Pathology explained · Thyroid
Thyroid hormone movement: how T4 becomes T3, and what gets in the way.
Your thyroid mostly makes T4, a storage hormone that does very little on its own. The hormone that actually switches your cells on is T3, and most of it is made outside the thyroid, one step at a time. That step needs specific nutrients, and under stress the body can steer it down a different road entirely. This page walks through the whole journey, from the signal in the brain to the lock on the cell.
The short version
TSH is the signal. T4 is the storage form. T3 is the active form. One enzyme makes the switch from T4 to T3, and it cannot work without selenium, zinc, iron and glutathione. Under stress, illness or too little food, T4 is diverted into reverse T3 instead, a brake that fits the cell’s lock but will not turn it.
core helpers the switching enzyme depends on: selenium, zinc, iron and glutathione. If one runs low, less T3 gets made.
The pathway in four steps
Thyroid hormone does not go straight from gland to cell. It moves through a short chain of steps, and each one can be the place where things slow down.
The brain sends the signal
Thyroid stimulating hormone (TSH) is released by the pituitary gland. It is an instruction, not a thyroid hormone: “make more”. A higher TSH means the brain is asking harder. Many functional practitioners aim toward a TSH of about 1 to 2, which sits well inside the standard lab band. There is more on that in TSH: the standard range vs the functional range.
The thyroid makes T4
The gland builds T4 from iodine and the amino acid tyrosine, which comes from protein. T4 carries four iodine atoms. It is stable and long lasting, which is why it is the storage form, but it is only weakly active. Iron is also needed here, because the enzyme that attaches iodine depends on it.
T4 is switched into T3
Enzymes called deiodinases remove one iodine atom from T4. What is left is T3, which is several times more active. This happens mostly in the liver, kidneys, muscle and gut, not in the thyroid. The enzyme is built around selenium and needs zinc, iron and glutathione to keep working. Insulin, a signal that you have eaten enough, also supports it.
T3 turns the key in the cell
T3 enters the cell and binds to a receptor, which works like a lock. When T3 turns it, the cell switches on: energy production, warmth, clear thinking, a steady heart rate, healthy hair and skin. Zinc, vitamin A and vitamin D all help this receptor respond properly.
The picture
This is the diagram we draw in clinic. Green boxes are the active road. The grey box is the brake. Both roads end at the same lock.
The figures in brackets are the targets many functional practitioners aim toward (TSH in mIU/L, free T4 and free T3 in pmol/L). They are narrower than the standard laboratory range and are a prompt to look closer, not a diagnosis on their own.
The helpers: what each one actually does
The enzyme that turns T4 into T3 is a piece of machinery. Like any machinery, it has parts it cannot run without. These four are the ones that most often decide how well the switch works.
Selenium
The switching enzyme is literally built around selenium. It sits at the cutting point, in the form of an amino acid called selenocysteine. Low selenium means a slow enzyme, so less T3 gets made. It also protects the thyroid from the oxidative stress that iodine handling creates.
Zinc
Keeps the switching enzyme working, and helps shape the receptor inside the cell where T3 plugs in (a “zinc finger” structure). Low zinc means less T3 made, and less T3 heard. Zinc is also needed for the brain to release TSH in the first place.
Iron
Thyroid peroxidase, the enzyme that attaches iodine when T4 is being built, depends on iron. Low iron stores (low ferritin) also slow the T4 to T3 switch. This is one reason a person can have a normal TSH and still feel underactive. Ferritin is worth checking alongside thyroid markers.
Glutathione
The switching enzyme uses up chemical “charge” every time it makes a cut and needs recharging before the next one. Glutathione and related thiol compounds do that recharging. Your body makes glutathione from the amino acid cysteine, so adequate protein matters here too.
The supporting cast
| Helper | What it does |
|---|---|
| Magnesium | Powers the energy dependent steps that make and move thyroid hormone. |
| Vitamin B2, B3, B6 | Recycle glutathione so the enzyme can keep working, and help build the hormone. |
| Vitamin A | Partners with the T3 receptor so the cell hears the message clearly. |
| Vitamin D | Also sits alongside the receptor. Low vitamin D blunts the response to T3. |
| Iodine and protein | The raw materials. Without them there is no T4 to convert. |
| Insulin (eating enough) | Signals that fuel is available. Very low calorie intake lowers the switching enzyme’s activity. |
Reverse T3: why the body has a brake
T4 can go two ways. Down one road it loses an iodine atom from the outer ring and becomes T3, the active hormone. Down the other road it loses an iodine atom from the inner ring and becomes reverse T3 (rT3). Same starting hormone, one atom’s difference, opposite effect.
Reverse T3 is a mirror image of T3. It fits the same receptor in the cell, but it does not activate it. While it sits there, T3 cannot get in. The cell stays “off” even when the T3 level in the blood looks fine.
What pushes T4 toward reverse T3
| Driver | Why it matters |
|---|---|
| Ongoing stress, high cortisol | Cortisol shifts the balance of deiodinase enzymes toward the rT3 road. Long running stress is the most common driver we see. See stress and adrenal function. |
| Illness, injury, inflammation | Inflammatory signals suppress the T3 making enzyme and favour the rT3 one. This is well documented in hospital patients and is called non-thyroidal illness. |
| Very low calorie diets, long fasting | Falling insulin and leptin tell the body that fuel is short. Conversion to T3 drops within days and rT3 rises. |
| Low iron, selenium or zinc | The T3 road slows when its helpers run low, so relatively more T4 ends up as rT3. |
| Some medicines | Beta blockers, corticosteroids, amiodarone and some contrast agents can raise rT3. Always discuss medicines with your prescriber. |
What we look at in clinic
A standard thyroid check often measures TSH alone. That tells you about the signal, not about whether the hormone is being made, switched, and used. When symptoms and TSH do not agree, we look at the whole chain.
The hormones
TSH, free T4 and free T3 together show whether the problem is the signal, the making, or the switching. Reverse T3 shows whether the brake is on. Thyroid antibodies show whether the immune system is involved.
The helpers
Ferritin, zinc, selenium, vitamin D and a marker of protein status tell us whether the enzyme has what it needs. A pattern of low T3 with normal T4 often traces back to one of these rather than to the thyroid itself.
If this pattern sounds like you, our thyroid and metabolism page explains how we assess it, and hypothyroid food ideas covers the food side of supporting conversion.
Sources
Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 2006.
Peeters RP, Visser TJ. Metabolism of thyroid hormone. In: Endotext. 2017.
Köhrle J. Selenium and the thyroid. Curr Opin Endocrinol Diabetes Obes. 2015.
Zimmermann MB, Köhrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism. Thyroid. 2002.
Severo JS, et al. The role of zinc in thyroid hormones metabolism. Int J Vitam Nutr Res. 2019.
Chatzitomaris A, et al. Thyroid allostasis: adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming. Front Endocrinol. 2017.
Frequently asked questions
What is the difference between T4 and T3?
T4 is the storage form of thyroid hormone and the one the thyroid mostly makes. T3 is the active form that switches cells on. Most T3 is made outside the thyroid when an enzyme removes one iodine atom from T4, largely in the liver, kidneys, muscle and gut.
Why can T3 stay low when TSH is normal?
TSH only measures the signal from the brain. It does not show whether T4 is being switched into T3 or whether T3 is being used. Low iron, selenium or zinc, ongoing stress, illness or very low food intake can all slow the switch while TSH still reads as normal. Free T3 and reverse T3 give a fuller picture.
Which nutrients help convert T4 to T3?
The switching enzyme is built around selenium and also depends on zinc, iron and glutathione. Magnesium, B vitamins, vitamin A and vitamin D support the process, and adequate food intake matters because very low calories reduce conversion. Whether any supplement is appropriate depends on testing and should be discussed with a practitioner.
What is reverse T3?
Reverse T3 is made from T4 when an iodine atom is removed from the other ring. It is a mirror image of T3 that fits the same receptor in the cell but does not activate it. It acts as a brake on metabolism during stress, illness or low food intake, and becomes a problem when that state does not end.
Does stress affect thyroid hormone?
Yes. Ongoing stress and high cortisol shift the balance of the deiodinase enzymes toward making reverse T3 rather than T3. The result can be tiredness, feeling cold and sluggish metabolism even when standard thyroid tests look normal. Addressing the source of the stress is part of restoring normal conversion.
Reviewed by Rohan Smith, BHSc Nutritional Medicine · Elemental Health & Nutrition, Adelaide. Last reviewed 7 September 2026.
Important: This summary is general information, not personalised medical advice, diagnosis, or a treatment protocol. Speak with a qualified practitioner about your individual situation. Book a consultation →