D3, the deiodinase enzyme that makes reverse T3 (NOT Vitamin D3)

Because reverse T3 is elevated when a certain deiodinase enzyme known as D3 is high, a closer look at D3 is warranted.  D3 is the deiodinase enzyme that converts T4 to reverse T3 and inactivates T3 to T2.  Its purpose is to keep T3 levels low.  D3 is absent from most adult tissues, though it is found in the skin and certain parts of the brain.  It is also found in fetal tissues, the uterine endometrium, and placenta, where it serves to protect the fetus from the mother’s adult levels of thyroid hormones. [16]

There is a condition called Nonthyroidal Illness Syndrome (NTIS), also known as euthyroid sick syndrome or low T3 syndrome, where reverse T3 is high, T3 is low, and T4 and TSH are normal.  This condition is the result of a change in the proportion of the three deiodinase enzymes (D1, D2, D3) that convert the various thyroid hormones.  In NTIS, they work together to lower T3 and raise reverse T3, making the patient more hypothyroid.  The illness itself causes the derangement in thyroid levels. [15]  This is an important concept to understand–the thyroid itself has not gone bad (as in autoimmune disease), but a serious illness has taken control of, and downregulated thyroid levels. These are the patients that can take the high doses of T3 recommended in this protocol without any hyperthyroid symptoms, because their extremely high D3 levels inactivate much of their T3.

The brain and spinal cord prefer stable blood serum T3 levels.  The deiodinase enzymes work together to ensure that T3 levels are kept at the same, ideal level in all conditions.  A rise in T3 will also cause a rise in D3 levels, increasing T3 clearance to T2, while D2 levels are decreased, decreasing T3 production.  More T4 would follow the reverse T3 pathway, so less T3 would be made. [17]  In effect, too high a dose of T3 can cause high reverse T3, by increasing the D3 enzyme.  Desiccated thyroid has a higher proportion of T3 than produced by the human thyroid gland, so as some patients raise their desiccated dose, their reverse T3 also increases.  Desiccated thyroid also contains reverse T3, so while it raises Free T3, it also raises reverse T3.  A large dose of T3 taken all at once (when T4 is also present) could also have the same effect and raise reverse T3 levels.

D3 is reactivated in certain medical conditions in adults.  After a heart attack, the heart muscle itself expresses D3.  Mice who suffered heart attacks were found to have increased D3 activity in the heart muscle, with a corresponding 50% decrease of T3 in left ventricular tissues. [18]  This implies that patients who have had cardiac episodes may always have high reverse T3 levels, and there are some people on the thyroid internet forums that fit this profile.

High D3 activity has been found in vascular (blood vessel), brain, and other tumors, and some malignant cancers. [69]  There is even a condition called consumptive hypothyroidism, where D3 activity from a tumor is so pronounced that it literally consumes any thyroid hormone, resulting in profound hypothyroidism.  Blood serum T4 and T3 levels do not increase even with increasing doses of T4 medication, though reverse T3 stays high. [19]  In one case, high levels of D3 were found in a woman’s liver tumor, and her elevated TSH returned to normal after the mass was surgically removed. [20]

D3 can also be reactivated when cell proliferation is desired, to lower T3, which stimulates cell differentiation and inhibits cell growth.  Healing from a burn is an example where cell proliferation is desired, to regenerate new tissue.  In one experiment of partial liver removal in rats and mice, D3 activity increased 40-fold in the mice 36 hours after surgery.  In the rats, there was a corresponding 2- to 3-fold decrease of blood serum and liver T3 and T4 levels 20 to 24 hours after the surgery. [21]  Other studies show high D3 activity in various states of tissue injury: starvation, cryolesion (frostbite or medical procedures that purposely freeze tissue to destroy it), cardiac hypertrophy (thickened heart muscle, usually due to high blood pressure), infarction (heart attack), and chronic inflammation. [22]  High reverse T3 should then be expected anytime there is tissue damage that needs repair.

Another experiment showed that during acute bacterial infection, granulocytes (a type of white blood cell) in infected organs expressed D3, and serum thyroid hormones decreased proportionately to the severity of the illness.  D3 was also highly expressed in response to chemical inflammation (a turpentine induced abscess). [23]  Infections and abscesses would then be expected to cause high reverse T3.

Perhaps those with high reverse T3 have an underlying condition, like those just listed in the paragraphs above.  Quite a few thyroid patients have reported tonsillectomies (infection/inflammation), hysterectomies (fibroid tumors), heart conditions, problem root canals (infection), and various cancers.  Sinus infections and gut inflammation (celiac) are other possible causes.

Recent research shows individual genetic differences in many aspects of thyroid physiology, and these can all impact T3 and reverse T3 levels.  Genetic variations have been found in the TSH receptor, thyroid hormone receptors, thyroid transporters (that take hormone into the cells), and the deiodinase enzymes (a variation in D2 correlates with diabetes, and diabetics have high reverse T3). [24]


15. Simone Magagnin Wajner, Iuri Martin Goemann, Ana Laura Bueno, P. Reed Larsen, and Ana Luiza Maia. IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.  J Clin Invest.2011 May 2;121(5): 1834–1845. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083773/

16. Huang SA. Physiology and pathophysiology of type 3 deiodinase in humans. Thyroid. 2005 Aug;15(8):875-81.  http://www.ncbi.nlm.nih.gov/pubmed/16131330

17. Antonio C. Bianco and Brian W. Kim. Deiodinases: implications of the local control of thyroid hormone action.  J Clin Invest.2006;116(10):2571–2579. http://www.jci.org/articles/view/29812/version/1

18. Pol CJ, Muller A, Zuidwijk MJ, van Deel ED, Kaptein E, Saba A, Marchini M, Zucchi R, Visser TJ, Paulus WJ, Duncker DJ, Simonides WS. Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology. 2011 Feb;152(2):669-79. Epub 2010 Dec 15. http://www.ncbi.nlm.nih.gov/pubmed/21159857?dopt=Abstract

19. Howard D, La Rosa FG, Huang S, Salvatore D, Mulcahey M, Sang-Lee J, Wachs M, Klopper JP. Consumptive Hypothyroidism Resulting from Hepatic Vascular Tumors in an Athyreotic Adult. J Clin Endocrinol Metab. 2011 Apr 20.  http://www.ncbi.nlm.nih.gov/pubmed/21508133?dopt=Abstract

20. Huang SA, Fish SA, Dorfman DM, Salvatore D, Kozakewich HP, Mandel SJ, Larsen PR. A 21-year-old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase. J Clin Endocrinol Metab. 2002 Oct;87(10):4457-61. http://www.ncbi.nlm.nih.gov/pubmed/12364418?dopt=Abstract

21. Kester MH, Toussaint MJ, Punt CA, Matondo R, Aarnio AM, Darras VM, Everts ME, de Bruin A, Visser TJ. Large induction of type III deiodinase expression after partial hepatectomy in the regenerating mouse and rat liver.  Endocrinology. 2009 Jan;150(1):540-5.  http://www.ncbi.nlm.nih.gov/pubmed/18787028?dopt=Abstract

22. Huang SA, Bianco AC. Reawakened interest in type III iodothyronine deiodinase in critical illness and injury. Nat Clin Pract Endocrinol Metab. 2008 Mar; 4(3):148-55.  http://www.ncbi.nlm.nih.gov/pubmed/18212764

23. Boelen A, Boorsma J, Kwakkel J, Wieland CW, Renckens R, Visser TJ, Filers E, & Wiersinga WM. Type 3 deiodinase is highly expressed in infiltrating neutrophilic granulocytes in response to acute bacterial infection. Thyroid 18: 1095-1103, 2008.  http://www.ncbi.nlm.nih.gov/pubmed/18816180

24. Wendy M van der Deure, Robin P Peeters and Theo J Visser. Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters.  J Mol Endocrinol 201044 1-11.  http://jme.endocrinology-journals.org/content/44/1/1.full

69. Sibilio, A., Ambrosio, R., Bonelli, C., De Stefano, M. A., Torre, V., Dentice, M., & Salvatore, D. (2012). Deiodination in cancer growth: the role of type III deiodinase. Minerva endocrinologica, 37(4), 315-327. http://www.ncbi.nlm.nih.gov/pubmed/23235188