Genetic Causes of Low T3 and Hypothyroid Symptoms (with Normal TSH)

In a hurry? Click here to read the key takeaways. If you have some time, we should probably start by with a quick explanation of genetic SNPs…
There are several different reasons why people may not convert the inactive thyroid hormone T4 into the active thyroid hormone T3. These include weight loss, stress, nutrient deficiencies and inflammation, amongst others. However, researchers may have unmasked a new reason why patients may need both T4 and T3 hormones to feel their best. A common genetic SNP known as DIO2 Thr92Ala may be the reason. A genetic SNP (single nucleotide polymorphism) is a small difference in a gene that varies between individuals. We all have polymorphisms in our DNA – in fact more than 335 million SNPs have been found in humans. A SNP can change the way proteins are made in the body. 

Genetics and Thyroid Hormone Conversion

Research has found that a common genetic SNP DIO2 Thr92Ala affects thyroid hormone metabolism, reducing the conversion of T4 into T3. (1)

It has been known for some time that in patients who are treated with T4 medication, TSH levels within the reference range don’t guarantee tissue euthyroidism (e.g. the thyroid resuming normal function). (2) This means that your TSH can be totally normal, but your cells still aren’t getting the thyroid hormones they need – this is particularly true if you have low levels of T3 and normal TSH.

In the body, three enzymes known as deiodinases  regulate thyroid hormone activation and inactivation in cells. Dio2 encodes for deiodinase 2, which is involved in converting T4 to the active hormone, T3.

Currently, DIO2 is believed to produce most of the T3 that’s required each day, while DIO1 provides a relatively smaller amount. In addition, the T3 produced by DIO1 exits the cell in around 30 minutes, whereas that produced by DIO2 remains in the cell for around 8 hours. (3)

What’s interesting is that this thyroid-related genetic SNP seems to occur in around 15-30 % of individuals. Studies have found that this polymorphism is associated with diseases ranging from metabolic to mental health, and an altered hypothalamic pituitary thyroid axis that’s “sluggish” in producing thyroid hormones in response to TSH. (4)

Effects of polymorphisms in DIO genes

PolymorphismDeiodinase activityThyroid Hormone
Cys785Thr(DIO1)DecreasedIncreased T3 levels and reduced T3:rT3 ratio
Alal814Gly (DIOl)IncreasedIncreased T3 levels and increased T3:rT3 ratio
Thr92Ala (DIO2)DecreasedIncreased T4 and reduced T3 levels, and reduced T3:T4 ratio
ORFa-G3A (DIO2)IncreasedReduced T4 levels and increased T3:T4 ratio
Thrl54Gly (DIO3)UnchangedUnchanged
Table Ref: Luongo et al 2019

Each Patient is Unique

This is likely why many patients simply never feel well on T4 only replacement. At the clinic, we frequently treat patients who have “normal” levels of TSH, and low T3 levels and have never felt well since their hypothyroidism diagnosis. This is despite being on a recommended dose of T4-only medication which they are having difficulty converting to the active form T3. What we’ve found is that each patient is unique and requires individual attention to the various factors that may be affecting their response. This involves medication that includes both T3 and T4 (and all of the other thyroid hormones), as well as adjusting a variety of lifestyle factors. In the clinic we use natural dessicated thyroid (Erfa) in highly customized doses to help patients overcome persistent symptoms of hypothyroidism. Often this is the answer for patients taking T4 only medication who are still symptomatic. Symptoms of low T3 include fatigue, brain fog, slow metabolic rate, weight gain, constipation, dry skin and depression.

Key Takeaways from this article

  • a common genetic SNP DIO2 Thr92Ala affects thyroid hormone metabolism, reducing the conversion of T4 into T3
  • This thyroid-related genetic SNP seems to occur in around 15-30 % of individuals and this is likely why many patients simply never feel well on T4 only replacement despite showing “normal” levels of TSH.

Next Steps What to do If you have persistent hypothyroid symptoms

If you’re trying to find as much information you can on hypothyroid symptoms, we recently published a similar article on different types of thyroid hormone treatments that can help patients who have low T3 levels and hypothyroid symptoms. If you missed that article, check it out here: Why Do I Still Feel Hypothyroid on Synthroid?

As far as general reading on thyroid, here’s a list of all our thyroid focused articles if you’d like to browse our library.

If you are trying to address hypothyroid symptoms with your doctor and are still seeing symptoms despite normal TSH levels, here are some things to keep in mind or to discuss with your doctor.

  1. The full thyroid panel including TSH, free T3, free T4, Anti TPO, Anti TG and reverse T3 are important to fully understand thyroid function.
  2. Thyroid health can shift due to changes in hormones, weight or lifestyle. Always get reassessed if you feel something isn’t right even if you’ve been on the same dosage for years.
  3. Patients with positive thyroid antibodies are more likely to develop hypothyroidism over time and experience fluctuations in their thyroid hormone levels – and as a result need more monitoring.

If you’re in the Toronto area and feel like your hypothyroid symptoms are present despite normal TSH levels, our doctors are familiar with the contents of all our articles and would be happy to take a deeper look at your case!  You can read about our Naturopathic Thyroid Program, or click here to book online!

Studies and publications referenced in this article

  1. Luongo, C., Dentice, M., & Salvatore, D. (2019, August 1). Deiodinases and their intricate role in thyroid hormone homeostasis. Nature Reviews Endocrinology. Nature Publishing Group. https://doi.org/10.1038/s41574-019-0218-2
  2. Yavuz, S., Salgado Nunez del Prado, S., & Celi, F. S. (2019). Thyroid Hormone Action and Energy Expenditure. Journal of the Endocrine Society, 3(7), 1345–1356. https://doi.org/10.1210/js.2018-00423
  3. Bianco, A. C., & Silva, J. E. (1987). Nuclear 3,5,3‖-triiodothyronine (t3) in brown adipose tissue: Receptor occupancy and sources of t3 as determined by in vivo techniques. Endocrinology, 120(1), 55–62. https://doi.org/10.1210/endo-120-1-55
  4. Butler, P. W., Smith, S. M., Linderman, J. D., Brychta, R. J., Alberobello, A. T., Dubaz, O. M., … Celi, F. S. (2010). The Thr92Ala 5’ type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: A pharmacogenomic study. Thyroid, 20(12), 1407–1412. https://doi.org/10.1089/thy.2010.0244

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