroid status. That is a real view, sensitively measured, but it is one tissue's. Whether it can stand in for the liver's and the muscle's is the actual question underneath a debate that usually gets conducted as though it were about assay quality.

Two more things come out of the same mechanism. Type 3 activity rises during serious illness, after injury and in starvation, pushing T4 towards reverse T3 rather than T3. So thyroid hormones genuinely shift in someone who is unwell, without any thyroid disease being present. And all three enzymes contain selenium at their active site, which is one of the links between the Minerals and bone section and this one.

What the profile looks at

Free T4 is the main hormone the thyroid makes, and mostly a starting material for the conversion to T3.

Free T3 is the active form, and most of it is converted from T4 out in the tissues rather than produced by the gland.

The word free is doing real work in both. The overwhelming majority of thyroid hormone in your blood is bound to carrier proteins and cannot enter a cell. Only the small unbound fraction is available, and that is the fraction these tests measure.

Total thyroxine, which can be added to any venous test, measures T4 including the bound portion, so it reflects the carrier proteins as well as the hormone.

Thyroid antibodies, TPO and thyroglobulin, come as a single add-on. They answer a different question from the rest of the profile. They look at whether the immune system is involved rather than how much hormone is present.

That question is worth asking because the immune system is usually the culprit. Where there is enough iodine in the diet, the most common cause of an underactive thyroid by a long way is the immune system attacking the gland, which is Hashimoto's thyroiditis. It is one of the most common organ-specific autoimmune conditions there is, and it affects women several times more often than men.

Two things about the result matter before you order it. Antibodies are present in more than 1 in 10 women in the general population, most of whom have entirely normal thyroid function, so a positive on its own is not a diagnosis and plenty of people carry them for years with nothing happening. And about 1 in 10 people who do have autoimmune thyroid disease have no detectable antibodies at all, so a negative does not rule it out either.

What antibodies give you is direction. A raised TSH with antibodies present has a cause attached to it. A raised TSH without them is the same number with the question still open. And since the answer rarely changes, this is a once-ever test rather than something to repeat.

What moves each of these numbers, and what to know before reading one, is in the Biomarker Guide.

What changes when the thyroid is under strain

An underactive thyroid tends to slow things down: tiredness, feeling cold, weight gain, dry skin, thinning hair, constipation, low mood, slower thinking. An overactive one speeds them up: weight loss, feeling hot, palpitations, anxiety, tremor, loose stools, difficulty sleeping.

Both lists read like modern life. That is exactly why the measurement matters more than the symptom.

One connection is worth carrying over to the Muscle section. An underactive thyroid raises creatine kinase on its own, and it increases the risk of muscle injury in people taking a statin. So a raised creatine kinase with muscle symptoms is a reason to look at thyroid function rather than to stop at the obvious explanation.