New article has appeared in full discussing how to design trials for determining use of combination therapy. Naturally, being US based, it makes no mention of our work whatsoever.
Interesting. Do you see any obvious flaws or oversights in their recommendations Diogenes? (I’ve just had a quick scan through). I note that they say TSH readings give a good indication of euthyroidism which, to me, is a failing at the first hurdle unless I’ve misunderstood what they’re saying!
Shame they’ve not taken time to read or quote from the excellent work you and your team have been doing.
I confess to not reading all of it ( i started chuntering in the middle somewhere) , and I'm not a researcher.... but it seems, to 'simple little me', that they are making a relatively simple problem ridiculously complicated.
What would be so wrong with;
Advertise for dissatisfied patient's who are willing to do 2x daily dosing,
measure FT3/FT4 , and ThyPRO QoL score,
use patient's with a crap T4/T3 ratio who do badly on the ThyPRO thingy,
dose/test properly so you don't make them Thyrotoxic , continue for a year,
measure FT3/FT4,
see if they do better on ThyPRO.
Simples.
ok , i know it's not that simples , but really !
Why are they so frightened they are going to kill someone with T3...... have they never heard of an FT3 test ?
The problem that they continually raise is the instability of FT3 concentrations in the body. They miss the point. I would not rely on exact FT3 levels, but on the ballpark area (lowest one third, middle one third and top one third) to get a satisfactory therapeutic response. Variation within those areas I would not worry about. AND let's not forget the PATIENT. Presentation, symptoms and a general discussion between the doctor and patient face to face is essential. To my dismay I read that the Royal Society of General Practitioners is advocating telephone discussions as the routine contact between doctor and patient. At least for new thyroid sufferers and those on therapy, this will be a terrible decision. Not everyone is eloquent about their problems, and essential needs and action may be missed if a patient can't describe their problems and give an impression of an easily settled problem when it will not be. This is one step even further away from the intimate doctor-patient relationship, on top of computer screen fixation at the practice where the doctor often surveys the screen and not the person in front of them..
To my dismay I read that the Royal Society of General Practitioners is advocating telephone discussions as the routine contact between doctor and patient.
That is appalling but doesn't surprise me. Doctors haven't wanted to touch those nasty, dirty patients for years.
I would simply never get in touch with a doctor if I had to communicate via telephone. I'm too deaf and after so many years of having no usable hearing aids when I needed them my word recognition (in speech) has deteriorated dramatically.
I think it has its place. My GP phoned me straight away after doing my thyroid function tests and to tell me that I was to start medication immediately (two days before Xmas) and not leave it over the holiday. A letter could have taken forever, and I don’t think I’d have survived into he New Year without action. He only used the phone in this way, he was a great GP, really caring and always listened. I owe my life to his phone calls. But I agree that phone alone is not good at all.
Oh sorry I missed the last bit of your post about the hearing aids speed reading with 2 mins of dinner break to go not good fue attention to detail 😳My hearing went very downhill as my thyroid deteriorated. I felt very isolated and it made me paranoid as all I could hear of nearby conversations were whispers - the stuff of nightmares with my tendency toward believing they are out to get you - but I was lucky that it improved a lot with thyroid hormone therapy. I still need the blower on full volume to hear the other person. I’d definitely rather see a doctor face to face, for you it must be imperative.
My hearing started to deteriorate when I was a child (over 50 years ago now ), so there is no obvious connection between my thyroid and my hearing loss. It has been getting worse over the last decade or so, so perhaps that part of my problem is thyroid related. I'll never know though.
We had experience of a telephone consultation after my husband had his elbow operated on a few weeks ago. After being discharged from hospital he noticed he had a nasty swelling on his leg which we thought was a blood clot. After trying for a long time to get in touch about 45 minutes the receptionist finally answered. We were allocated a time when the doctor would call us which was 2.30pm which I was not exactly pleased with because I thought the swelling might need some attention. When he finally spoke to the GP we were told to send a picture of his leg and because they had no intention of actually physically examining him in person. The diagnosis was a haematoma and to ring back if it got any bigger ... very reassuring!
"The problem that they continually raise is the instability of FT3 concentrations in the body. They miss the point. I would not rely on exact FT3 levels, but on the ballpark area (lowest one third, middle one third and top one third) to get a satisfactory therapeutic response. Variation within those areas I would not worry about."
Do you think it might help to comment or contact them directly, referencing some of your own research???
The problem that they continually raise is the instability of FT3 concentrations in the body.
The big problem with this is that FT3 and TSH both fluctuate with a similar circadian rhythm, with T3 lagging behind changes in TSH by about 90 minutes. Also TSH fluctuates far more than Free T3. I'm using this paper for reference (see first paragraph of the Discussion) :
Despite the fluctuations in both Free T3 and TSH, TSH is used as the gold standard and Free T3 is ignored. Thyroid treatment as it is currently carried out by the powers-that-be is totally inconsistent and illogical.
No doubt a well-meaning commentary that again misses the fundamental issues.
It's perfectly reasonable to make an initial assumption that some or all patients miss the T3 that used to come from the thyroid. This amounts to about 6 mcg daily plus a little from thyroidal deiodinase (much more if thyroid hormone levels are low and TSH high). This has been the basis of all the trials so far, some giving a little more T3 some less. Many reducing levothyroxine by a factor of 4 or 5 which overlooks the different half-lives and absorption factors. Nonetheless these studies at best found marginal benefits of combination therapy.
It is now being proposed that a large-scale long-term study is conducted, at considerable expense. I've no doubt this will find a significant small benefit for combination therapy and be of no use to patients. It will not show how to identify patients who will benefit or what dose of T3 they should receive. The data will be confounded by patients who will do a little worse with the delivered dose of T3. An expensive mess that will make it more difficult to get appropriate therapy.
A small dose of L-T3, perhaps 10 mcg daily is enough to 'supply the exogenous T3 whose production is lost due to thyroid failure'. I see remarkably few patients on this forum who have any noticeable benefit from this level of T3 intake. Clearly patients whose life is changed with the benefit of T3 require much higher doses. The problem is not mildly low serum T3. There are other causes.
Some patients have a form of resistance to thyroid hormone (RTH) and by definition require supraphysiological levels of thyroid hormone. By their nature endocrine disrupting chemicals produce RTH in susceptible individuals without disrupting the thyroid axis, if they affected thyroid blood tests they would be rejected during the approval process.
By far the most common group of patients who need T3 are those who have subnormal TSH secretion, perhaps due to their axis being down-regulated by a period of thyrotoxicosis as can happen in Graves' or Hashimoto's. They have low normal TSH, fT3 and fT4. I have a file of over 50 such patients from the fora who have quite pronounced hypothyroidism with devastating effects on their lives. I stopped keeping records after I got to 50. These patients are told their blood tests are normal (which they are) but their doctors fail to recognise their TSH is not responding as it should do.
TSH stimulates deiodinase, particularly type-2 deiodinase (D2) which is used to regulate local T3 levels in organs such as the brain. If we take two patients who have had their thyroid surgically removed, both on similar doses of levothyroxine, one with average fT3 and the other with low normal fT3 and inappropriately low TSH. The loss of T3 has come from reduced deiodinase, primarily D2. Hence, we can deduce the organs that rely on D2 have local hypothyroidism. Restoring normal fT3 levels with liothyronine will not restore T3 levels in the D2 expressing organs. T3 from tablets does not fully compensate the loss of T3 from D2 regulated tissues. Larger doses of T3 are needed so that tissues such as the brain can take extra T3 from circulation.
Studies are needed that identify those groups of patients (cohorts) that are likely to benefit from T3 and establish appropriate therapeutic doses. These are likely to be high doses that probably carry some risk. These patients are already at considerable risk from tissue hypothyroidism and suffering wretched lives.
I believe we should oppose the proposals to conduct a large scale 'definitive' study based on current misconceptions. Thyroid doctors need to go back to basic school science and seek to identify the affected cohorts and determine effective doses before conducting any trials. Sadly this is unlikely as medicine is very much based on the 'not invented here' principle.
For those of you who don't know me I am definitely not a doctor.
The problem with the 3.3 m2 mcg T3 secretion daily is that this is wrong. The information has come from the 1990 Pilo et al paper [1], which makes my blood boil, it is that wrong. Pilo did not intend for his results to be taken as they have been since, to define in other studies the T4:T3 ratio to be used.
Tania Sona Smith of the Canadian Thyroid Patients Support FB group has delved into the Pilo paper to the nth degree [3]. The main problem, and there are lots, is they didn't look at the rate and ratios of the thyroid secretions of the thyroid healthy people in the small study cohort of just 14 people, 5 females, 9 males. The range of thyroid hormone ratios was 6:1 - 71:1.. T4:T3. Thats before they then compromised it further by adding in radioiodine. Pilo et al added a lot of complicated maths, which I have not so far been able to get deciphered. I've tried, asking a Cambridge maths graduate.
Pilo et al has been quoted many times but Bunevicius et al [2] who used the 3.3 m2 mcg in the final paragraph of his 1999 paper is quoted far more times. Why? Because many researchers realise the flaws in Pilo and Bunevicius is unencumbered with them.
This paper study due to patient safety considerations cannot be repeated so we could be subject to this papers wrong results ad nauseum.
I've read Tania's comments, without understanding them! I've seen statements that the thyroid secretes about 6 mcg which is the figure I quoted. On to that we must add some T3 that comes from deiodinase in the thyroid.
I don't have full confidence in these data. I prefer to fall back on common sense. When we add a fairly small dose of liothyronine it is enough to bring fT3 back to typical levels. So, whatever the T3 contribution from the thyroid we have restored normal circulating T3 levels with a little liothyronine. I've noticed very few patients recover with these doses.
It is difficult to measure fT3 in patients on T3 due to its short half life but we can get a rough idea by factoring in the timing of the dose and blood draw. Patients rarely recover when we use combined therapy that compensates for thyroidal T3 secretion. Therefore the loss of thyroidal T3 is not the reason they are still ill. I feel doctors and patients need to accept this logic if we are to make progress.
I agree completely. There is a reason why I have to keep adding t3 continuosly, at 25 mcg now and still hypo. I don't agree with ratios or even blood tests
Wow, this seems like much ado about nothing. I was sick as a dog for about two years and had a stupid Endo, I decided I needed T3, hopefully in a natural ratio of 1:4 or 1:3 so I managed to find a doc who prescribed it. The day I had that 'script in my hand was the last day I took Levo. The very next day I popped 1 and a 1/2 Armour NDT, I lay in bed wondering if I was going to die and slowly a big heavy cloud began to lift. Within 20 minutes I became normal again and I've never looked back.
Maybe researchers should contact a few thousand of us and do it all empirically. I think that would be simpler and faster.
This is my point, use basic science. Find out what ratios patients need and then try to identify reasons why these ratios are needed. It's wrong to demand that patients must get well with a ratio that restores normal levels.
No doubt high T3 / T4 ratios carry some risk but if effective treatments are discovered the risk / benefit decision can be made on an informed basis. Leaving patients hypothyroid (often undiagnosed) carries high risk as well as wrecking lives.
The paucity of data in the Pilo study and the enormously wide range of calculated thyroidal T3 production, does, as Tania Smith described completely illegitimise the conclusions. However, we are well into a trial that studies the FT4/3 levels of patients just before and just after thyroid ablation or removal for cancer or gross goitre (and before T4 supplementation). The halflife of T4 is one week so that a day or so without supplementation after the operation won't affect things much. However the half life of T3 is 1 day, so that two days say after the op, the T3 production will be essentially from body conversion only. The difference in FT3 before and after the op should give a reasonable view of the now lost thyroidal T3 output. If people try to undermine this way of doing things, then we can say, OK perhaps the body did increase its conversion after the operation, but this will be slow because the T4 storage will hardly be affected. Anyway, if this happened, then our estimate of thyroidal T3 production will be an under- not an overestimate. I look forward to the data being analysed, in a trial going on now for more than 1 year. It should put Pilo et al to bed, because a) we can study many more patients, and b) the problems in blocking T4-T3 production in the thyroid by adding Lugol will not occur.
I've never read the Pilo study, only printed it yesterday. I'm wary of complex studies because there are more opportunities for wrong assumptions and errors. I like your study, especially as it doesn't include Graves' patients whose TSH receptor antibodies influence deiodinase. It does seem rather obvious to compare people with and without a thyroid in order to determine thyroidal T3 contribution.
One question. What sort of TSH levels do the patients in your study have? If it is very low thyroidal T3 production may be underestimated and vice-versa.
I'm hoping they will straddle the reference healthy range, because there's no basic reason to think otherwise. The cancers and the goitres if euthyroid otherwise should mimc ordinary people.
Unless iv'e misunderstood the Pilo result's , they show a huge variation in the 'normal' amount of T3 between different people. ( at least in the tiny amount of cases they look at, all 14 of them! honestly , they could have got more data from an afternoon reading reply's on here )
This is my understanding too, and also from reaing Tania's interpretation. I've a poor brain for complex maths, so rely on interpretations of people I trust.
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), so there is no obvious connection between my thyroid and my hearing loss. It has been getting worse over the last decade or so, so perhaps that part of my problem is thyroid related. I'll never know though.
T4 & T3 combination therapy... day 9... awesome! 
Combination therapy T4 + T3 
