Low CSF/serum ratio of free T4 is associated with decreased quality of life in mild hypothyroidism – A pilot study
The study sciencedirect.com/science/a... is important since it invalidates current guidance on diagnosis of hypothyroidism (including the recent NICE guidance) and uncovers a novel form of hypothyroidism which cannot be detected by blood tests.
A prospective study, it investigated fT3, fT4 in serum and in CSF in untreated newly diagnosed patients with mild primary hypothyroidism compared to healthy matched controls. The patients had mild primary hypothyroidism which is usually wrongly described as ‘subclinical hypothyroidism’. The patients had a median TSH of 4.96 and controls had a median TSH of 1.6 (0.4 – 4.0 mIE/L). There was no difference in fT3 between patients and controls. Patients had a median fT4 of 11.7 compared to 13.5 for controls (11-22 pmol/l). A TSH greater than 4.0 was considered hypothyroid provided the patients had a Zulewski score > 5. Zulewski devised a scoring system for evaluating signs and symptoms of hypothyroidism academic.oup.com/jcem/artic... .
The patients in this study were diagnosed if they had a mildly elevated TSH with signs and symptoms of hypothyroidism. Patients had lower general health Likert scores than controls. This could be due to selection bias as the patients presented with recent onset of fatigue, hypersomnia or lethargy.
On AVERAGE the patients’ CSF fT3, CSF fT4, CSF/serum fT3 ratio and CSF/serum fT4 ratio did not differ from controls. However, patients (but not controls) with lower CSF/serum fT4 ratios had lower Health Likert scores and higher MADRS depression scores. This highlights the danger of using averages in thyroid research.
TSH responds to serum fT3, fT4 levels and stimulates thyroidal secretion and deiodinase (T4 to T3 conversion). Symptomatic patients had lower CSF/serum fT4 ratios. This study finds an association between a lower ratio and symptoms - an association not causation. It’s possible that patients’ impaired health or depression caused the lower CSF/serum fT4 ratio. This is unlikely as both non-thyroidal illness and depression present with a lowered TSH with reduced bioactivity and results in ‘low T3 syndrome’.
It is quite possible that the mildly elevated TSH was an irrelevant factor, that the impaired CSF/serum fT4 ratio has nothing to do with thyroid failure. For example, some endocrine disrupting chemicals such as PBDEs have a strong affinity for transthyretin (TTR) which is the major T4 transport protein in the CSF. This form of hypothyroidism may have nothing to do with the thyroid. It would be useful to repeat the experiment when the patients have had their TSH normalised, to see if their CSF/serum fT4 ratio changes. A second trial in symptomatic patients with normal thyroid profiles should also be undertaken. Finally, the relationship between thyroid hormone in the CSF and the brain is poorly understood. Whilst CSF hormone levels are probably indicative of brain levels, they are unlikely to be an accurate marker.
This study is of major importance because: -
1. The study proves that patients can be hypothyroid with a mildly elevated TSH and normal fT3, fT4. This invalidates current guidance on the diagnosis and treatment of hypothyroidism.
2. The study supports the concept that the hypothalamic pituitary thyroid axis responds to serum hormone levels rather than central (brain/CSF) hormone levels. The CSF/serum fT4 ratios were lower and the patients had symptoms originating from the brain indicating that brain hypothyroidism may not be reflected in serum hormone levels.
3. The study shows that even mild hormone deficiencies cause substantial symptoms. Subnormal TSH secretion presents with lower serum fT3 AND fT4 levels. This study supports my hypothesis that low normal fT3 AND fT4 causes a devastating form of hypothyroidism presenting with ‘normal’ TFTs.
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jimh111
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CSF is routinely ignored. Hardly anyone ever gets CSF tested in relation to thyroid, so far as I am aware.
Some time ago it was claimed that TPOab were elevated in CSF in cases of Hashimoto's encephalopathy. (And other antibodies are also found in CSF with various associated disorders.)
CSF is rather invasive, sticking a needle into the spine, so I can see why it isn't routine. Perhaps if this research is followed up there will be better (safer) ways of making a diagnosis (apart fromt the obvious, looking at signs and symptoms).
Even though routine testing of CSF is impractical, couldn't a study such as this become part of the discussion about the diagnostic criteria for hypothyroidism? Mightn't it be used to question the requirement of TSH greater than 10 for treatment?
Yes and other forms of hypothyroidism present with normal TFTs but the endocrinologists pretend it doesn’t exist so they don’t have to work hard or lose face.
It's a great shame that those who make the decisions regarding treatment very rarely see, or inwardly digest some of these studies, or they certainly don't appear to if the treatment of people on this forum is anything to go by!
Does this suggest that maybe not enough T4 is getting through the blood- brain barrier? And if so, might addition of T3 instead of T4 monotherapy help?
I can't express any certainty but the only fact we know is that CSF/serum fT4 ratio is lower which suggests conversion to T3 may be working OK. On the face of it perhaps a little more T4 would do the trick. The truth is the only way to find out is to separately trial L-T4 and L-T3 and see the response. The relationship between CSF and brain hormone levels is poorly understood although an abnormality in CSF levels combined with brain hypo signs tends to confirm a link. The good news for this group of patients is that TSH is responding to minor falls in fT3 and this should give good T4 to T3 conversion, the blood test results seem to confirm this.
The reference to cerebrospinal fluid is given in the first bit of the Abstract. Many journals have a convention that this is not put in the title, presumably to keep it brief. I know many patients have too much brain fog to wade through a full paper but if you look at Fig 2 it gives an idea of the what the study has found.
It’s pure speculation on my part but I suspect the reduced CSF/serum fT4 ratio might be caused by an endocrine disrupting chemical (EDC) binding to T4 and so reducing the free fraction. Most T4 is bound to transthyretin (TTR) in the CSF whereas T4 is mostly bound to thyroglobulin in the serum. EDCs such as polybrominated diphenyl ethers (PBDEs - common flame retardants) have a high affinity for TTR.
These EDCs are able to disrupt T3 binding to receptors and so cause hypothyroidism. Due to the way potential EDCs are tested the ones that slip through the net do not disrupt T3 activity in the hypothalamus/ pituitary and so blood tests are normal. They do disrupt T3 bindingin peripheral tissues. So, possibly the low CSF/serum fT4 ratio is a coincidence, a marker for rather than the actual cause of the hypothyroidism. This is my best guess based on my knowledge of how PDBEs disrupt thyroid hormone action. This is one reason why I believe this study is so important.
Yes, got it. No brain fog over here. It is no-one's convention to throw out an abbreviation in a title and while we are disputing scientific accuracy you should also specify UNITS in the quantities you are quoting. A TSH of 4.96! 4.96 what? Dogs, cats, buckets of spit? No, don't tell me, I know the answer but many will not especially if you are writing for an international audience who have different units for most of our common measurements. A topic which is brought up frequently.
But all that being put to one side, it was a pretty good post. Thank you.
I did, with the reference interval! "The patients had a median TSH of 4.96 and controls had a median TSH of 1.6 (0.4 – 4.0 mIE/L). " But don't ask me what mIE/L is! (I think the 'L' is litre).
You do raise a relevant point. Endocrinologists are diagnosing and treating patients on the basis of hormones in the blood. This can be really useful sometimes but it is just a bodily substance, a surrogate that tells us how much hormone supply is circulating. They could just as validly measure how much hormone is in our poo. It might even be a better marker, perhaps we dump excess hormone we don't need? It could have 'exquisite sensitivity', I doubt it, but it hasn't been formallly validated. Neither has TSH been validated as a quality marker for thyroid hormone activity, not even for the majority of potential hypothyroids let alone all of them.
This study finds that low CSF/serum fT4 ratio acts as a marker for hypothyroid signs and symptoms. Serum hormones do not, CSF fT4 levels don't. It's the relationship between CSF and serum fT4 that reveals hypothyroidism. This is one reason I like the study, it puts markers in context and shows that it's clinical response that matters. For some reason free T4 is not getting into the CSF (and presumably the brain) even when there is adequate free T4 sloshing around in the blood. The balance between serum and CSF fT4 has broken down.
It's purely a guess on my part, intuition if you like, but I suspect this is due to endocrine disruption which a much neglected area of endocrinology. If I was offered decent odds I'd place a bet on this. Blood tests can be really useful but they are not definitive, signs and symptoms with response to homone therapy is definitive.
As someone in exactly this category (can’t speak for T4 and T3 levels as GP wouldn’t/couldn’t test them) this makes for interesting reading - thank you for sharing.
Thanks for the article, it’s very interesting. Some T4 converts to T3 in peripheral tissue, like the brain, so low T4 in CFS might mean less T4 to convert to T3 in the brain even when serum TSH and T4 and T3 are in range. This is another small piece of evidence that you really can feel ill with ‘normal’ bloods. It implies getting more T4 into CSF or getting more T3 into CSF might help.
I really liked this as it’s something specific to show an endo when seeking a T3 trial and it supports the other research on poor peripheral conversion as a cause of ongoing symptoms even with normal bloods.
Sorry about the long post I’m under lockdown in Spain so catching up on all things thyroid. Stay safe and well everyone.
Michael
• in reply to
"... so low T4 in CFS might mean less T4 to convert to T3 in the brain even when serum TSH and T4 and T3 are in range. This is another small piece of evidence that you really can feel ill with ‘normal’ bloods. It implies getting more T4 into CSF or getting more T3 into CSF might help."
Thank you. Put into words what I was trying to get at. My FT4 was over range and T3 almost at top but I still felt hypo mentally and in a couple of other ways. Suspect something like that may be part of the reason
Forgot to answer all of your questions. The study suggests there may be less T4 in the CSF and presumably in the brain and this could lead to brain hypothyroidism. This would seem to be confirmed because the patients had impaired health and higher depression scores.
Thank you. I'm not depressed but my concentration and mental energy is definitely not as it should be, so it's helpful to know that this is one possible reason, and maybe something to mention at a coming endo appointment.
But on the other hand I don't fancy having a lumbar puncture to check!
Do you think that a small amount of added T3 might help? The molecule size is only a bit less than T4, but it may have a better chance of getting where it's needed. Not much chance of getting it on the NHS but something to consider trying. For Hidden too maybe.
The brain mostly relies on T4 but can take in a bit more T3 if the fT3 levels are above average. Just my view but I think brain hypothyroidism can come from two causes 1. a down-regulated axis (TSH lower than it should be) which reduces deiodinase (T4 to T3 conversion) and 2. endocrine disruption, chemicals that disrupt thyroid hormone binding. In both cases T3 would help but I would try taking simeticone for a few months first (see my profile). Simeticone is cheap and safe, hence it is an easy first option.
• in reply to
Hi @Jnetti, I did a nine month T3 trial with the NHS last year and the very first improvement I noticed (within a day) was that my thinking became clear and I felt switched on again. Unfortunately, the consult I saw left and I got very little advice from the nhs on finding a dose combo of T3 and T4 that worked for me and was put back on T4 only. I’ve slowly got some improvements to energy and much pain but am definitely not as mentally sharp as on T3.
I tried to tag you in this but not sure it worked?
I have a similar response. L-T4 works for many hypo symptoms but L-T3 is needed for brain function. I'm sure many do fine on L-T4 only but some of us need varying doses of L-T3.
My last test (Medichecks) showed suppressed TSH, T3 nearly top of range and T4 well over range, but there seemed no improvement from the previous dose. I decreased Levo a bit in February but that didn't seem to make much difference either.
Too complicated to go into but in general my approach is to stay on the lowest hormone dose that works and if an increase does not give improvement go back to the lower dose. This doesn't apply to anyone whose hormone levels are below average or are pregnant with a TSH above 3.0.
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