Deiodinase type 3 and Reverse T3

The Three Deiodinases

Every person has three deiodinases responsible for thyroid hormone conversion.

Dear thyroid patients: if you’ve never heard about the deiodinases, your life and future health may depend on you learning. They can either work with your thyroid meds or against them. It’s a lifelong condition, being on thyroid therapy, so there’s time for it to sink in. I don’t have a bioscience degree and I eventually got this.  Don’t be intimidated. There are only some new words and concepts to learn.

Read about Deiodinase type 1 and Type 2 in the PART 1 blog post:

• How the three deiodinases regulate T3

Deiodinase type 3

• The DIO3 gene is responsible for producing the Deiodinase type 3 enzyme (D3).
• This gene is very sensitive to its environment: it is very flexible to “epigenetic” influence. It is ready to spring into action very quickly when called upon.
• DIO3 is highly expressed in the placenta, where it is believed to play a role in preventing excess thyroid hormone from transferring from the mother to the developing fetus. In adult life, it is mainly expressed when called upon.

How D3 works

• Deiodinase type 3 inactivates T4 to Reverse T3 and at the same time, inactivates T3 to T2.
• Normally, the three diodinases are in active balance with each other, carefully maintaining healthy levels of T3 hormone.
• However, in certain situations, D3 becomes overactive and it can deplete T3 hormone.

When does D3 become overactive?

• The role of DIO3 is to monitor the supply of thyroid hormone above the body’s current “set point.”
• In illness, it lowers the metabolic rate by depleting T3, the active thyroid hormone.
• In case of oversupply of T4 or T3 above the body’s set point, it removes what it believes to be excess thyroid hormone by inactivating both at the same time.

Then what happens?

• D3-mediated hormone inactivation occurs in all locations, within the bloodstream as well as within cells and peripheral tissues.
• The deiodinases are in reciprocal relationship, so when DIO3 is upregulated, DIO1 is downregulated, and it thereby slows down D1 hormone conversion activity in the bloodstream.
• It is also in reciprocal relationship with D2, so when DIO3 is upregulated, it slows down D2 conversion activity in the cells and peripheral tissues.
• When Deiodinase type 3 dominates over D1 and D2, the net effect is the depletion of the T3 hormone to the degree that D3 dominates.

How bad can it get?

• In critical illness, it can deplete T3 to very low levels within days. Unfortunately, as T3 levels become lower, the body becomes weaker and sicker. Research says that the lower T3 goes, the greater is the chance a sick person will die.
• Because D1 and D2 activity regulate T3 supply differently in each organ, each bodily organ and system may suffer to a different degree. The harm of T3 depletion also depends on which bodily systems are weakest in that particular individual.
• Even though the body is trying to lower its set point or get rid of excess T3, this process can get out of hand. There are costs and consequences. A T3 deficiency is always harmful, whether it happens temporarily when a person is very ill, or whether it is maintained chronically over the long term.
• Learn more about this process here:
  • GRAPHIC and discussion: T3 Depletion

Measuring D3 activity

• In people with normal thyroid glands who are NOT taking thyroid hormones, the body’s set-point for thyroid hormone is most likely to be reduced by illness. DIO3 will be stimulated to the degree that you are ill.
  • T3 levels will drop first, followed later by T4 levels.
  • The TSH will not rise, since the pituitary gland does not sense a thyroid hormone deficit.
• In thyroid patients who ARE taking thyroid hormones, The thyroid hormone set-point may be lowered by illness AND/OR the intake of thyroid hormone may temporarily or continually exceed the set-point. DIO3 can be stimulated by either or both because it monitors the set-point.
  • TSH will be maintained until or unless T4 begins to be depleted.
    • Because TSH secretion is primarily tied to T4, the TSH will not rise above reference range to notify the doctor that the most vital thyroid hormone, T3 is being depleted.
    • The pituitary gland, which secretes TSH, upregulates its D2 enzyme in times of T3 deficiency. It can survive a T3 deficiency by converting more T4 to T3 within its own tissues. Meanwhile, the rest of the body may suffer Low T3.
  • T4 and T3 thyroid hormones:
    • If the patient is on L-T4 monotherapy, a distinctive pattern appears in their blood test results, as described below. (The pattern may be less extreme if the patient is supplying T3 to the body via T4/T3 combination therapy, whether synthetic or desiccated thyroid).
    • Free T4 levels will be maintained to the degree that the patient keeps replenishing the T4 supply every day by taking their pill.
    • Free T3 levels will be lower in their reference range. As long as the patient continues to take the same dose of T4 every day, the DIO3 gene will remain active at the same level, and the Free T3 level will remain low.
    • The result is a lower T3:T4 ratio and a lower T3 supply. In extreme DIO3 activity, Free T4 hormone levels can be at the top or above the reference range while Free T3 levels are near the bottom of reference range, or even below reference range.
    • This puts the body in a state of biochemical hypothyroidism due to T3 deficiency even while T4, the inactive hormone, is in excess.

Reverse T3

• To the degree D3 is overactive, Reverse T3 will build up in the body.
  • Reverse T3 is the most abundant product of D3 conversion because of its inactivation of T4 hormone, which is usually far more abundant in blood than T3.
  • Because D1 is also responsible for breaking down Reverse T3 into T2, when DIO3 is dominant and DIO1 is suppressed, Reverse T3 will be broken down more slowly. This also contributes to Reverse T3 buildup in the bloodstream.
  • The Reverse T3 test is available at some laboratories in most developed nations, or blood can be shipped by courier to a laboratory that offers the test.  We don’t yet have access to a commercial test that can measure T2 hormones; it is currently studied only in research.
  • This buildup of Reverse T3 in blood makes it a useful marker of the degree of D3 activity, when interpreted in light of the Free T4:T3 ratio and T3 levels in blood.

Related posts and pages

• Thyroid patients excluded from research
• Rationale: Low T3 Syndrome, part 1
• Rationale: Low T3 syndrome, part 2

REFERENCES

Thyroid hormone conversion (and inactivation)

Arrojo e Drigo, R., & Bianco, A. C. (2011). Type 2 deiodinase at the crossroads of thyroid hormone action. The International Journal of Biochemistry & Cell Biology, 43(10), 1432–1441. https://doi.org/10.1016/j.biocel.2011.05.016

Charalambous, M., & Hernandez, A. (2013). Genomic imprinting of the type 3 thyroid hormone deiodinase gene: Regulation and developmental implications. Biochimica et Biophysica Acta, 1830(7), 3946–3955. https://doi.org/10.1016/j.bbagen.2012.03.015

Chatzitomaris, A., Hoermann, R., Midgley, J. E., Hering, S., Urban, A., Dietrich, B., … Dietrich, J. W. (2017). Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00163

Larsen, P. R., & Zavacki, A. M. (2012). Role of the Iodothyronine Deiodinases in the Physiology and Pathophysiology of Thyroid Hormone Action. European Thyroid Journal, 1(4), 232–242. https://doi.org/10.1159/000343922

Sabatino, L., Lubrano, V., Balzan, S., & Kusmic, C. (2015). Thyroid hormone deiodinases D1, D2, and D3 are expressed in human endothelial dermal microvascular line: Effects of thyroid hormones. Molecular and Cellular Biochemistry, 399(1–2), 87–94. https://doi.org/10.1007/s11010-014-2235-8

Taylor, P. N., Peeters, R., & Dayan, C. M. (2015). Genetic abnormalities in thyroid hormone deiodinases: Current Opinion in Endocrinology & Diabetes and Obesity, 22(5), 402–406. https://doi.org/10.1097/MED.0000000000000180

Too, H. C., Shibata, M., Yayota, M., & Iwasawa, A. (2017). Iodothyronine deiodinases: key enzymes behind the action of thyroid hormone. Reviews in Agricultural Science, 5(0), 45-55–55. https://doi.org/10.7831/ras.5.44-55