Higher CSF/serum free-T4 ratio is associated with improvement of quality of life during treatment with L-thyroxine

[helvella]

An interesting paper.

Note a parallel with Pernicious Anaemia/B12 deficiency in which some have low CSF B12 while having high serum B12.

Asking the question, though the answer is almost certan, has anyone ever had their CSF thryoid hormone levels tested?

On Twitter:

Johannes W. Dietrich @drjwdietrich

Does impaired transport of #thyroid hormones into the central nervous system contribute to #syndrome_T / #SORSHOT? A recent study observed CSF/serum FT4 ratio to be associated with #QoL in treated #hypothyroidism.

Higher CSF/serum free-T4 ratio is associated with improvement of quality of life during treatment with L-thyroxine

Anders Funkquist, Birger Wandt, Kaj Blennow, Henrik Zetterberg, Johan Svensson, Per Bjellerup, Yvonne Freund-Levi, Stefan Sjöberg

First published: 31 March 2023

doi.org/10.1111/jne.13272

Abstract

Up to 20% of individuals with primary hypothyroidism treated with L-thyroxine still suffer from severe symptoms. These are supposedly brain derived and involve both cognitive and emotional domains. Previously, no consistent relationship has been found between thyroid hormones (TH) or TSH levels in blood and quality of life (QoL). Recently, we reported an association between cerebrospinal fluid (CSF)/serum free-thyroxine (f-T4) ratio and QoL, in juvenile hypothyroid patients. Here, we investigated if CSF/serum f-T4 ratio and QoL estimates correlate also during L-thyroxine treatment. Moreover, the CSF biomarker neurogranin (Ng) was used as a biomarker for synaptic function and integrity in clinical research. Ng is partially controlled by TH and therefore we investigated the relationship between QoL parameters and Ng levels. Patients diagnosed with primary hypothyroidism were investigated using vital parameters, serum and CSF analyses of TH, TSH, Ng and QoL questionnaires. Similar procedures were performed after 6 months of treatment. The most marked associations with QoL were found for CSF/serum f-T4 ratio, which was strongly related to several QoL parameters such as the mental subscore of SF-36 (r = 0.83, p < .0005). Ng, which did not differ from that in our healthy controls, was lower in some patients during treatment and higher in others. However, the change in Ng during treatment was significantly correlated with QoL parameters including the mental subscore of SF-36 (r = −0.86, p < .0001). In addition, the CSF/serum f-T4 ratio correlated with the change in Ng (r = −0.75, p = .001). Our results suggest that the ratio between CSF and serum f-T4 is an important biomarker for QoL during treatment of patients with primary hypothyroidism, so far in research, but in the future maybe also in clinical settings. Moreover, this ratio also correlates with the changes in Ng levels during L-thyroxine treatment, further supporting the impact of the TH balance between serum and CSF on QoL.

Open Access here:

etj.bioscientifica.com/view...

[HealthStarDust]

What exactly is CSF in laypersons terms? And, how would one go about getting such a test?

Intriguing.

[helvella Administrator Thyroid UK in reply to HealthStarDust]

Cerebrospinal Fluid - what is colloquially called a spinal tap!

The clear fluid that circulates round the brain and spine.

A reasonable starter with piccies ( ) here:

en.wikipedia.org/wiki/Cereb...

[HealthStarDust in reply to helvella]

Ahhhh! Me and the husband love shouting spinal tap when watching the evolving diagnostic investigations in medical dramas!

I’ve always wanted one of those.

[greygoose in reply to HealthStarDust]

I believe they're very painful!

[HealthStarDust in reply to greygoose]

Pain schamain! We all experience it differently and my threshold for it is pretty high.

And, is the TV lying? All the shows make it look not so bad? 😇

I actually have always wanted one!

[greygoose in reply to HealthStarDust]

Glad you can be so blasé about pain! lol Of course the TV is lying! It always does. And - to be fair to them - perhaps they don't want to put people off who really need one.

[helvella Administrator Thyroid UK in reply to greygoose]

NHS says this (using its 'proper' name):

Lumbar puncture

A lumbar puncture is where a thin needle is inserted between the bones in your lower spine. It should not be painful, but you may have a headache and some back pain for a few days.

It's carried out in hospital by a doctor or specialist nurse.

nhs.uk/conditions/lumbar-pu...

The headache can be excruciating, I've heard.

[HealthStarDust in reply to helvella]

Ha! I already live with pain including headaches and have developed all sorts of techniques to over come it. Well, tolerate it. In fact, pain in another area of my body would give me a break from the pain in other parts of the body.

Besides, what can be worse than tooth pain?!

None of yous will take my dream away from me.

HM… side note, my good mood may be a sign the treatment is beginning to work in some ways at least! 🤞🏽

[greygoose in reply to helvella]

Yeah well, they're a lying bunch of scum-bags, too! I've had a needle 'between the bones in my lower spine', and let's just say I don't want another!!! They'll tell you anything isn't painful just to get you to do it. I remember being told by doctors and nurses that childbirth wasn't painful, either! But none of them had ever had one. And I don't suppose the people that wrote that blurb had ever had a spinal tap!

[nightingale-56 in reply to helvella]

Might it be more painful than having a spinal anaesthetic then? It doesn't sound as though it should. Thanks for posting this helvella .

[helvella Administrator Thyroid UK in reply to nightingale-56]

One problem is that these procedures are so often done when the poor patient is already suffering. Not easy to make a balanced assessment in the circumstances.

I've never had anything like it so cannot comment from experience.

[nightingale-56 in reply to helvella]

I've had a spinal anaesthetic, so wondered if it was worse than that (not too bad for me). I guess it could be a bit worse as it is drawing fluid off rather than adding an anaesthetic. Thanks for replying.

[Zephyrbear in reply to helvella]

My husband had it done for his viral meningitis diagnosis… his head was already pretty painful before the LP, but he said it felt like his head been run over by a steamroller after it, which took several days to subside. The meningitis took several weeks to get over initially, but the long-term effects are still here nearly 40 years later… Definitely not an illness or procedure I’d recommend!

[Maztee in reply to helvella]

Yes and a chunk of the patients didn't go back for the second one because of this, it says, so their results aren't included. I don't blame them. I have eye injections and it's sensitised me to pain so I can barely stand any procedure except a good blood draw now - luckily my GP surgery and hospital have good phlebotomists 🙂💉

[HealthStarDust in reply to greygoose]

Humour is the best defence mechanism in the face of all trauma, especially iatrogenic trauma which is globally evident in the sh€t show that is the diagnosis and treatment of thyroid disease.

After that, shouting and swearing with a pinch of Hip Hop on the side works well for me too 🤣

[greygoose in reply to HealthStarDust]

Oh, totally agree with you about humour - it's a gift from the gods. Unfortunately, the gods don't seem to give it to many doctors! But, laughter is the best medicine, as they say. (Could tell you a good story to illistrate that, if you like. lol)

And I'm all for a bit of shouting and swearing, but a bit too hold for Hip Hop - with my hips, hopping is totally out of the question!

How does that work, anyway?

[HealthStarDust in reply to greygoose]

😆

I think you can get away with just touching your hip with a glass of hops in the other hand.

And, always up for a story and probably have some to share also.

As for TV, the other day on the show Fortitude (by the way helvella I have feeling you may like that show) I saw a child character get a spinal tap, didn’t even squeal and he does not look like the lying type.

I’m looking forward to reading the study when I my brain allows.

[greygoose in reply to HealthStarDust]

OK, so here goes with the story, then - a true one, I hasten to add!

Laughter is the best medicine

I got divorced when I was 50, and that’s when I went to live in Paris – although I prefer to say I ‘ran away to Paris to go on the stage’! All true except the running part, I’ve never been able to do that.

Anyway, there I was starving in a cockroach infested garret.. no, a very small flat on the third floor – in Paris without a job, or any money, or any health insurance, and one of my molars decided it was tired of life and wanted to be taken out. The pain was excruciating. And I could barely afford aspirin to dull it. So, decided to find out if laughter really was the best medicine.

In drama school, they taught us an exercise to make us laugh when we felt least like laughing, so I gave it a go. You start out by saying out loud ‘Ha’. Then, ‘Ha, ha’. Then, ‘Ha, ha, ha’. Counting on your fingers as you go. Before you get to finger number five you’re usually laughing hysterically. Works every time – well, nearly every time. So, I did this and, yes, the toothache calmed down. After a couple of hours of hysterical laughter, I couldn’t feel a thing! So, over the coming weeks, I did this every time I felt a twinge coming on. Even in the car, which got me some very funny looks at traffic lights.

One evening, I was invited to the theatre by an actor friend, to see a play he was in called ‘The Wedding’. The invitation was made to look like a wedding invite. And, when I handed it to the usher at the door, I was given in return a little tulle bag of sugared almonds, just as they do at a wedding in France.

Now, although my tooth wasn’t actively aching anymore, it was still very sensitive, and easily set off. And, the smell of the sugared almonds that permeated the theatre was beginning to have an effect. The theatre was beginning to fill up, and the smell was getting stronger. And, all around me, people were crunching on sugar almonds and just the sound made my poor tooth ache.

A couple of rows down, I could see a director I wanted to impress, with his latest pretty boy, so no way could I start my laughing exercise now to calm my aching tooth! Then I remembered that I had a small packet of effervescent aspirin tablets in my bag! Eureka! But, I hadn’t any water. I thought about it… Hmmm, maybe I could suck them… I’d give it a try, and popped one in my mouth – well, better make it two, just in case. Within seconds I was foaming at the mouth. These things were melting slowly but the foam they produced was disproportionate! I kept my mouth tightly closed, at the risk of choking, but the foam forced its way out at the corners. I panicked. Swallow them, swallow them, my brain advised. Stupid brain. The bloody things stuck in my throat, causing me to cough, and the foam came tumbling out and ran down my chin. People were beginning to stare, and I was terrified the director would turn around… And, then, the curtain rose…

So, there I was, with a handkerchief over my mouth, frantically trying to swallow, and assuring myself that they would definitely melt any minute now. And I become absorbed in the play. It was very funny, and as soon as I got the tablets out of the way, I laughed out loud and forgot about the tooth. So, laughter it is. Effervescent aspirin it definitely isn’t!

Sorry, Rod, for hijacking your thread. 🤓

[HealthStarDust in reply to greygoose]

This was absolutely fab to read. Thank you so much. And yes, sorry Radd for hijacking your thread.

I blame GG. If you read our profiles, we are quite clearly potters!

Best wishes and I’m not going to come back with a story as nothing but your own other stories I suspect can top that 🫶🏽

[greygoose in reply to HealthStarDust]

[nightingale-56 in reply to greygoose]

Alka Seltzer does the same greygoose , in the Cinema. Tissues come in handy, but the AS definitely worked!

[greygoose in reply to nightingale-56]

😂😂😂

[jimh111]

I suspect CSF fT3 levels would be even more useful. Will read the study when I have time.

[helvella Administrator Thyroid UK in reply to jimh111]

The old, old story - ignore T3 in every possible way.

[helvella Administrator Thyroid UK]

A few more Twitter comments:

Dr KL @dr_kevinlee

I think it’s very insightful also, confirms what has been suspected, thyroxine therapy lowering CSF fT3 level

Johannes W. Dietrich @drjwdietrich

This is in fact important. It results from suppressed TSH-T3 feedforward control. Therefore, L-T4 treatment may in some cases do more harm than no treatment at all.

Dr KL @dr_kevinlee

It’s interesting to think about CNS thyroid status, as such probably is correlated with various neuropsychological conditions and it could highlight the importance of T3 rather than T4.

scielo.br/j/rbp/a/XDwBh3BBg...

[HealthStarDust in reply to helvella]

CNS thyroid status, as such probably is correlated with various neuropsychological conditions

100% and the more I learn, Duh!

[Pearlteapot]

I don’t understand what it means. Does it mean testing T4 in CSF is a better marker than blood serum?

How did Johannes conclude t4 might do more harm than good? I’m really interested in that bit

[helvella Administrator Thyroid UK in reply to Pearlteapot]

Testing T4 in CSF is neither better nor worse. It is different.

As I understand, the suggestion is that T4 treatment could end up causing lower T3 in CSF. Not even as much as had been maintained prior to treatment.

That doesn't necessarily mean that treatment can, or should, be delayed indefinitely. After all, the body is continually changing and even if initially treatment was not good, there will likely come a point where it is necessary. And, quite likely, some combination rather than T4-only.

[Pearlteapot in reply to helvella]

Thanks. What is the suggested mechanism for the deleterious effect of T4? Is it that it breaks the hpt axis compensatory production of T3 which would give up at some point anyway? Or something particular about levothyroxne or any other t4 replacement. What I’m getting at in my second question is whether it suggests t3 only would e better?

[helvella Administrator Thyroid UK in reply to Pearlteapot]

Are you on Twitter? Or BlueSky?

Just I don't feel comfortable putting words into Johannes Dietrich's mouth. Last thing I'd want is to misinterpret him, his view - and that is all too possible.

Maybe diogenes is around and could jump in?

[Pearlteapot in reply to helvella]

I’m on X. X is being beaten up by the EU for its moderation. Never heard of blue sky till I saw dr johannes refer to it.

edit. My sentence was ambiguous. The EU data commissioner is threatening a massive fine.

[Pearlteapot]

I’ve looked up dr johannes on twitter ❤️

[jimh111]

On reading it I think it is a very useful study which is why I'm takinig the unusual step of prompting everyone helvella HealthStarDust greygoose nightingale-56 Zephyrbear Maztee

First we should look at reference 22 which is their earlier study doi.org/10.1016/j.jcte.2020... .

This is quite enlightened because the patients had 'mild' hypothryoidism (or at least mild numbers) with average TSH 4.96 and fT4 11.7. Usually patients with these numbers are told to get lost. Both studies included fT3 but serum and CSF levels and ratios were not different from controls.

I don't know why a low CSF / serum fT4 ratio should correlate to decreased quality of life. Since most CSF fT3, fT4 I believe comes from the pituitary and hypothalamus it may not reflect brain fT3, fT4 levels. Possibly reduced CSF fT4 provides less substrate for the brain to convert to T3 locally.

They assert TSH stimulates deiodinase (I believe it does) but the reference they cite is not good evidence for this. Possibly patients with similar serum fT4 and a higher TSH would show higher CSF fT3 levels, maybe some of these patients have subnormal TSH secretion.

Zulewski score which measures general hypothyroid signs and symptoms did not differ according to CSF / serum fT4 which suggests the effect is limited to the brain.

Coming back to the later study it shows that the patients who recover are the ones with a higher CSF / serum fT4 ratio. The Ng numbers show it is most unlikely to be a placebo effect.

I wonder if these patients have TSH with reduced bioactivity, it would be interesting to see what happens if they are given some TRH, how it affects their fT3 / fT4 ratios.

Most important, I notice that when studying my cognition is fine but after 15 to 20 minutes it can start to decline. It takes time to recover but if I struggle for another five minutes it takes much longer to recover. When I've experimented with a touch more liothyronine this effect is reduced. The evidence is TSH stimulates the RATE of deiodinase. It is quite possible that these patients have impaired deiodinase in the brain but have been rested prior to taking the blood in the morning. Perhaps if they were given some heavy reading to do prior to the blood take we might see quite different CSF fT3 levels.