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Pathophysiological relevance of deiodinase polymorphism

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Further thoughts on DIO2 polymorphisms. Bianco - again.

Curr Opin Endocrinol Diabetes Obes. 2018 Jul 30. doi: 10.1097/MED.0000000000000428. [Epub ahead of print]

Pathophysiological relevance of deiodinase polymorphism.

Bianco AC1, Kim BS2.

Author information

1 Division of Endocrinology, University of Chicago.

2 Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois, USA.



To assess new findings and clinical implications of deiodinase gene polymorphism. Deiodinases are enzymes that can activate or inactivate thyroid hormone molecules. Whereas the types 1 and 2 deiodinase (D1 and D2) activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3) via deiodination of T4's outer ring, D1 and D3 inactivate both T4 and T3 and terminate thyroid hormone action via deiodination of T4's inner molecular ring. A number of polymorphisms have been identified in the three deiodinase genes; the most investigated and likely to have clinical relevance is the Thr92 substitution for Ala substitution in DIO2 (Thr92Ala-DIO2). There are a number of reports describing the association between the Thr92Ala-DIO2 polymorphism and clinical syndromes that include hypertension, type 2 diabetes, mental disorders, lung injury, bone turnover, and autoimmune thyroid disease; but these associations have not been reproduced in all population studies.


A new report indicates that carriers of the Thr92Ala-DIO2 polymorphism exhibit lower D2 catalytic activity and localized/systemic hypothyroidism. This could explain why certain groups of levothyroxine-treated hypothyroid patients have improved quality of life when also treated with liothyronine (LT3). Furthermore, Ala92-D2 was abnormally found in the Golgi apparatus, what could constitute a disease mechanism independent of T3 signaling. Indeed, brain samples of Thr92Ala-DIO2 carriers exhibit gene profiles suggestive of brain degenerative disease. In addition, African American carriers of Thr92Ala-DIO2 exhibit an about 30% higher risk of developing Alzheimer's disease.


The finding of deiodinase polymorphisms that can diminish thyroid hormone signaling and/or disrupt normal cellular function opens the door to customized treatment of hypothyroidism. Future studies should explore how the racial background modulates the clinical relevance of the Thr92Ala-DIO2 gene polymorphism.

PMID: 30063552

DOI: 10.1097/MED.0000000000000428

Full paper behind paywall.

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Oh yes 😊 I knew combination therapy was better for me.

Oh no 😣 Looks like I have a greater chance of getting Alzheimer"s.

in reply to Musicmonkey

Press report today that lifting a glass in middle age may be preventative of alzheimers.

I was put on levothyroxin over 20 years ago. I did have a vast improvement of my terrible thyroid symptoms. I'd gained a lot of weight which I couldn't shift and I'd been sleeping over 20 hours every day. I just could not stay awake.

On levo, I lost a small amount of weight and slept a lot less but still a lot 12 to 14 hours a day. I still felt unwell all the time - mostly feeling "out of it". I had poor memory and poor concentration. The mornings were worst as I struggled to get going - just sitting in a chair for over an hour trying to wake up.

I'd read about liothyronine and argued with various doctors about being prescribed it. it took several years before I was finally referred to an endo. I had quite an argument with him. I think more to get rid of me than anything else, he authorized me having 20 mg once a day, to be taken on waking.

This helped enormously in the morning but by the afternoon I was as bad as I had been before. I argued with various doctors who told me that I was imagining my symptoms in the afternoon and evening!!

After eight or nine years I finally got referred to another endo. This time I saw a newly qualified guy. He said that he had read about people needing liothyronine more than once a day. He said most people did not need liothyronine at all. He said he was happy for me to have 20mg x three times a day as long as I understood it may make no difference, it may make me worse or it might make be better. He said I should give it 3 months.

The difference was truly amazing. I lost all the extra weight. I could concentrate again. I had my life back. I felt better than I had for over 20 years.

When I returned to the hospital, I saw the head endo. He told me to immediately stop ALL liothyronine. It is very dangerous to be on it and it will shorten my life considerably. I walked out.

I had a minor argument with my gp but he was coming up to retirement and said I could remain on the 20mg x 3 a day if I wanted to.

I did and I am really glad I did although I still have occasional arguments with doctors to come off it.

We just have to fight for what we know we need.

in reply to dizzy864

It has taken many years, in fact decades, for you to get what you needed. In my own case too. Why oh why can't they try different types of thyroid hormone replacement after, say, one year if a patient is not improving.

in reply to dizzy864

Inspiring and I am happy for you. I'm sad that it took so long. And to have to battle too. Head endo - his comment on shortening life! Ha - well compared to poor quality of life and being miserable but living longer, I know which option I'd go for. I wonder what his evidence was for this? I'm only on the starting dose 20mcg and have been since 2010. I'd like to increase the dose and lower levo and see what happens. However, at the moment, I'm fighting as liothyronine has been completely withdrawn. Thanks for posting your story xx

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