A new important study details the persistent symptoms of about 6,500 LT4-treated patients in the UK Biobank. No association with gene polymorphisms was detected.
Hopefully this study puts to bed the naive hypothesis that a single SNP variant could underlie a “poor converter” phenotype.
Antonio C Bianco:
I feel similarly about LT4 resolving all symptoms of hypothyroidism.
Received reply by Simon Pearce:
That is not in doubt. The question is why not.
Lack of access makes it impossible to assess these comments and the paper itself.
The paper:
Association of DIO2 and MCT10 Polymorphisms With Persistent Symptoms in LT4-Treated Patients in the UK Biobank
Christian Zinck Jensen 1 2 , Jonas Lynggaard Isaksen 1 , Gustav Ahlberg 3 4 , Morten Salling Olesen 3 4 , Birte Nygaard 2 5 , Christina Ellervik 5 6 , Jørgen Kim Kanters 1 7
PMID: 37740545 DOI: 10.1210/clinem/dgad556
Abstract
Context: Some evidence suggests gene-treatment interactions might cause persistent symptoms in individuals receiving levothyroxine (LT4) treatment.
Objective: We investigated, as previously hypothesized, if single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms) in rs225014 (Thr92Ala), rs225015, or rs12885300 (ORFa-Gly3Asp) in the deiodinase 2 gene (DIO2), or rs17606253 in the monocarboxylate transporter 10 gene (MCT10) were associated with outcomes indicative of local tissue hypothyroidism in LT4-treated patients and controls.
Methods: We included 18 761 LT4-treated patients and 360 534 controls in a population-based cross-sectional study in the UK Biobank. LT4 treatment was defined as a diagnosis of hypothyroidism and self-reported use of LT4 without use of 3,5,3'-triiodothyronine. Outcomes were psychological well-being, cognitive function, and cardiovascular risk factors. Associations were evaluated by linear, logistic, or ordinal logistic multiple regression. Adjustments included sex, age, sex-age interaction, and genetic principal components 1 to 10.
Results: Compared to controls, LT4 treatment was adversely associated with almost all outcomes, most noteworthy: Increased frequency of tiredness (P < .001), decreased well-being factor score (P < .001), increased reaction-time (P < .001), and increased body mass index (P < .001). Except for a significant association between the minor rs225015 A allele and financial dissatisfaction, there was no association of rs225014, rs225015, rs12885300, or rs17606253 with any outcomes in LT4-treated patients. For all outcomes, carrying the risk allele at these 4 SNVs did not amplify symptoms associated with LT4 treatment compared to controls.
Conclusion: rs225014, rs225015, rs12885300, and rs17606253 could not explain changed psychological well-being, cognitive function, or cardiovascular risk factors in LT4-treated patients. Our findings do not support a gene-treatment interaction between these SNVs and LT4 treatment.
How can they say DIO2 shows no association and infer there's no problem for DIO2 patients? I have DIO2. On Levo after 7 years I felt even worse, because I needed T3!!
The research is nonsense and probably started with the conclusion and worked backwards!!
It makes a mockery of thyroid patients and thyroid treatment.
I tested Dio2 positive/ homozygous which results in particularly poor conversion, according to Panicker et al. T3 resolved most of my debilitating symptoms which had left me barely able to function. Without T3 my body would have continued to shut down
I asked the geneticist, who tested me for a rare genetic deletion found in my family, if there could be a connection to my form of Thyroid Hormone Resistance. His reply, "We just do not know, there are very likely many genetic variants, so far unrevealed, that may relate to many conditions".
Patients are the expert witnesses to their health....they live with their ill health 24/7/365+ but their views are frequently ignored in favour of "numbers".
The endo I saw refused to believe that I needed T3 and totally dismissed my suggestion that I may have a form of RTH.....I had worked this out myself and he didn't like that!
It turned out he was wrong on both counts and had to admit that I might need a little T3, after I produced the results of the Dio2 test.....I need a lot of T3, around 125mcg! My " homework" supported this.
My heart goes out to the people quietly suffering behind closed doors, as I once did, who are being treated ( or maybe not) by so called experts whose lack of knowledge is astounding.
This paper is another example of what we are up against....it does nothing to improve patient's lot. I'm not convinced that even entered the frame when this investigation was initiated.
To quote Drummond Rennie (the founding father of peer review research) who wrote the following more than 20 years ago:
“There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.”
I went from a TSH of 44.25 to 1.0 within a month of getting T3 (aware TSH not best measurement) post the D102 genetic test. Obviously felt so much better, so personally cannot accept no link.
I have a suspicion that the genetic basis is real but maybe in quite a number of people, there is a more complex picture. For example, a certain D102 variant AND having one or more other genetic variants or other causative factors.
Without the full paper, it is difficult to go further. (Mind, not sure how far my brain is capable of going even it it became available.)
Absolutely agree. The degree of interplay between genetic mutations are massively complex as likely infinite and all may be further influenced by multiple factors more than sex, age, sex-age interaction. What about socioeconomic status, other health conditions, other medications, etc.
Well he has enough to engineer not only navigate through a clearly nepotistic system but also to ensure it still exists. He is the proud overseer and he is as determined as he can be, to ensure its existence whilst in his ‘hands’. Unfortunately he is not near retiral so he will happily see many of us off.
The lizard part of his brain is clearly operating optimally. I used to feel reptilian when I was horribly hypothyroid and untreated - it wasn’t very nice. Awful that he’ll most likely survive long after we have gone causing untold suffering. I can only hope the new knowledge that diogenes was involved in discovering will eventually prevail over the claptrap he espouses.
Thank you for saying that. I definitely only understood the overview. I love that Pearce’s comments and Bianco’s robust reply were also reported (by yourself?). Then a pathetic follow up by Pearse, even he should have been ashamed of.
Pearse only has time for research he can use to prop up his rubbishing of the patient’s experience. I noticed as soon as his name was mentioned I had a physical reaction. His word is poison for hypos.
A visit to his brain would be a pretty scary experience I dread to think what exactly is in there - a lot of mysogyny for sure. I was shocked to see he had a greyhound - poor dog!
I have been reading a bit about politics with a small ‘p’. It’s totally self serving with empathy absent. It’s perfect for Pearse. In my opinion he should not be in medicine at all.
You are right that the real issue is thyroid patients lived experience is being rubbished and our wishes for a choice in thyroid hormone therapy is being denied us. The basic fact that a thyroid gland makes both t4 and t3 is irrefutable proof that combination therapy should be the first line of treatment and resorting to t4 monotherapy only if this proves ineffective. NOT the other way round. All this stuff is a red herring and a tool to treat us like children, not adults able to decide for ourselves what’s suits us best
It might explain why close relatives of mine were fine in T4 monotherapy but I was not. I have thyroid hormone resistance markers and one DIO2 suspect allele. But who knows what else genetics as yet undiscovered might be at play. I do not have any genetic results bar my own which is a shame as I can’t test it out.
In answer to that fool Pearce: T4 monotherapy is not what nature intended or designed for a fully functioning thyroid - it’s as simple as that! There’s nothing to discover - it’s a plain as daylight to someone with a brain, in fact even with half a brain.
What amazes me is that anyone feels well on T4 monotherapy at all! I fully believe even then, in the long term it’s detrimental to health because it is so abnormal.
Yes I now worry about the many many people I see here in Tyneside (where Pearse broods) who are clearly having thyroid problems and if they are having treatment it’s lousy. Do they think their doctors are doing right by them? Crikey I am complaining lots and completely unsatisfied with treatment. However I personally know others who would not say anything to their doctors. Are they part of this number that are quoted as ‘satisfied’ with their treatment? Probably. I would not like to confront that incredibly rude ignorant man in a consultation. It just does not feel right on any level that he has this level of ignorance and at the same time this level of power!
By the time many get thyroid diagnoses (me) they already have multiple health problems and may be on many different medications (not me I steer clear of this scenario). How on Earth would they necessarily be able to work out what’s giving them difficulties?
It’s awful I agree; that one person can do so much damage to so many yet remain unchecked and get the title professor - it makes a mockery of learning and academia, not to mention the countless lives wrecked by this heartless unfeeling individual. I hope he’s nicer to his greyhound than he is to his patients god help it if it ever becomes hypothyroid.
I imagine many put up with feeling rubbish because they’re told it’s as good as it gets. That’s what the stupid thyroid nurse at Guys told me that it was the best it would ever be. It was total rubbish. One day on NDT made a huge difference 2 months and I felt like me again. The half baked garbage we are expected to swallow without question makes my blood boil. One day Pearce will be laughed at for his out of touch, patronising, ageist mantra, the sooner that day arrives the better for all of us and especially for those in the north east. Can you mobilise and make a great big noise about how bad he is? It needs doing these charlatans need unmasking .
Yes TSH110. I would love to but I have a full time job trying not to die prematurely - I know that sounds melodramatic but I am putting myself first. I feel the need to get my oxygen mask on first, before I am useful to anyone else. Otherwise it just won’t work. If I ever get over this b…dy nonsense I have promised myself I will be using some of my energy to the wider cause.
My only brush with actual Pearse and my ‘case’ was catastrophic. It left me bruised and bewildered but I have learned so much since then.
I worry about mobilising anyone re: this cause, especially when we are still ill. Look how difficult it was to get signatures for the Dr. Peter Taylor petition and that required the absolute minimum effort. I have in the past involved myself in broadly similar issues. Believe me I know how difficult it is to rally support even for genuine good causes.
Oh gosh I’m so sorry to hear how badly affected you are. It’s really difficult trying to get people together when you’re well let alone if you’re not firing on all cylinders plus it’s finding them and what action might be worth taking. It’s just so annoying that they can get away with it. Although I was very poorly indeed before treatment and for two years after on Levothyroxine I made a remarkable recovery on NDT - I was extremely lucky.
I am so glad you are well. It’s fantastic - really. Hopefully not luck. I hope it’s just how it should be - good treatment. And it all seems possible, it’s just idiots carrying out this nonsense ordered by someone with no empathy whatsoever. It really is too much and I too would like him and his like to be gone! Keep well TSH110.
Just as an aside what made you decide after two years to attempt NDT? I feel I have wasted another three years trying to sort things out.
Two close relatives took Levothyroxine and felt great on it so I knew something was not right when I never felt well on it, even after two years. I began to wish I had not got help and that it would have been better to have died of untreated thyroid disease that to be trapped ina living hell. I tried more, felt even worse. I tried less and was dire. The prescribed dose was dreadful too. Despite being optimised my t3 was rock bottom basement but I didn’t understand all that back then. I’d been told there was nothing else by way of treatment (lies) and it was as good as it would ever get (more lies) by the horrible thyroid nurse I saw once my numbers were a lot better. They aimed for tsh between 0.2 and 0.5 which is a lot better than some with the anywhere in range brigade.
I got iller and iller, I had terrible heart pains, I put on 4 stone, everything looked browny grey and grim. I was incredibly depressed to the extent that I just felt like a thing not even human. I was incompetent at work despite having done the job well for over 10 years I was confused and had dreadful memory problems and began to have suicidal thoughts a lot of the time. I had joined thyroid uk and was beginning to learn more about hypothyroidism. I was furious to discover there were other treatment options, after being told t4 monotherapy was the only one.
I started to think about trying NDT out of desperation. I was a vegetarian and had been happy to take levo because it wasn’t animal derived but I felt so dire I decided to try it because I had nothing to loose it had all been lost anyway. I sourced some found a guide as to how to take it, swallowed hard and started on a wonderful journey finding myself again. From the first tiny dose things changed it felt like I was a jigsaw puzzle with a piece missing that suddenly slotted into the empty space and I felt whole again. My depression vanished altogether so that was even better than it had ever been since I was a girl! The colour came back into everything which was magical. The weight dropped off me and I felt completely normal again. I didn’t need much either 1.25 grains was the perfect dose when all symptoms ceased. It was a life changer. I’ve been on it ever since.
Yes. Similar as everything you said until you tried NDT. Until recently I never considered NDT because I was put off by the likely continuing worries about access to it. However I understand there is an online chemist in the UK who can supply. You waited only two years I feel remiss having waited three (since diagnosis although I have had it unbeknownst to me, I now realise for a good many years). I have tried T3 with not a good result so far. It irritated my heart condition no end. So at the moment I have now got a referral to an endo who writes papers on heart and thyroid. I will be keeping NDT in mind. I just never made this decision before. Thanks for replying so fully.
That’s a shame it upset your heart. Perhaps NDT would be more forgiving. At least the t3 goes quickly out of the system so you can easily pull back. I titrated very slowly up to when I felt well again. I had to split the dose too or I felt weird. I don’t need to nowadays
Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patients
Conclusion
Genetic polymorphisms in the DIO2 gene may affect psychological well-being in patients on T4 replacement and predict those who will have improved well-being in response to combination therapy with T3. Replication of this result, including prospective studies with genotype-selected populations, are required before changes in treatment approach can be recommended in routine practice.
Hi Helvella, sorry to post on this article but I've forgotten how to post to you privately with what will probably be a long post & wouldn't want to clog up the 'airways' with my droning on. I've been off thyroxine for a year, am not losing weight & need to know if I need to go back on it. I have obtained a full print out of my annual health check & with the help of my husband (because I'm a technophobe) will post my results & find out whether I need to get some private bloods done. Thank you in advance of your assistance.
I generally don't answer on private messages (chat) unless they are things which cannot be posted.
The reason being a combination of things:
I want others to see what I say and have the opportunity to tell me when I make mistakes.
I might not be around when you ask. If you post on forum, someone will answer! But if I am genuinely unavailable, you simply won't get an answer. At least not in a sensible time period.
' I've been off thyroxine for a year, am not losing weight & need to know if I need to go back on it.'
wimpyshrog, Please keep in mind that this is a patient to patient forum. No-one here, including the admin team, is medically qualified.
By all means post your long post on the forum for others to offer their support, ideas and suggestions. But ultimately, your medical treatment needs to be discussed and agreed with your doctor.
Hi RedApple, thank you for your reply I know you are not medically qualified but I have been left up in the air after having come off thyroxine which I was put on round about the time of my menopause which was before I was 50. I am now 62. Always told same thing like most people 'within range'. This will be the first time I have had a printed read out & that's because I requested one. Perhaps when I explain my situation you might understand more why I am asking for your opinion.
wimpyshrog, That's fine, I just want to make sure you understand 😊
So please do start a new post (just click this link healthunlocked.com/write ) and write about whatever you need help with. Members can then offer their thoughts and suggestions.
I'm convinced there is a generic component. My father and 2 of his 3 sisters all had thyroid problems with. Onset post thirty. Apart from one who was borderline over active. My brother was diagnosed with borderline overactive at 19 which settled in mid to late twenties. I was diagnosed with immune hypo after the age of thirty. Whilst we have research of this manner things will just be circular arguements. I wish they would train Drs how to conduct research . I've even spoken to an endo who thought that research to make a case for T3 didn't require a methodology or even a review of current research.
There’s has to be in my case. Grandma, mother my mothers sister (and possibly her other sister who died quite young) a hypo sibling, a hyper sibling and a sibling with signs of thyroid disease no one can tell me that’s pure coincidence it has to have a genetic component to it.
I started on T4 around 1998 and was fine for about eight to ten years before the hypothyroid symptoms returned. Through Barry Peatfield I was able to move to NDT but after a few years the cost rose to become unaffordable. I then moved to T4 and T3 combination therapy which I am still on. I tested positive for the DI02 genetic mutation which to me explained why I felt bad without T3. My grandfather and father were both hypothyroid.
So:
1. I was born with the genetic mutation, or it developed over time
2. I was fine on T4 monotherapy for a few years so the genetic mutation did not automatically mean that T4 monotherapy did not work at all for me
3. Now I need both T4 and T3 to feel well in body and mind
4. It is wrong for a medic to insist that T4 monotherapy is the only way to treat all patients all of the time, they should read the NICE guidelines
5. It is wrong for a medic to dismiss as evidence a patient’s statements about how they feel or the results of a physical clinical examination (remember those?) which show slowness of movement, thinking and speech (from being hypothyroid, not simply depressed) even though the T4 and TSH are in the ‘normal range’
6. It is wrong that the NHS pays so much for T3, instead of sourcing it more cheaply, so medics are prohibited from prescribing it and have to use T4 monotherapy only. Why does the NHS always pay so much? I have seen in the construction industry that such a thing can be a sign of corruption. Explanations from the NHS procurement department please!
I wonder whether the thyroid can produce enough T3 to manage initially, but once the thyroid gland has been completely destroyed by the autoimmune attack, it can no longer compensate. We become more dependent on peripheral conversion and the need to extra T3 increases?
Thyroid UK advisors have done studies that show the thyroid contributes to T4 to T3 conversion, so once the thyroid is gone there is less circulating T3.
does anyone have a theory as to why? Is it the HP axis slowly resetting itself? Even with NDT I don’t feel as good on it as I first did - it’s not major or anything but it’s deffo not as good as it was. Dose increases /decreases don’t help either
I think it’s jimh111 who often brings up the situation of ‘laziness’ with just about anything to do with the NHS. I very much agree. This can be worked to one’s advantage sometimes. However it clearly permeates all the way through the system. It’s unlikely in my opinion that there is a clear case of corruption. However there is a clear case of utter indolence everywhere in this process. Nobody wants to collect the flack of raising issues. In fact I think I heard that there is to be a whole investigation into why ‘whistle blowers’ themselves are subject to more investigation (and bad outcomes) than the people doing the wrong doing.
I think endocrinology have got this inbuilt ‘indolence’ and politics with a small ‘p’ sewn up. There are a few who seem to be working away doing good work but under the constant vigilance of those who have engineered it to be just how it is and do not want the status quo changed. I have said it before and I say it again, this is all a huge scandal, from every direction just waiting in the wings to be discovered - if anyone but us is interested.
Your comment about Dr Bianco is very interesting. I’m encouraged as he appears to be at the forefront of research and I hope his work continues to shed the light of truth on this benighted area of medicine. Genetics and human physiology are complicated; who would have thought!
Content on HealthUnlocked does not replace the relationship between you and doctors or other healthcare professionals nor the advice you receive from them.
Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked.
