REVIEW: Genes MCT10 and DIO2 and combination therapy

OUR GENES can partly explain our body’s individual response to T4 in thyroid meds like Synthroid / Levothyroxine.

It may explain why some thyroid patients do just fine on Synthroid / Levothyroxine, while others continue to have hypothyroid symptoms.

Review of:

Carlé, A., Faber, J., Steffensen, R., Laurberg, P., & Nygaard, B. (2017). Hypothyroid Patients Encoding Combined MCT10 and DIO2 Gene Polymorphisms May Prefer L-T3 + L-T4 Combination Treatment—Data Using a Blind, Randomized, Clinical Study. European Thyroid Journal, 6(3), 143–151.


Reduced T4-T3 conversion

A lot of research lately has proven that DIO1 and DIO2 gene polymorphisms can reduce T4-T3 conversion in patients on T4-only.

This reduction becomes significant when patients levels of T3 are even slightly under their individual healthy set point.

You don’t need to have T3 levels below reference or a TSH above reference to be deficient from your body’s point of view. An individual’s set point is narrower than the statistical lab reference range.

DIO1 polymorphisms can reduce T3 availability in bloodstream. If levels drop below the individual’s set point, they can harm the cardiovascular system and organs that depend on T3 supply from serum

DIO2 polymorphisms are especially bad for your other organs that have less access to T3 in bloodstream and depend on D2 for conversion. Even if your T3 levels in blood are okay, you’re not converting T4 to T3 in your cells and tissues as much, and therefore your brain and bones might not be getting enough T3.

Reduced thyroid hormone transport

More recently, researchers have been investigating some of the genes responsible for T4 and T3 transport into the cells, such as MCT10 and many others.

These are important to our understanding of conditions like osteoporosis and mental decline in patients whose T4 and T3 levels in blood seem “normal.”

Each organ and system relies on certain thyroid hormone transporters more than others.

  • Therefore, if thyroid hormones can’t get into certain organs, those will be deficient while the rest of the body could be fine.

Some transporters prefer to carry T3 rather than T4.

  • If thyroid hormone levels in blood are unevenly skewed toward higher Free T4, this may cause a problem for patients who can’t efficiently carry T4 into cells where it can be converted later into T3. They will therefore be more dependent on blood levels of Free T3.

This article

These genetic variants may all cause limited FT3 supply in cells for patients on LT4-only. This research focused on DIO2 and MCT10.


This article by Carle and team conducted a trial that replaced 50 mcg of the patients’ LT4 therapy with 20 mcg of T3, and then adjusted the therapy to normalize TSH.

They looked at 3 polymorphisms in DIO2 as variables:

  • rs225014 (Thr92Ala),
  • rs225015, and
  • rs12885300 (ORFa-Gly3Asp)

They also looked at an MCT10 thyroid hormone transporter polymorphism as a variable:

  • rs17606253

Unfortunately the article claims thyroid patients with these two polymorphisms would “prefer” combination T4/T3 therapy.  This makes it seem as if FT3 availability is a “preference” not a health issue.

But in the researchers’ defense, they wanted some way of measuring the effect of thyroid hormone on peripheral tissues, which you can’t always measure in serum, so they used symptom questionnaires.

They also looked at weight change, but not every thyroid patient is overweight to start with, and weight is not going to change much in a short trial of T4/T3 therapy.

They really should have measured well-established peripheral hypothyroidism markers like ankle reflex and basal metabolic rate.


Despite the limitations of their study, most patients preferred combination therapy.

>> “27 patients (60%) preferred the combined L-T3 + L-T4 treatment, 7 patients preferred the L-T4 monotherapy, whereas 11 patients had no preference”

In addition, these two genetic polymorphisms were associated with patient preference for combination therapy.

>>> “subjects harbouring the combination of 2 polymorphisms (rs225014 encoding the DIO2 enzyme and rs12885300 encoding the MCT10 transporter) were more prone to benefit from the experimental L-T3 + L-T4 combination therapy.”

So my dear researchers, this is very interesting and promising, but please, in future, measure more than weight loss and preference so you can actually tell us if these polymorphisms make a difference to the bottom line of T3 getting into hormone receptors in the brain and body… keep researching…

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