Serum Thyrotropin and Triiodothyronine Levels in Levothyroxine-Treated Patients

[helvella]

Comment by Bianco:

In LT4-treated patients (blue box=ref. FT4 range), the increase in FT4 is associated with a major drop in TSH, but the increase in blood T3 is minimal. LT4 is really good at normalizing TSH; not nearly as good at restoring T3, the active thyroid hormone.

I don't think many members who have real experience will be surprised by this. Only disappointed that it has taken this long to even get here - which is not far enough.

J Clin Endocrinol Metab

. 2022 Dec 14;dgac725.

doi: 10.1210/clinem/dgac725. Online ahead of print.

Serum Thyrotropin and Triiodothyronine Levels in Levothyroxine-Treated Patients

Matthew D Ettleson 1 , Wesley H Prieto 2 , Pedro S T Russo 2 , Jose de Sa 2 , Wen Wan 3 , Neda Laiteerapong 3 , Rui M B Maciel 2 4 , Antonio C Bianco 1

Affiliations

• PMID: 36515655

• DOI: 10.1210/clinem/dgac725

Abstract

Context: Small adjustments in LT4 dose do not appear to provide clinical benefit despite changes in TSH levels within the reference range. We hypothesize that the accompanying changes in serum T3 levels do not reflect the magnitude of the changes in serum TSH.

Objective: Characterize the relationships of serum FT4 vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio.

Design: Cross-sectional observational study.

Setting: A large clinical database from January 1, 2009, to December 31, 2019.

Participants: 9850 participants aged 18 years and older treated with LT4.

Exposure: Treatment with LT4, subdivided by serum FT4 levelMain Outcome Measures: Model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated.

Results: The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at a FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following two negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels.

Conclusions: In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.

Keywords: hypothyroidism; levothyroxine; thyrotropin; triiodothyronine.

Full paper is not yet published and is behind a paywall.

pubmed.ncbi.nlm.nih.gov/365...

I am reminded of this paper from 1995:

Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.

europepmc.org/article/MED/8...

 diogenes - any comments appreciated.

Adding emphasis: This paper is based on Total T3 - not Free T3.

[Tythrop]

Is this why people feel worse after a while when put on low dose t4 before it is eventually titrated up to optimum .Except that GPs and Endos looking only at tsh numbers going down will not increase the dose? ...For readons of my health and attempts at self empowerment I'm currently making another big effort to get my head around all of this so please forgive me if I'm a pain ... By the way I like the blue box on the graph which makes sense of so-called Range .

[radd in reply to Tythrop]

It is emphasising what we know are the three main issues;

That TSH doesn’t always correlate with FT4 & T3 levels , and especially in people with thyroid issues where endocrine signalling and changes may form a lower TSH base line. 

That for many the amount of dosed FT4 (Levo) that TSH levels misguidedly allow is often not enough to convert adequate FT3 for wellbeing. 

Where FT4 levels are high without adequate FT3, to take levels any higher (usually outside of range) risks unusable hormone being converted into inactive forms that may impair further T3 conversion. I think this is possibly the most misunderstood part of thyroid physiology. 

(Free T3 edited to total as per SmallBlueThings rely below - 17.12.2022).

[Tythrop in reply to radd]

This last point is going to be very useful to me as I have just been officially prescribed T4 ,and will probably have to stop taking Armout NDT which I have been taking for 3 years " off the books"

[SmallBlueThing in reply to radd]

Note that it's discussing the relationship with total T3, not FT3.

[radd in reply to SmallBlueThing]

SmalBlueThing,

Yes, apologies. You are absolutely correct so I have edited my reply for the first observation. 

My other two refer to conversion of which we need enough T3 (& other factors) to happen, so have left these as they are. 

[helvella in reply to Tythrop]

Imagine someone who needs 125 micrograms of T4.

But their body is only making 100.

And they get prescribed 25.

Which would initially appear great - 100 of their own plus 25 in a tablet.

But the person will then see their TSH drop and their body might only make 75. Ending up with 75 + 25 = 100. Exactly where they started!

Worse, they could even end up making less than 75. Therefore, in total, a reduction in T4.

(I am ignoring all the complicating factors. Like the person not absorbing 100% of the T4 tablet.)

With a small dose, the reduction of the person's own T4 production can be greater than teh amount they are taking.

Nothing is ever this simple, this neat, this exact. I have just tried to write it so as to illustrate why a small dose can make it worse.

[Tythrop in reply to helvella]

So useful I understand but not sure how to deal . Maybe take lots of private tests ? and self medicate accordingly if can get t3 .Didn't they used to medicate according to clinical. s ymptoms ? But of course this would require GPs and Endos to exercise clinical judgement rather than to treat patients by computer algorithms.

[helvella in reply to Tythrop]

I think a computer algorithm (worthy of that term) would almost certainly do better than many GPs!

It would have to be approved before use.

The reality is that most people end up on a slightly high T4 dose in order to produce enough T3 (and compensate for their reduction in thyroid hormone production).

[Brightness14 in reply to helvella]

I have been looking at one recently. It's worked out by Age, Male/Female. BMI. etc.etc. It is suppose to be 68% accurate. I tried to work it out it took me an hour and I landed up with x 1.52 kilo. Which gave the woman only 118.5 Levo she was over 12 stones in weight with a BMI of 29 and only 28 years old. Some time ago I did the simple thing my weight 63 kilos x 1.6 in Levo more or less 100 Levo dose. It does not work, there are so many other things involved in feeling well. Those poor rats. Your graphs make interesting reading thoug

[helvella in reply to Brightness14]

There are lots of calculators. Indeed, I created a spreadsheet which implements several published formulas.

They don't work, they can't work. They cannot allow for variable absorption from the tablets. Varying by person, by make, even by dosage (e.g. 2 * 50 might not be identical to 1 * 100 or 4 * 25).

You have to overcome these variations before you can get anywhere.

The obvious next approach requires frequent blood tests - such as only happen in research. Cost is too great.

At best, a formula gives an idea for post-thyroidectomy dosing and might suggest significant under- or over-dosing in someone on a stable dose. But the person might need that dose!

helvella - Estimation of Levothyroxine Requirement in Adults

A discussion about the use of formulas to estimate levothyroxine dosing.

From Dropbox:

dropbox.com/s/gzeknihf815rb...

From Google Drive:

drive.google.com/file/d/1Zs...

A spreadsheet with several active formulas which work out possible levothyroxine requirements including NICE NG145 guidelines. These formulas are referred to in the document above.

This is an Excel spreadsheet but is likely to work in other spreadsheet software.

From Dropbox:

dropbox.com/s/aciho6m7x6f1e...

From Google Drive:

docs.google.com/spreadsheet...

[Brightness14 in reply to helvella]

I have to laugh, my adopted father was a Pick Farmer and when I was about 5 years old I found out what happened to the pigs when sent of to market. Although I have never been a vegetarian I never ate anything from the pig. Its' ironic that after my thyroid was removed 64 years later the pigs that I never ate came to my rescue in the form of NDT. Ironic, yes.

[Brightness14 in reply to helvella]

I meant to say PIG not PICK early morning confusion.

[Tythrop in reply to helvella]

"Slightly high dose " ???? the chance of any at all would be a fine thing

[radd]

helvella,

That other paper. ... 1995!!!

It makes me wonder if those rats were thyroidectomized for nothing. I had no idea that knowledge had been common for so long as was only introduced to T3 in 2015 and it seemed to be quite a new general addition then, or perhaps it was just my hypo head in those days getting mixed up? 🤷‍♀️

[helvella in reply to radd]

First became available in 1956. Certainly not a new medicine.

There was a flurry of excitement in the 1950s/60s.

Have a look here:

europepmc.org/search?query=...

President Kennedy was one of the first to take it! And he died in 1963.

[Charlie-Farley]

🙄 how long will it take them to catch up? It’s like watching a soap opera with a long drawn out, cringey story line.

GPs and many endocrinologists are simply not in possession of enough knowledge to effectively treat hypothyroidism and the panel writing the guidelines are presuming underlying knowledge, which simply does not exist. That is patently obvious from the daily posts of people landing on the site under medicated.

Some of the absent knowledge is fairly generic in nature and no doubt will be affecting other treatments and diagnoses.

If I were watching all this unfolding (painfully slowly) on the telly, I would be shouting at it 😱

[helvella in reply to Charlie-Farley]

The Archers has been running longer than liothyronine! Just. (1951 launch vs. 1956 availability as a medicine.)

[Charlie-Farley in reply to helvella]

😂. I used to like the Archers then it started dealing with edgy issues. We get enough of them in real life. It’s like Emmerdale - I stopped watching it when they dropped the ‘Farm’ from the title. In truth I’ve not watched soaps for well over 20 years now (could be 30). I’ve sometimes thought of donning a tee shirt saying soaps make you stupid but I fear I might get stoned in the street.😱😂👍

[helvella in reply to Charlie-Farley]

I've just realised that I started listening to The Archers due to rail strikes!

I commuted about 20 miles by train - and another chap gave me a lift on strike days. He had The Archers on in his car.

That must have been mid 1980s. Haven't listened for years but occasionally catch a few minutes.

[Charlie-Farley in reply to helvella]

I can’t do any of it - I need documentaries and history, abandoned engineering and alike. I have no time for morning TV and in truth everything I watch now is not in the ‘telly’. Stopped watching terrestrial almost a year ago - it just irritated me.

Saw a brilliant interview with an economist the other day. Uncommon knowledge- the population bomb. I’ve never considered economics, but it was such an interesting programme. There were things I thought were missing from consideration, but that would have turned the programme into an all day event.🤣 😊👍

[radd in reply to Charlie-Farley]

Well, at least you have other interests outside of thyroid 😁

[Charlie-Farley in reply to radd]

Ha! Plenty- that’s my problem radd - I’m like a cat in a tripe shop most days. So many interests! I’ve just started silk painting again- and I’m thinking of picking up a couple more mediums I used to dabble with 🤗🤣👍

[radd in reply to Charlie-Farley]

I have things on the go too such as up-cycling furniture (I love painting) or sewing something but then might open an article regarding thyroid over lunch, and suddenly the afternoon has disappeared and my unfinished items remain unfinished 🤣

[Charlie-Farley in reply to radd]

I do up-cycling as well! Drives hubby mad! 🤣

After

[radd in reply to Charlie-Farley]

Oh very nice! 😍

Yes, it drives my hubby mad too as 'everything' gets painted in our house 🤣

[Charlie-Farley in reply to radd]

I’ve had to pack that pastime up for now we are hoping to sell up! So back to art! Hubby a lot happier smaller pieces.

Silk paintings

[TiggerMe Ambassador in reply to Charlie-Farley]

Glad it's not just me that finds the mainstream standard of tv offerings makes me swear, you can just feel your intelligence leaching out of you 🤬 takes a bit of digging to find something worthwhile... other half loves a bit of dross, I insist the dogs aren't allowed to watch it either🤣 generally strop off and read in the bath instead!

[radd in reply to TiggerMe]

With the dog?

[TiggerMe Ambassador in reply to radd]

They get the bath mat....sometimes I let them read to me 😉🤣

[radd in reply to TiggerMe]

🤣

[Charlie-Farley in reply to TiggerMe]

Awww! ❤️ we used to have a staffy that loved drinking warm bath water - no suds in you understand. She used to stand by the bath , paws on the top and wait for me to provide her with cupped hands of warm water. She was a lovely fun dog.

[TiggerMe Ambassador in reply to Charlie-Farley]

Ahh, my first terrier was a bubble chaser 🛀

[Charlie-Farley in reply to TiggerMe]

love it! 🤣❤️

📚 🐕

[Regenallotment Ambassador in reply to Charlie-Farley]

we have a cat 🐈‍⬛ that likes to get in the tub after we shower, she washes her paws and drinks from the warm water on the side of the bath, then leaves muddy footprints all over the tub 🤣🦋

[Hidden in reply to Regenallotment]

My cat circles the rim of the bath while I'm in it likes she's on sentry duty.I just spend the whole time praying she doesn't fall in. 😂

[TiggerMe Ambassador in reply to Hidden]

Regenallotment I'm glad it's not just me that is constantly supervised by a furry friend or two 🤗... cat in the bath though... thing of nightmares like someone throwing razorblades in 😱

[Hidden in reply to TiggerMe]

It turns a nice bath into a rather stressful game of Russian Roulette. 🫣

[TiggerMe Ambassador in reply to Hidden]

Perhaps you need a dog to read to the cat 🤣🤣🙃

[Hidden in reply to TiggerMe]

Got 2 of them. ones a ratter though and rather sees the small black cat as 'probably just a big rat'. 🫣😂

[TiggerMe Ambassador in reply to Hidden]

Mine are both utterly confused by cats as when they were pups their playmate was a kitten, which has utterly skewed their expectations of cats as most they meet now just don't play nicely at all!😂

[TiggerMe Ambassador in reply to Hidden]

You can't leave tattybogle and I in suspenders... which emoji is under your 🫣😂 looking back you are a repeat 🫣😂 offender

[Hidden in reply to TiggerMe]

This is what I posted.

Screenshot

[Hidden in reply to Hidden]

'peeking-through-fingers' is one of my favourite emojis!

[helvella in reply to Hidden]

Do you mean this one?

🫣

emojipedia.org/face-with-pe...

[Hidden in reply to helvella]

That's the one!

[TiggerMe Ambassador in reply to Hidden]

Works on my phone but not on new laptop running Microsoft Edge!

[Hidden in reply to TiggerMe]

I won't use Microsoft edge. The icon irks me. 😂

[TiggerMe Ambassador in reply to Hidden]

I'm know I'm going to regret this but why?

[Hidden in reply to TiggerMe]

It's too cold and spikey. Lovely soft, warm, round, Google chrome for me. 😂

[TiggerMe Ambassador in reply to Hidden]

Weirdo 🤯Mind Blown emoji 😂 Laughing..... I'm not sure I could tell the difference!

[helvella in reply to TiggerMe]

In my documents (the ones I link to from time to time), I tried to use emojis to keep the documents small and make them simpler for me.

But I ended up using Apple versions of them collected as images from Emojipedia, because they were so inconsistent. (Apple because I am using an Apple machine - so they are what I would see - and they are often one of the graphically most pleasing of the options.)

The image I used is below. But on, for one example, Microsoft platforms, it shows as [GB] (or something like that).

Union flag

[Ukie in reply to TiggerMe]

As a child I experienced both those situations. The soggy cat swimming in the bath was hilarious. Razor blades less so, but ended well.

[Charlie-Farley in reply to Regenallotment]

I love pets they keep our souls topped up. Because we intend to sell and move we know it’s or fair to take on another dog at this stage - so hard to keep to!

[Hidden in reply to Charlie-Farley]

Circumstances meant we got an 8 week old puppy when our older dog was just 10months old. It's been pretty stressful but goodness me; the joy they bring is 100% worth it.

You're right; they do keep our souls topped up.

[FancyPants54 in reply to TiggerMe]

I've only lived in a house with a TV in it for 7 years in my entire life. It's all pretty much just a waste of time.

[Tythrop in reply to Charlie-Farley]

GPs and many endocrinologists are simply not in possession of enough knowledge to effectively treat hypothyroidism and the panel writing the guidelines are presuming underlying knowledge, which simply does not exist. That is patently obvious from the daily posts of people landing on the site under medicated.Absolutely right

[Charlie-Farley in reply to Tythrop]

But who to tell who will listen?😔

[helvella in reply to Charlie-Farley]

I always come back to variations around this:

Now I think I know

What you tried to say to me

And how you suffered for your sanity

And how you tried to set them free

They would not listen, they're not listening still

Perhaps they never will

[Charlie-Farley in reply to helvella]

I’m not chopping my ear off any time soon - but I am determined 😊👍

[Tythrop in reply to Charlie-Farley]

Sooo frustrating init

[Charlie-Farley in reply to Tythrop]

unbelievably- keeps me awake sometimes. 😞

[humanbean]

Regarding T3, I can't see many doctors in the UK paying any attention to this paper, even though it has Bianco in the author list. UK doctors have said some absurd things to patients on the subject of T3. The worst I heard was that it was a waste product from metabolising T4. The second worst was frightening patients into believing that T3 was going to given them heart attacks, strokes, and osteoporosis, or even kill them.

[radd in reply to humanbean]

hb,

Agree and it will take simply years to filter through to mainstream practitioner training (if ever), after those at the top have finally got a grasp that this paper speaks truth.

[TaraJR in reply to humanbean]

Sadly lots of patients are still being told T3 is dangerous eg AFib etc. It's a myth that's grown and grown. And maybe as T3 became so expensive it was looked upon as something very out of the ordinary, like black magic! So treat with ultra caution. Either way it's done us all a massive dis-service. All we want is a choice. Which other conditions are allowed no choice?

[humanbean in reply to TaraJR]

The stupid thing about this supposed danger is that in the UK information has been collated on adverse effects reported about all prescribable drugs, and even a few non-prescribable drugs.

Since 1967, when this collation of adverse effects began (for drugs existing at the time - others were added as they were created), there have been zero deaths recorded as a result of taking T3.

[helvella in reply to humanbean]

It would appear logical, especially in current awful states, that we should maintain statistics on those who suffer adverse events due to LACK of a medicine.

Simply the other side of the coin, really. If you are recording what happens when you take something, then isn't it pike-staff plain that you should also record what happens when you don't? Especially if due to shortage, failure to prescribe, etc.

[humanbean in reply to helvella]

I never thought of that!

[raine-wager]

My endo dropped my Levo from 100 to 75 and added 5mg liothyronine I tried it for 6 weeks and felt much worse , liothyronine was stopped and Levo up to 125mg now a bit better but still have all the symptoms, so not sure if I need more Levo, but liothyronine certainly made me feel worse…

[helvella in reply to raine-wager]

I'm not keen on making big claims about T4:T3 ratios but, sometimes, we need to talk in those terms.

Many suggest that the practical conversion of T4 to T3 is around the ratio of 3:1, maybe 4:1.

Dropping by 25 T4 and increasing by 5 T3 implies a ratio of 5:1. Very unlikely to be sufficient T3 to make up for the reduced T4.

Not at all a surprise you felt worse on that basis alone.

In your case, as you appear to have been under-dosed on 100 T4, I suggest 5 T3 could have been added without reducing T4 at all.

[Tythrop in reply to helvella]

What we're your blood test results for t4 and t3 before intro of t3, then when you had been on the t3 for about 6 was? THEN after t3 taken away and re- replaced by t4 again ?? Is there a correlation between the blood test numbers and how you feel or should we go back to the old days when patients were treated by competant doctors observing clinical symptoms ???? Just a thought

[Tythrop in reply to helvella]

Im a bit brain fogged , but with these ratios ,does it mean that 1 unit of t3 is 3 or 4 times as potent as 1 unit of [the carrier] t4?

[humanbean in reply to Tythrop]

Yes.

I always use a conversion ratio of 3 to 1 i.e. 30mcg T4 is equivalent to 10 mcg T3. I'm often shocked by the number of patients who have T4 reduced by huge amounts only to be replaced by 5mcg T3.

It's as if doctors believe that T3 is explosive and will blow the patient's head off.

Being a cynic as I am, I also believe this is done to set the patient up to fail so the doctor could say, "See? I told you T3 was rubbish!"

Another way this is done is to give the patient a prescription for T3 of, say 25mcg, and the patient will be told to take all of it in one go in the morning which, if you've been ill for a long time, will probably not be tolerated.

And another way that things are screwed up by doctors is by them prescribing different doses of T3 on different days.

[Tythrop in reply to humanbean]

I too am a conspiracory theorist .My husband tells me that I'm going mad ....but I know that the flat earth society are wrong . By the way on Armour ndt leaflets they say that t3 is 3 or 4 times as powerful as t4 .

[helvella in reply to Tythrop]

Very much agree with humanbean

I suggest you don't look at it as something being stronger than something else. (Like you might say about codeine versus paracetamol.)

Just realise that approximately one third of T4 gets converted to T3.

In my brain, that is both simpler and better reflects what actually happens.

[Tythrop in reply to helvella]

Makes better sense to me too

[raine-wager]

it’s taken 3 years to get to this dose, I don’t feel any better than when I started it, I’m so fed up with it all.. so many other things going on with me I don’t know what’s causing what😩

[tattybogle in reply to raine-wager]

on 100mcg Levo:

TSH 0.34

fT4 18.9 [12-22]

fT3 4.8 [3.1-6.8]

Then reduced levo to 75mcg and added 5mcg T3:

TSH 0.57 .... now higher, indicating overall reduction in thyroid hormone dose .

fT4 14.6 [12-22] ...... now lower, as a result of reduced levo dose.

fT3 4.5 [3.1-6.8] ... ALSO lower as a result of the reduced Levo dose .. less T4 to convert to T3 .

So ...it probably wasn't T3 that made you feel worse ,, it was the fact that by lowering your Levo and not adding enough T3 to compensate , you had less T4/T3 than you had on 100mcg Levo .

Then they say " Oh .. T3 made you feel worse, so we'll take you off it" .. which if you as cynical as me you might say was probably their objective . either that or they are just incompetent and very bad at maths.