Levothyroxine (LT4) at doses that maintain the serum thyroid-stimulating hormone levels within the normal range constitutes the standard of care for the treatment of hypothyroidism. After a few months, this eliminates the signs and symptoms of overt hypothyroidism in the majority of patients, owing to the endogenous activation of thyroxine to triiodothyronine, the biologically active thyroid hormone. Still, a small percentage of the patients (10%-20%) exhibit residual symptoms, despite having normal serum thyroid-stimulating hormone levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life.
Objective
To provide a summary of progress in the approach of patients with hypothyroidism that exhibit residual symptoms despite treatment.
Methods
We reviewed the current literature and here we focused on the mechanisms leading to a deficiency of T3 in some LT4-treated patients, the role of residual thyroid tissue and the rationale for combination therapy with LT4 + liothyronine (LT3).
Results
A score of clinical trials comparing therapy with LT4 versus LT4 + LT3 concluded that both are safe and equally effective (neither is superior); however, these trials failed to recruit a sufficiently large number of patients with residual symptoms. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4 + LT3; desiccated thyroid extract has also been used with similar results. A practical approach to patients with residual symptoms and on initiation of combination therapy with LT4 + LT3 is provided.
Conclusion
A recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism that do not fully benefit from therapy with LT4.
The mechanistic explanation for the residual symptoms is under current investigation; however, it could involve a relative deficiency of T3.
Could!
Where have these people been.....asleep like Rip Van Winkle?
Is this their way of getting round the fact that they have been missing/ sidelining the point.....a volte-face presented as a discovery?
And...serum T3 isn't the end of the journey!
They need to expand their thought process and instead consider cellular T3 as the finish line, because, for a low cohort of patients.. the clue to " residual symptoms" can be hidden there.
Many of us already understand this!
T3 isn't the enemy.....without exogenous T3 my body would very likely have shut down by now.
But no....apparently I didn't have a problem and levothyroxine should have resolved my symptoms.
I wonder what would have been written on the death certificate!!!
I think the words in this paper are absolutely clear.
The full paper says this:
Conclusion
Patients with hypothyroidism appropriately treated with LT4 (who have normal serum TSH levels) may remain symptomatic. This has been documented in several studies and should be discussed with patients starting therapy for hypothyroidism or those considering definitive treatment for thyroid disease. The mechanistic explanation for the residual symptoms is under current investigation; however, it could involve a relative deficiency of T3. New trials focusing on LT4-treated patients who remained symptomatic revealed preference and superiority of combination therapy containing LT4 + LT3. Given the new long-term safety data available for LT3, a recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism who did not fully benefit from therapy with LT4.
But does NOT have a specific reference to the paper. I've looked but there is, in my mind, some uncertainty about exactly which paper.
helvella I Googled the specific phrase "recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism" and found this link to the joint statement - it says which specific paper the information comes from.
Apologies if this is not what folks were looking for, or if it's been posted before...
Thanks Eric107. Love this bit:-The task force concluded that the goal of future L-T4/L-T3 combination studies should give L-T3 at least twice a day while waiting for the development of a sustained release L-T3 preparation which is not yet available for clinical use.
Hmmm they seem to have forgotten that NDT is slow release... hey ho...
"The results of such redesigned trials could lead to improved understanding of the treatment of hypothyroid patients with thyroid hormone replacement therapy."
Again that word " could".....have they tried looking at what is actually under their noses?
NICE have said that they are changing to make it easier for patients and others to provide suggestions, complaints, issues, and information into guideline reviews.
Definitely worth contacting them to push for this to be taken into account.
However, NICE also manages the Clinical Knowledge Summaries (CKS). They are often confused with each other but CKS does not have the status of a full NICE guideline. And CKS have been going for many years.
When discussing it is important to be sure which is meant!
There are conflicts in their advice!
Thyroid disease: assessment and management
NICE guideline [NG145]. Published: 20 November 2019
In my view, words like "small" - and many others including rare, normal, etc. - should be defined in scientific papers, if they are used at all. Very often you can see both the word and the number so can make some assessment as to whether the word is being used properly. And they do not always align.
For another example, Patient Information Leaflets often divide side effect frequency by common, uncommon, rare, very rare and unknown. (And I think these are formally divided by percentages.)
But none of this gets past the use of such terms to dismiss patient experience. For example, if someone has a 1 in 500,000 disorder. Or suffers a 1 in 100,000 side effect. And gets told they are wrong, it can't be that because it is very rare.
If. there is a number which is core to the whole paper, then choice of word can be critical. In this case, 10-20% is critical.
a) it is only an estimate and could go higher;
b) 20% of anything really can't reasonably be dismissed as some sort of special case which needs exceptional handling;
c) this is only those who exhibit symptoms sufficient to be recognised - what if it ends up that in reality ALL on LT4-monotherapy have symptoms but they are too easy to dismiss?
I totally agree! I know of at least 6 acquaintances who are hypo, on T4, and are suffering, but because their doctors have told them they are not thyroid symptoms, they have just accepted that this is their new normal! How many patients put their doctors on a pedestal and take them at their word and don't complain loudly like we do? My own mum was like this and no matter how hard I tried, she dismissed it out of hand because her doctor said so. I'm baffled by how they collate these percentages.
Baffled how they collate these %'s... me too .. how can they get any idea of the scale of it ?
and it's not just those who accept the line that "its not a thyroid symptom"
i've never really thought my remaining symptoms on Levo were not thyroid related , and have said such to GP's at the time, and since .. but i'm certain i'm not included in any count of patients with 'remaining thyroid symptoms on levo' .. if anybody looked , my NHS record will give the firm impression of "hypothyroid~ treated with Levo now 'normal', plus ( unrelated) chronic fatigue ~ referred to CFS/ ME service ".
(the fact that the i didn't have a chronic fatigue problem prior to becoming hypo, it only became apparent at the same time as i got to the full dose of levo and said i couldn't function properly , is deemed to be entirely coincedental)
Seems to me there is a flickering of dissent in the ranks of monitherapy at long last. Even NDT got a positive mention! Must be treason going on here.... Will the researchers be burnt at the stake? Probably!
Research as we all sadly know so well is frequently disconnected from shop floor practise and often takes years to filter down. So whilst I'm delighted that some researchers are arguing that for a small.percentage monotherapy isn't enough, it will not be enough to turn the jugganaut around.... At bests seeds of doubt maybe sewn in a few minds...maybe. More likely though to save face this research will be ignored or announced as flawed.
I think they're more likely to put sticking plaster over the cracks.. Given what happened to Dr Skinner and the likes it would take several avalanches to knock their brains into gear. Can't help thinking though that if the ratio of women to men who suffer with hypothyroidism was turned on its head the story would be very different!!
Yes but we need new unadulterated brains. The new brains currently keep getting contaminated!I think the new 'clean' NDT and the likes is a get out for the medics to back down and save face... If they take it..... am sure big Pharma will convince them.... They're very good at that after all!!
”……Nonetheless, a consensus exists today that a poorly defined minority of LT4-treated patients exhibit persistent symptoms that are thyroid-related despite normalization of the serum TSH levels.13 It is difficult to ascertain the exact number …..”
Ha ha ha! Because they don’t bloody listen to us when we say we feel like shit!
The last face to face with the endo/ent chap, he asked how I felt and seemed shocked when I said I felt totally rough, dreadful etc!
Reading further; they mention cholesterol levels being raised, something so many of us report on and yet the docs ignore it and attempt to treat the symptom not the underlying cause.
Oh yes eat low fat! Never mind that low fat foods are usually compensated for with sugar which is inflammatory and the body produces more cholesterol to deal with the inflammation.
A private doctor told me to avoid low fat and eat full fat butter, milk if I could tolerate it, and cream, but avoid sugar as much as possible.
I'll admit I could be better on the sugar front as I add it to my tea
No, no, not necessarily the starch based thickeners in gravy or sauces, but the gums and gels they add to things like yogurt when they take the fat out. I make my own yogurt (more that I can’t stand the myriad of little pots rather than any domestic goddess-hood), making full fat yogurt from full fat milk always results in a thicker consistency than when made with skimmed.
Oh I didn't know this thank you. You are trying to play down the Domestic Goddess label but it's not working. My kids are lucky if I throw an apple crumble in the oven these days.
Yoghurt: to your pot add a dollop of last week’s yogurt, a couple of scoops of dried milk powder (bought in bulk from Amazon coz Tesco stopped stocking it in our local store, important when making skimmed yogurt, it thickens it a bit), get the baby whisk out of whatever drawer whoever emptied the dishwasher put it in, add a couple of inches of longlife skimmed milk, whisk to mix, top up to the top of the pot with milk while whisking. Clip the lid of the pot, put it in the instant pot along with some warm water, press the yoghurt button. Go to bed, get up the next morning when it’s finished and put the pot in the fridge, warm yogurt is not right.
A few examples. Where available, the standard versions of these might contain substances to ensure the product doesn't separate, etc., but they are only needed for that reason. Whereas in low fat foods, they are essential to give the product a thickness we associate with fat. And ensure an acceptable mouth feel. Fat also carries many flavours differently.
Note the bizarre custard where the other ingredients are so low fat they actually ADD palm oil (which is, of course, just about pure fat).
A low fat yogurt
Yogurt (Milk), Fig (8%), Sugar, Tapioca Starch, Lemon Juice Concentrate, Carrot Juice Concentrate, Stabiliser (Pection), Natural Flavouring, Milk Minerals
Whereas in low fat foods, they are essential to give the product a thickness we associate with fat. And ensure an acceptable mouth feel. Fat also carries many flavours differently.
I honestly despair what is the point? And why is low fat desirable anyway? Do people think low fat means they'll lose fat?
The low fat cheese and the custard...you'd be healthier eating the fat. Thank you for those examples that is eye opening!
Low fat exists to fulfil the demand engendered by the demonisation of fat - all fat - and by so doing make profit for the companies.
But, in generally, it is madness.
Taking dairy alone, we are inundated by semi-skimmed, low fat, dairy foods - such as milk and yogurt.
What happens to the fat they skim? Why - they then sell it back to us as cream. Something "naughty, "indulgent", highly marketable.
If we want to reduce dairy fat consumption, the only real answer is to produce less. Whether by choosing breeds that intrinsically produce less fat, feeding them such that they produce milk with lower fat content, or reducing the total quantity of milk produced. (Even switching to non-bovine milk such as goat, sheep, or even that extreme boutique milk from camels.)
Note that low fat products are almost exclusively produced in large factories. Sure, a small dairy can skim milk, but the actual manufactured products like low fat yogurt or cheese, are not produced by small outfits.
"Make sure he gets plenty butter, cheese, cream (etc) to build him up" , was the advice our GP gave my mother after my father had been hospitalised for weeks following a serious skin condition, the result of a plant allergy.
That was 1950! He recovered well.
I think they had a better handle on health/food back then when food was basic and free from added nasties.
I was going to post something else today which relates directly to this post - before reading this paper. Apparently some new thyroid medication, based on NDT has come on to the market. A ‘clean’ NDT. It’s called Adthyza. Dr. Westin Child’s has done an article on his website.
But the point I really wanted to make about this ‘new’ medication is not only that it is a combination of T4 and T3 but that the marketeers are there before the medical community are onboard. You can be pretty sure things are changing when this happens! For them the 10 to 20% of the market is worthwhile. It does not mean that the drug will actually do any better than the tweaking we already do in the utter absence of medical help but the message is clear. Big Pharma is listening to you, even if your medics are not! (And all that entails).
There is perhaps a separate discussion at some point on the forum to discuss this medication if it has not already been discussed and I have missed it.
I am heartily sick of the word 'clean' used like this - it is a marketing term without proper definition. They hope people see the word and have the reaction "Oh good - that's much better than anything else" - without details checks.
For me the ideal would be WP Thyroid, with (from memory) Medium chain Triglycerides, Inulin and Magnesium Stearate (? not particularly good). This one suited me so well with good blood results other than just Thyroid bloods.
I googled that earlier as I also get emails from Dr WC. One person put a review and said they felt it’s strength wasn’t as good as their previous NDT (think that was Armour)
Oh goodness, I'm hallucinating...a paper that speaks, nay positively recommends that LT3 therapy be discussed with patients with residual symptoms? Can everyone see it or is it just me? Or is this yet a new hypothyroid symptom? Please help I must be low on all my vitamins. Recommendations immediately please!
My twisted sense of humour is finding The mechanistic explanation for the residual symptoms is under current investigation
Really hilarious for some reason😄😄
however, these trials failed to recruit a sufficiently large number of patients with residual symptoms.
Here's the rub though: Your continuing symptoms are not related to your thyroid, are they? They are psychosomatic. They are Chronic Fatigue syndrome. They are Fibromyalgia. They are Seeking Attention.
Since your continuing symptoms are Seeking Attention et al., there is no need for a discussion or trial of LT3 therapy, even if updated evidence recommends it. Especially if you have a long-standing history of depression during the period you were 'sub-clinical' aka extremely hypothyroid with TSH 5 for 10 years +
I agree that the authors point out the flaws in previous studies not including enough patients with residual symptoms in trials. Not asking 'a whole load more patients'
However, in practical terms I don't believe patients haven't been reporting problems to doctors and endos for years in large enough numbers. Myself among them. What have they been ascribing those continual symptoms to? How can you have a list of hypothyroid symptoms that prompt you to investigate hypothyroidism on behalf of the patient, then dismiss the patient when he still has the very same symptoms on the list in front of you??
That said I am unfairly merging clinical research with actual experience on the ground. But the way I see it at least in the NHS (ignoring motives of BP) due to financial constraints there is active drive to persuade patients that they must be well on LT4 and convince them that their symptoms are something else. Even better if that something else can be their fault in some way so we can save funds (eat better, exercise, get a better job)) I've heard them all. If the researvh recommends xyz be done there is still that drive to force down numbers who take it up.
I guess I see ignoring the need for LT3 as very deliberate bad-faith. Not 'oh we simply didn't know and need the research to catch up' As far as I'm concerned it is intentional and if there is disgruntlement and a quiet push for change it must be for factors that involves looking increasingly professionally backwards and possibly even increasingly litigious.
No I meant that if there is on the whole planet just one patient, with just one remaining symptom that is resolved by LT3, which means that universal LT4-only is wrong.
We only need that single counter-example, that single contradiction, to undermine the theory.
A single right-angled triangle in which the square on the hypotenuse doesn't equal the sum of the squares on the other two sides.
A single circle where the circumference isn't 2 times pi times radius.
I am heartily sick of the word 'clean' used like this - it is a marketing term without proper definition. They hope people see the word and have the reaction "Oh good - that's much better than anything else" - without details checks.
Thanks for the thread on Adthyza. Terrible I know but normally I avoid anything on NDT because I am already on information overload and still experimenting with T4/T3. Still the post was hugely interesting and on point for NDT (in particular) users.
My point is really about where the two threads meet. Marketing (from perhaps a Smaller Pharma) is ahead of the medics and in this case (unless there is a whole load of complaints) is showing a way forward which might make a difference especially in combination with this new statement/paper from the endocrine royalty.
I think the product sounds interesting. (Shame about the mannitol. ) But some of the "commentators" say/write some nonsense even when there is a core of truth.
I can’t for the life of me understand why a GP would be so reluctant to prescribe Liothyronine when all it says in the NICE guidelines is ‘do not routinely prescribe’, which is basically the essence of this article anyway in my interpretation.
They can bloody use their clinical judgement and just put NiCe guidelines to bed. Simples. But then, I have been accused of being a maverick.
My Gp has written down on their website that Liothyronine is on the Black List therefore do not ask for it - or some such wording. There are not a lot of people on the forum from the North East (I think) but I do know there are no prescriptions. No clinical judgement in evidence here.
The wording is poor. To be fair to the authors, I think they might really have meant not to prescribe it to every hypothyroid patient as a matter of routine approach.
But it appears to be read as: If a doctor has a patient who needs it prescribed every month, that is routine, hence not within the guideline.
It also doesn't allow for the real world. Maybe somewhere there are many people who are related - and a disproportionate number of them need liothyronine? It becomes, or needs to become, routine for that area.
I'm not sure how to improve it, but something that says positively to prescribe if advised to do so?
I think the issue is much less to do with wording then it is to do with money. There are so many examples of off licence use, and the products are clearly available.
The other issue to the best of my estimation is in avoiding harm caused by lack of knowledge after all, GPs are barely trained in this area and when their peers are reluctant to try and learn, it has a knock on effect.
So, money and confidence are my guess because ultimately, they are but guidelines. Unfortunately, NICE Guidelines have become a way of protection for GPs to do as they state.
I need a tea before I can properly articulate my thoughts by the gist of my point is that they have the power to prescribe should they wish, so it’s CCGs and ICBs etc that as gatekeepers of money management (let’s face it, that’s all they are there for) are where the issue lies.
Many GPs will never have seen liothyronine prescribed as it should be.
We are still in the process of dealing with historically very low prescribing levels because it was never widely understood. And the extreme price gouging.
Will take years for GPs in all practices to gain experience of real patients taking liothyronine. And until they have that experience, it will continue to be difficult for patients.
As patients, part of our job in taking care of ourselves and in our advocacy is simply to be collaborators and educators with our health professionals. Whether rightly or wrongly.
It does seem the tide is turning and progress is a step in the right direction before the revolution ☺️
Thanks to the advent of virtual healthcare, more GPs will practice privately as well as within NHS where they are less throttled by the mainstream care madness, and that will enhance their care and their appetite for risks within their NHS Care. Own theory anyway.
But nothing has changed for real patients in the real world.
And the papers which went into that (which was really a sort of review paper) had obviously bee published over years before that.
Time from publication to effect can be extraordinarily long even when everyone seem to be happy enough with them and they are uncontroversial.
Must be around twenty years since research was published suggesting that taking levothyroxine at bed-time was a reasonable alternative to morning dosing.
Yet Patient Information Leaflets still only grudgingly say:
You should usually take your tablets before breakfast or your first meal of the day.
Imagine trying to raise a large, heavy stone. Someone manages to push a thin piece of metal, a knife blade?) under one corner. And their helped slides a piece of paper under it.
Then they do the same at another corner. And another.
The stone rises! Hooray.
By about one tenth of a millimetre. Boo!
Even that tiny bit is progress. But it will be some time before it is high enough to become the lintel of the doorway.
My most recent consult with a newly-minted endocrinologist produced this weak argument against NDT: the physiological proportion of T4:T3 in humans is 10:1. This is not matched in NDT. He didn't explain how the authorities arrived at their golden ratio.
I'm in graduate school now, and barely have time to read the posts, but I'm grateful for the eye-catching summaries in the daily email digest. The world would be a very dark and discouraging place without this vital information exchange.
Thank you have just read it, having found it posted on Twitter. I’m currently on Endo requested ‘cold-turkey’ for 6 weeks, feeling very fatigued but managed to take in most of it especially the latter part about adding in T3. Current Endo, very dismissive of any suggestion of T3. Next appointment Aug, watch this space! As they say.
And although they talk about NDT, it is also against liothyronine, and treats levothyroxine like the king, despite their own linked evidence often simply being a draw. Hysterical.
Even one study called 'even, even, even, more weight loss on NDT' - win goes to levothyroxine. Huh? 🤔😁🙄
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'Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers' - Lancet journal article 
Do b12 injections use up thyroid hormones and therefore increase hypothyroid symptoms?
Thyroid symptom checkv+ levothyroxine
