The Gene Associated with "Hidden Hypothyroidism" (DIO2)

The DIO2 (Iodothyronine deiodinase 2) gene encodes an enzyme that converts T4, a storage thyroid hormone, into the active thyroid hormone, T3. It does so by removing one iodine atom from T4 [R].

DIO2 is responsible for T3 production in the thyroid, muscles, brain, heart, and fat tissue. It accounts for up to 60% of all T3, which has vital roles in energy production, blood sugar control, cognitive development, and more [R, R, R, R].

At first glance, one might think DIO2 doesn’t have much of an impact on thyroid health. Multiple studies failed to make a connection between variations in this gene and thyroid hormone levels [R, R].

But are they missing something?

“Hidden Hypothyroidism”

Many people have symptoms of low thyroid hormones despite their lab results being in the normal range. 

That might be because their thyroid hormones don’t function well on a cellular and tissue level, which cannot be measured by blood tests.

One DIO2 variant may be involved in this phenomenon. The less common “C” allele on rs225014 (Thr92Ala) is associated with:

• Poor response to thyroid meds [R, R]
• Obesity and insulin resistance [R]
• Inadequate blood sugar control [R]
• Impaired cognitive development (lower IQ) [R]

All of the above may indicate low thyroid hormones in DIO2 target tissues such as the brain, fat tissue, and muscles.

That said, a couple of larger trials concluded that DIO2 variants have a marginal association with weight gain and glucose metabolism. Other environmental and genetic factors play a more prominent role [R, R].

DIO2 enables the activation of thyroid hormones so they can play their crucial metabolic roles. One variant (rs225014-C) correlates with poor cognition, weight control, and glucose metabolism, which may indicate “hidden hypothyroidism.”

Response to Thyroid Meds

Did you know that synthetic T4 (levothyroxine) for hypothyroidism is the second most prescribed drug in the US? We’re witnessing a massive rise in thyroid disorders [R].

The same DIO2 variant (rs225014) is associated with an inadequate response to thyroid meds in some people.

Out of 45 patients, those who carried at least one “C” allele didn’t respond as well to standard T4 treatment and were significantly more depressed. They preferred a combination of T4 and T3 (liothyronine) instead [R].

A larger trial came to a similar conclusion, though the effects were significant only for patients who had both copies of the “C” allele [R].

A Dutch study with over 12,600 participants found no connection between DIO2 and thyroid treatment response. However, they didn’t investigate the effects of the T4+T3 combination [R].

Some carriers of the “C” allele on rs225014 may not respond as well to standard T4 treatment for hypothyroidism. They may prefer a combination of T4 and T3 instead.

Joe’s Experience

According to Joe’s experience with his clients:

“Thyroid hormones aren’t always beneficial for people with symptoms of hypothyroidism. They may even make things worse in some cases. It seems like some doctors overprescribe thyroid meds, while others may underprescribe them. It might be worthwhile to get opinions from both ‘conventional’ and ‘alternative’ endocrinologists if your results are not 100% clear.”

NOTE: Always consult with your doctor before taking or discontinuing any drug or nutritional supplement.

The “C” allele on rs225014 reduces DIO2 activity and thus hinders the production of active T3 in the brain, muscle, and fat tissue [R]. 

This effect may prevent thyroid hormones from boosting cognition, energy production, and glucose metabolism [R, R].

Doctors give synthetic T4 to thyroid patients and count on the body to produce the active form, T3. Possibly, due to impaired conversion in muscles and other tissues, patients with rs225014-C may prefer a combination of T4 and T3.

Given the expression of DIO2 in muscles, variations in this gene have a stronger correlation with thyroid hormones in young adults (and, presumably, those in better physical shape) compared with the elderly [R].

The “C” allele on rs225014 reduces DIO2 activity and T3 production. It may thus prevent thyroid hormones from boosting cognition, fat burning, and glucose metabolism, but more clinical research is needed to verify this. 

Primary SNP: DIO2 rs225014

• ‘C’ = associated with “hidden hypothyroidism”
• ‘T’ = not associated with “hidden hypothyroidism”

Population frequency:

Around 22% of the global and 14% of the European population have both copies of the “C” allele, so it’s not rare and not something to be alarmed about.