The Thyroid Madness: Two Apparently Contradictory Studies. Proof?

by johnlawrenceaspden10 min read10th Apr 201680 comments

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Recap: (See also: http://lesswrong.com/r/discussion/lw/nef/the_thyroid_madness_core_argument_evidence/ and previous posts)

Chronic Fatigue Syndrome and Fibromyalgia all look far too much like the classical presentation of hypothyroidism for comfort, but thyroid hormone blood tests are normal.

Many alternative medicine practitioners, most prominently John Lowe, and several conventional medical doctors, most prominently Kenneth Blanchard, a practising endocrinologist with a longstanding practice completely free of lawsuits, have tried diagnosing hypothyroidism 'by clinical symptoms', and treating it with various combinations of thyroid hormones, and they all report success, but the practice is dismissed as ignorant and dangerous quackery by conventional medicine.

I suspect that there are acquired 'hormone resistance' or 'type II' versions of all the various endocrine disorders. These would produce the symptoms without reducing the levels of the hormones in the blood. However hormone treatments should still work, simply by overwhelming the resistance.

We know that diabetes comes in two forms, (type I) gland failure and (type II), 'insulin resistance', and that the resistance version is usually acquired rather than inborn. The mechanism for the resistance version of diabetes is mysterious.

There are known to be corresponding 'gland failure' and 'resistance' versions of diseases associated with all the other endocrine hormones, but for some reason the resistance versions are thought to be very rare, and only to be inherited, never acquired.

Should such acquired resistance mechanisms exist and be common, then on evolutionary grounds they would have to be caused by the direct action of pathogens, be a side effect of immune defense against such pathogens, or have an environmental cause. Nothing else would be stable.

Chronic Fatigue Syndrome often seems to start with an infection.


 


I thought until recently that the problem must be rather complex, and depend on subtle balances of hormones in a complicated system. The idea is so simple and obvious that if it were straightforwardly true, it isn't credible that it would have been missed.

But it turns out that there have been two formal studies of the simplest possible version of idea (treat the symptoms of hypothyroidism with thyroxine) in the medical literature. And they're all I've managed to find. Further examples would be most welcome.

The two studies are apparently contradictory, but there's no real contradiction, in fact the second supports the first.

The first:

Clinical Response to Thyroxine Sodium in Clinically Hypothyroid but Biochemically Euthyroid Patients
G. R. B. SKINNER MD DSc FRCPath FRCOG, D. HOLMES, A. AHMAD PhD, J. A. DAVIES BSc and J. BENITEZ MSc

was an open trial done in 2000, by Gordon Skinner in Birmingham.

Dr Skinner took 139 patients, all of whom had symptoms consistent with a clinical diagnosis of hypothyroidism.

Of these the majority had been diagnosed with CFS or ME or Post-Viral Fatigue Syndrome, but thirty had been diagnosed with Major Depression, which also has all the right symptoms.

Dr Skinner started off with small doses of thyroxine, and slowly increased the doses, to quite high levels, until the patients got better. He reported that they all got considerably better. In fact his results are phenomenally good.

He mentioned the possibility of placebo effect, and the necessity of ruling it by placebo-controlled blinded randomised trial in the paper, but thought it unlikely. Many of these patients had been seriously ill for many years, and had usually tried a lot of things already.

[ From the study ]  In the absence of a control group, a placebo effect cannot be excluded in this or any study. However, the average duration of illness was 7.5 years in patients who had usually undergone an alarming array of traditional and alternative medications without significant improvement as evidenced by their wish to seek further medical advice. Secondly, certain clinical features allowed objective assessment, namely change in appearance, hair or skin texture, reduction in size of tongue and thyroid gland and increase in pulse rate.

If these patients hadn't had a hormone resistance, he would have done them very serious harm! He kept increasing the dose until it worked, and the highest dose he used was 300mg of thyroxine. That's more than the amount you'd usually use to completely replace the output of a removed thyroid gland. Given that all these people had normal hormone levels to start with, if the patient was not resisting the hormone, this should have caused a range of extremely unpleasant symptoms, including death.

He mentions no adverse effects whatsoever.

Dr Skinner wrote to the British Medical Journal suggesting that thryoxine should be tried in cases where the clinical symptoms of hypothyroidism were present but the blood tests were normal.

This prompted a small trial:

Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial  

M Anne Pollock, Alison Sturrock, Karen Marshall, Kate M Davidson, Christopher J G Kelly, Alex D McMahon, E Hamish McLaren


This trial looks very well designed and established that:

(a) There was a huge placebo effect in the patients

(b) Thyroxine is very strongly disliked by the healthy controls (they could tell it from placebo and hated it)

(c) The patient group couldn't tell the difference between thyroxine and placebo (on average).

This result is very interesting of itself, and I make no criticism of the brave GPs who organised it in response to Skinner's letter, but unfortunately it has been taken as a refutation of Skinner's methods. Which it is not. In fact it supports him.

In fact there are two obvious relevant differences between what they did and what Skinner did:

(i) They used a fixed dose for everyone (100mg thyroxine / day) and made no attempt to tailor the dose to the patient.

I suspect that this would have made Skinner's treatment less effective, but it should still have worked.

(ii) They used very different criteria for selecting their patients.

Skinner had carefully done a 'clinical diagnosis' of hypothyroidism, using 16 symptoms, most of which were present in the majority of his patients.

The criteria for the formal trial were:

At least three of the following symptoms for six months: tiredness, lethargy, weight gain or inability to lose weight, intolerance to cold, hair loss, or dry skin or hair.

So a fat person with dry hair who didn't get enough sleep would have qualified as a patient.

This is utterly inadequate as a diagnosis of hypothyroidism! It is a famously difficult disease to diagnose!

Their patient group would have consisted mainly of people who didn't have the clinical symptoms of hypothyroidism. (EDIT: Obviously these people would have had symptoms of *something*, and thus probably been ill, but they are equally valid as symptoms of mild anaemia, or mild diabetes, which also seem to go undiagnosed a lot. The whole trick with hypothyroidism was to tell the difference between it and other similar diseases.)

If the type II version is rare or non-existent, then it would have included no real patients at all.

If the type II version is very common, then at least some of the patient group should have had the disease Skinner said he could cure.

What I think must have happened here is that the treatment produced great improvements in a few patients, and caused unpleasant symptoms in all the rest. This averaged out to 'can't tell the difference between placebo and treatment'. Remember that healthy people can!

I deduce that Skinner's treatment works pretty much as well as he thought it did, and that the disease he was curing is very common indeed.

Can anyone explain these two studies in any other way?




Conclusion

When combined with Sarah Myhill's paper showing that the principal cause of chronic fatigue is 'mitochondrial dysfunction', and that the action of the thyroid hormone is to stimulate the mitochondria, I think the case for a 'thyroid hormone resistance' disease manifesting as Chronic Fatigue Syndrome is unanswerable.

At the very least, this should be investigated.

I now believe my own argument, which until I saw Skinner's paper appeared even to me to be a wild idea made up from shreds of mathematical intuition and questionable evidence from biased sources. I think that Skinner's treatment is unlikely to be optimal, and research into what is actually going on needs to be done.

The problem, if it does exist, is likely to be extremely widespread, and explain far more than the mystery of Chronic Fatigue Syndrome and Fibromyalgia. I immediately claim Major Depressive Disorder and Irritable Bowel Syndrome as alternative labels for: 'type II hypothyroidism'. There is a large cluster of these diseases, all mysterious, all with very similar symptoms, known as the 'central sensitivity syndromes'.

And I should like to add that 'blood cholesterol' was once a test for hypothyroidism, so there are probably implications for heart disease as well. Anyone interested in the wider implications might want to take a look at Broda Barnes' work. I started off thinking he was a lunatic. I'm now fairly sure he must have been right all along.

I think it's now urgent to bring this to the attention of the medical profession and the sufferers' groups. Has anyone got any ideas how to do that?

 


 

Edit:

Two excellent arguments made on reddit's r/CFS group by EmergencyLies (I paraphrase/steelman him):

  • If there's a widespread hormone resistance version of hypothyroidism, where are the most severe cases?

(i) The mild version may be polymorphic, but the severe 'myxoedema' described in Victorian literature was the sort of thing that could be diagnosed on sight (or by hearing the voice) by anyone who'd seen a few severe cases.

(ii) One hears anecdotes of people who can tolerate insane levels of T3. If the hormone resistance can get that severe, why isn't the same problem killing people, or at least making them obviously hypothyroid?

I can't answer this one. Where are they? This is the best objection to this idea that I have seen in three months. Does anyone know of people with really obvious hypothyroidism and normal TSH values?

EDIT: Actually there are such people! They get diagnosed with 'central hypothyroidism', which is thought to be very rare.  John Lowe thought that about 1/4 of fibromyalgia cases were undiagnosed 'primary hypothyroidism', 1/2 were 'central hypothyroidism', and 1/4 were the 'hormone resistance version'. He thought that the hormone resistance version was very rare and genetic. I think it's more likely acquired in some way. Or it's possible that 'mild central hypothyroidism' is much more common than generally believed. It makes sense that the mild version should be more common than the severe version. It would be very difficult to tell the difference between 'central hypothyroidism' and 'acquired hormone resistance hypothyroidism'.


and:

  • CFS should look like hypothyroidism, but doesn't

(i) Skinner and Pollock together strongly suggest that there's a widespread form of hypothyroidism, undetected by usual blood tests, but treatable with thyroxine

(ii) Anyone with hypothyroidism but normal blood tests is going to get diagnosed with something like CFS/FMS/IBS/MDD etc...

(iii) Some of those people are going to end up diagnosed with CFS. Probably lots, if it's widespread.

(iv) Hypothyroidism causes lowered heart rate

(v) But CFS patients have raised heart rates, (on average?).

Those five things together look like a proof of contradiction, so one of them must be wrong.

 

I think it's (iv). Billewicz's clinical hypothyroidism test doesn't think heart rate has diagnostic value. Thus there were both low and high heart rates in hypothyroidism. I suspect that there's a low basal heart rate because of low metabolism, but that it goes high and stays high after even mild exercise because of the need to clear fatigue poison. Also, of course, hypothyroidism weakens the heart like any other muscle, so heart rate would actually need to be higher to pump the same amount of blood.

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Anyone who's been following this idea as it metastasised might be happy to know that I'm now a retired amateur endocrinologist. This is as good an argument as I'm ever going to make, and it should be turned over to adults now. Thank you all for your helpful comments and suggestions. Everyone's been wonderful.

Eric Drexler pointed out to me the other day that there probably is a path to superintelligent help without bringing on the apocalypse, so maybe we can get to paradise after all. His argument is very good. That looks like it might be more interesting than endocrinology, which seems to be more of a social problem than anything I can help with.

1Gram_Stone5yOut of curiosity, does he mean uploading researchers?
3johnlawrenceaspden5yNo, he's got some cool arguments why we can make superintelligent tools without making fully general intelligences. My preliminary feeling is that he's right. I need to think about it though, and so do we all! Screw Fibromyalgia. I'm recovered (for now). I have lots of practice not caring about things that affect hundreds of millions, and this just goes in the 'the world is mad, everyone is wrong' bin. But seriously, I am never trusting anything medical again. Whether I'm right or wrong, what a bunch of incompetents. I wonder what it is they think they're for?
3Gram_Stone5yIf there's any way that I can read more about this, I'd be extremely interested.
2johnlawrenceaspden5yGram, he's at FHI in Oxford these days, they have a technical report (FHI TR 2015-3) by him. That's public, and I've got his permission to spread it, but I can't find a link. There's no way I can see to attach a pdf here, but if you give me your e-mail address I'm happy to send you a copy. He also gave a talk at CSER in Cambridge which went into lots more detail, but not written up yet. The tech report looks really important on its own though.

I think it's now urgent to bring this to the attention of the medical profession and the sufferers' groups. Has anyone got any ideas how to do that?

At least posting this stuff here is a start, and thank you for doing this. I do not have this problem myself, but I saw the pattern often enough in others that I have independently (of any medical knowledge or opinions of other people) developed this reaction:

someone has chronically low energy / mood -> check if they have obvious problems with diet/sleep/exercise -> if not, suspect thyroid-related dere... (read more)

4johnlawrenceaspden5ySquirrel, it's bloody dangerous. I'm arguing that it should be investigated, not that everyone who feels tired should start glugging hormones. But it's not unfounded. I've found loads of anecdotal and circumstantial evidence, and very little against (hot daytime fibro-turks is the most surprising thing, and the alternative people seem to think there's often also adrenal issues, but usually secondary). And now two studies from the 'proper' literature. And I'm fairly sure that endocrinology has never bothered its pretty little head about type II versions, or the accuracy of its wretched TSH test, despite the example of diabetes staring it in the face. I'm as sure as I can be without formal trial (so maybe about 25% confident?). But I'm now certain that the lack of investigation and of formal trials is inexcusable negligence. J' totally accuse.
4FriendlyBuffalo5yThe TSH test is actually very accurate. Third generation TSH assays are able to detect 0.02 mIU/L or less. The problem is the way TSH testing levels are used without regard for the actual thyroid hormone levels. The relationship between TSH, T4, and T3 is much more complicated than it seems. A good explanation of the latest research into it is here: https://www.researchgate.net/publication/263321383 [https://www.researchgate.net/publication/263321383]. The title of the paper is "Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment."
2johnlawrenceaspden5yHi FriendlyBuffalo, welcome to Less Wrong! I've got no problem with the TSH test as a test for TSH. It's really good for that, and I seriously admire its cleverness and accuracy. In fact it probably is a good test for primary gland failure. I can't see how the gland itself could go seriously wrong without driving TSH into the stratosphere. What I hate is the idea that TSH normal <=> 'Thyroid Symptoms, improve when treated with thyroid hormones'. I think there are other dysfunctions going on. The very idea of assessing the state of a system that complicated by measuring one variable (or even three) is ridiculous. I'm pretty much 'clear clinical picture => therapeutic trial, and sod the blood tests' at the moment, as I think Gordon Skinner was. Of course the problem with that is you end up endorsing leeches and aromatherapy that way. I do have a lot of sympathy for basal metabolic rate, and for waking temperature as a proxy for that. I think we both agree that some CFS/FMS is just thyroid dysfunction, and will improve with various combinations of thyroid hormones. The only remaining question for me now is 'Is all of CFS/FMS thyroid related, or just a significant portion of it'? Lowe reckoned that it was 1/4 primary that had been missed, 1/2 central that there's no test for, and 1/4 the mysterious resistance that he had to overwhelm with high doses of TSH. I see no reason currently to doubt his word, and I'm pretty sure that his work has saved my life (I wouldn't have put up with CFS for much longer. It was awful, and there's no way I'd have found out it was thyroid without Lowe.) So I want to dig into his ideas until I can convince myself that they're either true or false. If they're false that's really strange. There are now two different diseases, which came into being in the 1970s, which look exactly the same as hypothyroidism, only one of them is, and one of them isn't. I have real trouble with that on Occam's razor grounds. And that's assuming FMS/CF
3SquirrelInHell5yYes. And I'm not planning to, you know, convince anyone to do this; however I myself would have liked to know that this is a possibility, if I had this condition. What to do about this is a different matter entirely. I guess you can't easily obtain the relevant medications without consulting a doctor in any case.
1Hafornin5yI agree. We should not spread this to potential patients. I think we should first talk about it with medical professions people, in order to raise consciousness of this hypothesis.
2johnlawrenceaspden5yI've been trying to 'go through channels' for about three months now. I've sent crank emails to every correspondence address on every endocrinology paper I've read that's expressed the slightest sympathy with the 'the patients might be right, you know' position, and they don't reply. I know a fair number of scientists and some doctors and medical students, and some of them think this is worth a look, and some of them know eminent medical researchers. There's just a wall of silence. I can't explain it. I know some of the medical researchers have read 'A medical mystery', and one prominent endocrinologist is reported to have said 'The narrative is broadly correct, but he seems obsessed with the sensitivity of the TSH test. I don't think that's the problem'. I can't even work out what that means. And I've promised (my word is good, and known to be good by my friends) that if there are already people taking this seriously and they just don't want to panic people, or if there are public safety concerns that I don't know about then I'll shut the fuck up. And in fact I'm keeping most of the scary conclusions to myself anyway. But the friends of friends won't meet me, or even reply to e-mails. I think it's generally agreed that a coffee with me is not an unbearable experience, and I can change my mind about major things in five minutes flat. I really wonder what the hell is going on. If this turns out to be true, the first person to publish proof is going to get most of the credit for it. You'd think they'd be avid to talk. There is one doctor who seems to have observed everything I've predicted in his clinical practice, and who still doesn't take the underlying idea seriously. I just don't get it. And another who says 'these concerns have been around for a long time, but if you ask endocrinologists for help they just say "The blood tests are normal, therefore it's not an endocrinological problem"', and obviously thinks that they're useless, but who won't even listen
4Lumifer5yWhat would "taking a look" entail? Taking it seriously means a large study which means applying for grants, going through ethics boards, devoting a lot of time and energy to it, etc. That's a rather big project and, presumably, serious people would require good reasons to commit to such a project. Other than a full-blown study, what else? Can doctors just try to give things like dessicated thyroid to their patients? Well, it's been done and the results, which you are well aware of, are inconclusive. Besides, I don't think the NHS would look kindly on such "experiments" which I'm pretty sure go outside of the accepted guidelines. Basically I think there is a large barrier to entry and no one is motivated enough to bring a wrecking ball.
2johnlawrenceaspden5yWell, talking about it, admitting doubt, those sorts of things would be a start. Before this became something routinely done on the NHS, it would need cast-iron proof sufficient to convince NICE, and I approve of that wholeheartedly. But there are a lot of smaller steps between 'suspicion' and 'certainty'. They used to hand it out routinely, back in the days when hypothyroidism was diagnosed by symptoms (up to ~1965), and everyone thought it was as good as medicine got. There seems to have been huge pressure to stop doing that, including striking people off, and I wonder what evidence was used to support those processes. If there is any, that's what I'm looking for. Now, I think you might be in serious trouble for not following the guidelines. The guidelines for CFS say: 'don't use thyroxine'. But they don't give a reason or a reference. It's mad. In America, apparently, doctors are much freer to try things, and some of them do, in full knowledge that endocrinologists disapprove, and it works. But actually, desiccated thyroid is also available as a 'food supplement', and you don't need a prescription for it in England or America, so chiropractors and osteopaths and homeopaths and naturopaths and mad people on the internet and the like are free to tell people to take it. And they do. And then they write books about it. Just Google! Actually, I'm not well aware of that. I really haven't found anyone saying 'We tried this on people with hypothyroid symptoms, and it just made them hyperthyroid, as you'd expect." Everyone who's tried it seems to think it works a treat. I'd love to see counter-evidence if you can find any. The worst anyone has to say is: "It works most of the time, but often we find that there's something adrenal going on as well, and in those people we have to fix both". The question answered inconclusively was "If we hand this out to fat, tired people with dry skin, does it work?". And the answer to that is: "On average they can't tell the diff
2FriendlyBuffalo5yThe main reason why desiccated pig thyroid (DPT) has been disliked by the medical community is complicated. It starts with one complaint that is true - there were large variability issues in DPT products even as late as the 1970s. When levothyroxine came onto the scene it promised three things: consistency, uniformity, and safety. No longer would patients have to deal with potentially dangerous levels of T3 in treating hypothyroidism. No longer would individuals become hyperthyroid due to supraphysiologic amounts of T3 from DPT. That it continued to have its own consistency, uniformity, and reliability issues didn't really bother many doctors. It finally managed to live up to its promise when the FDA put its foot down in the late '00s and mandated much tighter controls. But during that time, DPT also got its act together, and has much tighter manufacturing standards. The stability and uniformity is much better than it had been before.
2Lumifer5yI'm confused. Aren't these clinical symptoms of hypothyroidism? Besides, "works / doesn't work" seems like a too crude approach. There is a large middle zone of "works for some people some of the time" and there you have roll up your sleeves and get into the messy details which might still not give you enough information to be able to predict for which people at which time your treatment will work (or not). The "theoretically correct" approach would be, I think, to do a deep dive into biochemistry and figure out all the links in the mechanism connecting the T levels in the blood with the activity of the mitochondria. Once you do that, figuring out which link is broken in a particular patient subset shouldn't be too hard. But the initial research, mapping out the chain of effects, looks daunting.
0johnlawrenceaspden5yAh. They are clinical symptoms of hypothyroidism. But they are also symptoms of all sorts of other things. In fact they are symptoms that occur in people who have nothing wrong with them at all. To diagnose it by clinical symptoms you have to be much more careful than that! See e.g. Billewicz paper. More specific symptoms were apparently things like ankle tendon reflex, and cholesterol levels, but you need to be really careful. The disease was known as 'the great imitator'. It's easy to confuse with other things, and diagnosing it was really difficult and a job for trained professionals. I got the impression that if they had strong suspicions, they'd just try thyroid hormones and see if they worked.
0johnlawrenceaspden5yOh, I'd like to say that none of that makes hypothyroidism the sole cause of CFS. There appears to be raised heart rate in CFS, which seems strange if it's primarily a thyroid underregulation problem. But 'diagnose hypothyroidism by symptoms, ignore TSH, treat with any sodding thyroid hormone you like', seems to be straightforwardly the right thing to do, and uncontroversial amongst people who've tried it. All the debate is about what the best combination of T4/T3 is. But they all agree that they all work fairly well. And at least some 'hypothyroid symptoms, normal TSH' people are going to end up diagnosed CFS, FMS, IBS, MDD, etc, etc, etc....

Wim Hof demostrates that humans are able to regulate their body temperature when they train to do so. If hypothyroidism is basically about a downregulated metabolism, what happens if the techniques of Wim Hof are used?

0johnlawrenceaspden5yChrist knows! Sounds pretty fascinating though. Have they measured his various hormone levels while he is doing this?
1ChristianKl5yHe did make experiments that he can control his cytokine levels. I also taught that feed to other people.
0[anonymous]5ySounds cool. Can you keep yourself in a high fever? Used to be a cure for syphilis, apparently, and maybe leprosy? Would be nice to be able to do it without having to deliberately give yourself malaria!

You wouldn't need to invoke the idea of 'hormone resistance' because TSH and T4 tests normally used to diagnose hypothyroidism don't measure the active hormone - T3. T4 is just a prohormone with very little direct activity on metabolic rate.

In primates, metabolism is regulated primarily in the liver by T4->T3 conversion, so if this is inhibited for any reason it will suppress metabolism without showing up on those tests. Low calorie intake, and poor nutrition are known to cause this (e.g. Euthyroid sick syndrome). In cases of poor liver conversion, supp... (read more)

3FriendlyBuffalo5yThe reason why Barnes' paper showing that desiccated thyroid lowering cholesterol levels and seeming to prevent cardiovascular disease isn't cited is because he was basically making his patients hyperthyroid. Lower cholesterol levels occur in hyperthyroidism. There is a doctor I know of in California who gives his patients supra-physiological levels of T3 hormone (cytomel) to increase their metabolism, to help them lose weight, and to lower their cholesterol levels. It basically suppresses the thyroid's own production of hormone. In the short term, it works. It's brilliant. But it's crazy. We have no idea what the long-term consequences are. And since I'm pretty sure he's not running a study on it, we won't.
2CasioTheSane5yWhy is this a reason not to reject it? He is essentially arguing that the major cause of cardiovascular disease is population-wide high rates of hypothyroidism. It would be a circular argument to dismiss that because his treatment leads to a greater than average metabolic rate. One would also need evidence of a disadvantage that outweighs the advantages. His patients seemed to be doing well, or at least he doesn't report them exhibiting any classic signs of hyperthyroidism. He was primarily adjusting dose based on body temperature to the upper end of the normal non-hyperthyroid range. I have seen studies on thyroid supplementation as a weight loss strategy, and it causes loss of lean tissue (muscle, etc.) more than fat.
1johnlawrenceaspden5yHi, there can be all sorts of things going wrong! Mysterious resistances, gland failures, conversion disorders, broken pituitary, broken hypothalamus, faulty deiodinase enzymes, etc. All potentially inherited or acquired. We really do seem to have no idea how this complicated system works or what it's all for, or what can cause it to go wrong. But I would have thought that if there was widespread 'central hypothyroidism', someone would have twigged by now, since that form does show up if you do a full panel of hormone tests. Or I would have thought that when I wrote this. By now I am in such despair about the pitiful state of medical research that I wouldn't be surprised if they'd never thought to look, so maybe it is all just perfectly obvious from blood tests and the fools have ignored it. And the question of 'what is the optimal treatment' is bound to be tricky. I'm just trying to demonstrate that the problems exist and are widespread and thus worth looking at! Although Skinner certainly thought 'clinical hypothyroidism' could usually be fixed by bunging enough T4 at the problem. He does mention in his book that he sometimes used T3 or NDT, but he doesn't go into details. Various other people say 'mostly T4 with a bit of extra T3', but no-one has particularly clear ideas on what works and what doesn't or why. Thanks for the reference to Ray Peat, I hadn't heard of him before. Can you link to the best expression of his thoughts?
0CasioTheSane5yWhich tests? I am not aware of any simple blood test that measures the endpoint of thyroid activity on metabolic rate (except, arguably, cholesterol levels), rather than just the state of the T4->TRH->TSH->T4 feedback loop. The challenge with T3 is it has a very short half-life, one would need to take very small doses impracticably often to achieve stable levels. Taking mostly T4 with a bit of T3 helps compensate for the reduction in T3 production due to feedback without the problems caused by trying to obtain nearly all T3 directly from a supplement. His own essays at raypeat.com are the only accurate source, but can be challenging to read. Most of the summaries you will find online don't do him justice.

http://www.ncbi.nlm.nih.gov/pubmed/9513740

What do you make of this? I'll note that it's a very small sample size, and I don't think it says whether those particular CFS patients report feeling chilled all the time. It also wouldn't surprise the hell out of me if there's some way a body can go wrong so that a person has a normal core temperature (what about the periphery?), but feels chilled anyway.

Also, in regards to being stupid-- I know some people with CFS who seem pretty smart, but who complain of brainfog. Perhaps they do most or all of their posting when the brainfog lifts.

0johnlawrenceaspden5yHi Nancy, thanks! I've already seen that, it's in the evidence section of: http://lesswrong.com/r/discussion/lw/nef/the_thyroid_madness_core_argument_evidence/ [http://lesswrong.com/r/discussion/lw/nef/the_thyroid_madness_core_argument_evidence/] Even more disconfirmy is: http://www.sciencedirect.com/science/article/pii/S0024320515301223 [http://www.sciencedirect.com/science/article/pii/S0024320515301223] Where some Turkish fibromyalgia patients are actually hotter than they should be, to the point where the authors suggest it as a diagnostic criterion! There's no doubt they're evidence against. I would have predicted the opposite. When I first saw these two papers (within half an hour) I gave up on the idea. I even told my GP I'd managed to refute it. But after a couple of days of not believing it, I was just terribly confused, and I realised that they leave me wiggle room. Basal metabolic rate has to be strongly related to surface temperature (all other things being constant), but there's no reason it should be related to core temperature. And the thyroid hormones control the basal (i.e. sleeping) metabolic rate, not the active (field) rate. So I can ignore the Turks (hot during the day), and the main thrust of the Hamilos paper, even though I feel really weaselly doing it. But, the Hamilos group explicitly considered surface temperature, and they say that they measured basal metabolic rate and it was normal, but they don't give any details, and I can't figure out what they did with either. If they were careless with the metabolic rate (say, measured it after a rest during the day), it's meaningless as a hypothyroid test. In fact during the day the metabolic rate might actually be higher, if metabolism in hypothyroidism is inefficient because the mitochondria aren't working properly. And their core graphs do look a bit funny for CFS (but not for depression, which looks normal, sigh..) On the other hand, Lowe checked for basal metabolic rate and tem
0lorrainecleaver4yHi John, I came across this old discussion whilst researching prior to a meeting with NICE next week, they're scoping for Thyroid disease guidelines finally. I echo your frustration and sense that something is going on. I petitioned the Scottish Parliament five years ago on this matter, it's still live. http://www.parliament.scot/GettingInvolved/Petitions/PE01463 [http://www.parliament.scot/GettingInvolved/Petitions/PE01463] Dr Skinner, who saved my thyroidless life, wrote to support me but for some very bizarre reason, his evidence was not published. Too controversial no doubt. He correctly asserted that there is absolutely no scientific basis for thyroid function tests as they are applied. These tests do not show cellular thyroid activity. TSH can be as exquisitely sensitive till the cows come home, it still cannot show if a person is cellularly lacking in thyroid hormone. The fact that the guidelines for the use of Thyroid Function Tests are based on poor quality evidence and out of date speaks volumes. I have little faith NICE will research ALL the relevant evidence and fear CFS/Fibro/Thyroid patients will be further boxed into a dreadful 'computer says no' mode of diagnosis. But I am cynical after five years of fighting and ten years with no thyroid.

I think it's important to have a more global vision of the problem. Knowing what the situation is in different countries could be a start. Post it as replies to this comment, with the country you live in, and the situation there (the best would be to ask one or more doctors about it, in order to be sure we can trust it). Personally, I live in France. Here, desiccated thyroid isn't sold anymore to everybody. According to two doctors I know, it's because bad things used to happen back in the days where it was completely accessible (in the 60' I believe). I am still researching informations about the hypothesis itself in my country, I'll post it if I learn anything. Thank you for your replies by advance!

0johnlawrenceaspden5yThat's interesting. In England and America I think that it would be illegal to sell desiccated thyroid as a prescription drug without a prescription. But it's perfectly legal to sell it as a food supplement. It's just dried bacon, after all. It's quite difficult to find (people with TSH-detectable hypothyroidism get treated by their doctors with thyroxine, and for most people (~90%??) that seems to work perfectly), but it can be found. I expect some fascist bastards will get round to outlawing that sooner or later. Before they do, we ought to find out whether it will cure CFS etc. After all, once it's illegal people will have to buy it from criminals, and I don't trust their quality control. Also it might put the price up slightly. I'm interested in what the bad things that happened in France were. Obviously this is quite a potent drug, and so if it's for sale to the general public it is certain to cause harm from people taking far too much and overdosing. But at the moment I think it's fairly safe in small doses for trial periods. And I'd very much like to know if that's not true.
2Lumifer5yJust buy a whole pig and eat it snout to tail :-)
0johnlawrenceaspden5yWell quite. In America I think there have been episodes of 'hamburger thyrotoxicosis', so putting thyroids in food is now illegal, which is good. I'm not sure what the European situation is.
-2Lumifer5yWhat, you doubt Brussels which already saved the Europeans from the horrors of mis-curved bananas? X-0
0johnlawrenceaspden5yTsk, summoning the mind-killer in broad daylight. This is supposed to be a family-friendly discussion of taking mad drugs off of the internet for made-up diseases in futile defiance of medical advice. Let us not side-track onto the emotive issue of banana curvature, which is very difficult and sensitive for the English people (sniff). Downvote me back, will you? Tit-for-tat is the whole of the law.

Why is the Pollock trial evidence supporting your hypothesis? What outcome from the trial would you have considered to be evidence against it?

Also, what part suggests that the healthy controls could distinguish the treatment from placebo? From Table 4, it seems that the reverse is true.

At first glance, the results from that study look like straightforward evidence that this treatment is actively harmful. I’d also point out that RCTs need to be standardized across patients. I can’t say whether the inclusion criteria should have been different, but choosin... (read more)

0johnlawrenceaspden5yThank you so much, intelligent and careful criticism like this is exactly what I started posting on Less Wrong for! Well, it's only fairly weak evidence, but it does seem that the healthy controls reacted differently to the patient group. What it really proves is that thyroxine isn't just a nice recreational drug that everyone likes. Healthy people dislike it. But it seems to have been less bad for the patients on average. So I imagine there were some people in the patient group who reacted well. What I'm saying is that Skinner got strong evidence for the idea, and wanted it confirmed by PCRT (and I agree, that's necessary). So they did a PCRT, but not very well because they didn't find patients carefully. And yet they seem to have supported him anyway, but everyone thinks that they refuted him, because they didn't quite understand what he was saying. If none of the patients had had any sort of thyroid problem, I'd have expected it to be equally bad for everyone. If that had been the result, then I'd have had to think that 'type 2 hypothyroidism' is rare, or that 'fixed doses of thyroxine don't fix it'. For a long time that's exactly what I did think! I was assuming you might need T3 as well and you might need to adust the ratio carefully. Skinner and Pollock together make me think that it might be fairly common, and mostly fixable with T4 alone. That shows that when they were asked which was the active preparation, they couldn't tell. They appear to have had a 'nocebo' effect, where they interpreted everything they felt as an effect of the drug. That's as expected. What makes me think that they felt bad on thyroxine is table 2, where all the 'self-reported' psychological scores have got worse from thyroxine. In particular p=0.007 for the decline in Vitality. Since, as you point out, they really didn't know which was which, it's hard to see how they could have faked that. Absolutely this treatment is harmful to healthy people. It should cause 'hypermetabolis
4AstraSequi5yI’m talking about conservation of expected evidence [https://wiki.lesswrong.com/wiki/Conservation_of_expected_evidence]. If X is positive evidence, then ~X is negative evidence. An experiment only supports a hypothesis if it was possible for it to come out another way that refutes it. And if an experiment that could have supported the hypothesis actually didn’t, then it’s evidence against. Terminology then. When you said “Thyroxine is very strongly disliked by the healthy controls (they could tell it from placebo and hated it),” it suggests they could identify the active treatment. The people in the study had symptoms. Even if you think their symptoms were mild or unrepresentative, you shouldn’t call them healthy. It’s fair to extend the conclusion to cover people without those symptoms, but I think that’s an important difference. It’s more that you need an easily followed protocol. Anything else, especially anything subjective, is unlikely to be practically feasible, and will probably not be reproducible. This is normal. Clinical presentations often have many causes, which makes it almost impossible to progress. Eventually we break them down based on their causal mechanisms so we can treat them individually. Each time we find a new cause, some of the cases will be left unexplained. There are a lot of interesting hypotheses competing for resources, and we have to decide which ones are worth considering. I can’t say what the reason might be here, but there are a lot of possibilities. For example, it might not be possible to design a study like the one you want that could effectively answer the question. Yes. Expert opinion (i.e., the opinion of individual experts, not expert consensus) is the lowest level because you can find an expert to support pretty much any proposition that isn’t obviously ridiculous, and sometimes even if it is. In fact, this is true higher in the hierarchy as well, which is why we use syntheses of evidence so much. I can’t stress t
2Lumifer5yEt tu, Brut? That is obviously true for humanities and for things like observational studies of nutrition, but do you think it extends to most / all of biology? "For any hypothesis there is a mouse strain which proves it true"? :-/
3Lumifer5yHmmm [http://www.slate.com/articles/health_and_science/future_tense/2016/04/biomedicine_facing_a_worse_replication_crisis_than_the_one_plaguing_psychology.html] This piece claims that
2AstraSequi5yThis open-access article [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270077/] discusses some of the issues in cancer research. In most ways biology is intermediate between the hard and soft sciences, with all that implies. It’s usually impossible to identify all the confounders, most biologists are not trained in statistics, experiments are complex and you can get different results from slight variations in protocol, we're trying to generalize from imperfect models, many high-profile results don’t get tested by other labs, ... all these factors come together and we get something that people call a “replication crisis.”
1Lumifer5ytl;dr It's complicated. Yes, I know. But it would be nice if people recognized that it is complicated and not pretend that we know more than we actually do.
1johnlawrenceaspden5yOh God, where will this end? Is it really only physics and chemistry that aren't sloppy cargo-cults, or are they broken too? A lot of this, I think is to do with taking tenure away from young academics. Once upon a time once you'd proved basic competence and cleverness, you could spend your whole career being careful about stuff. These days you've just got to turn out crap as fast as possible. And you spend most of your time applying for grants.
0[anonymous]5yVocative!
0johnlawrenceaspden5ySure, this experiment is evidence against 'all fat, tired people with dry hair get better with thryoxine'. No problem there. Yes, it is kind of odd isn't it? One of the pills apparently made them a bit unwell, and yet they couldn't tell which one. I notice that I am confused. You're right. I think I should have said "This treatment is harmful to most people". But that's awful! Once, there was a diagnostic method, and a treatment that worked fine, that everyone thought was brilliant. Then they invented a test, which is very clever, and a good test for what it tests, and the result of that is that lots of people are ill and don't get the treatment any more and have to suffer horribly and die early. If that's normal then there's something badly wrong with normal. A new way of measuring things should help! Sure, I'm trying to make a case that this one is worth considering. I think the Scottish study with stricter entry criteria for the patient group would do. If that failed, I would be quite surprised. If someone did the same thing with stricter entry criteria and used desiccated thyroid and titrated doses and it failed I would be so surprised that I would give up. Seriously, if 'start off with low doses and keep raising the dose until you get a response' is inaccessible to testing, then something is broken. But in fact, just 'low basal metabolic rate in CFS' would be good evidence in favour, I think. We can work out optimal treatments later. And if it turned out that there wasn't a subset of CFS patients with high Billewicz scores and low basal metabolic rates, I'd give up. No study needed. At that point, we're all post-modernists aren't we? The truth is socially determined. Science is not unreliable. If I can surprise a physicist or a chemist about something he is sure of, he will be very very interested, and science will quickly rearrange itself around the new fact. It took about five years to completely overturn classical physics and replace it with so
2AstraSequi5yOkay, but you said it was evidence in favor of your own hypothesis. That’s what my question was about. Suppose they’re measuring on a 10-point scale, and we get ordered pairs of scores for time A and time B. One person might have 7 and 6, another has (4,3), another has (5,6), then (9,7), (7,7), (4,5), (3,2)...Even if they’re aware of their measurements (which they might not be), all sorts of things affect their scores and it’s unlikely that any one person would be able to make a conclusion. You’re basically asking an untrained patient to draw a conclusion from an n of 1. There are several assumptions here that I think are probably incorrect, the biggest being the causal link between introducing the test and people suffering. But what I described before is just the application of reductionism to better distinguish between disease states based on their causal mechanism. Sometimes, but replacing an objective measurement with a subjective one isn’t usually a step forward. Problems with this include: you can’t justify the parameters of the dose increase, you still have to agree on how to measure the response, and you also have a multiple testing issue. It isn’t inaccessible, but it’s a complication (potentially a major one), and that’s just in the abstract. Practically, in any one situation there might be another half dozen issues that wouldn’t be apparent to anyone who isn’t an expert. Not knowing anything about the subject, I would expect to observe a low basal metabolic rate in CFS regardless of its ultimate cause or causes. No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses. You’re talking about the overall process and how science moves in the direction of truth, which I agree with. I’m talking on the level of individual papers and how our current best knowledge may still be overturned in the future. But you ca
0johnlawrenceaspden5ySo, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p. Is the only way we learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence? And nothing done outside the system is worth anything at all? And the opinions of patients and doctors are 'placebo effect?'. And the patients' obvious symptoms are 'psychosomatic/somatoform/hypochondriac/malingering'? All the same bloody word, changed every decade or so when people realise what they mean. And someone invents a wonderful new measurement technique that bears on a hard problem, and it's used to make things worse?
0johnlawrenceaspden5ySo, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p. Is the only way you learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?
0johnlawrenceaspden5yOoh, why? I thought that was thyroid and starvation? I mean, low once you adjust for all the known predictive factors, e.g. age, sex, height, weight and exercise. Obviously people who have trouble standing up are going to show low BMR in absolute terms. But I mean 'even after adjusting for sedentary lifestyle'. Surely the 'stress' theory predicts high BMR?
0johnlawrenceaspden5yOK, but none of that funding is going in favour of the likes of John Lowe or Gordon Skinner or Barry Durrant-Peatfield or Sarah Myhill, in fact those people are losing/risking their licences and livelihoods in order to try to help people. They may or may not be right about their methods, but they're not doing it for the money! Ken Blanchard appears to have built an endocrinology practice out of treating hypothyroidism 'functionally', but I'm sure he could have done just as well doing it 'conventionally', and been risking far less legal trouble.
0johnlawrenceaspden5yI must be confused here. Sorry, I'm not deliberately evading your (good!) question. If none of the patients had had any sort of thyroid problem, I'd have expected it to be equally bad for everyone. That would be strong evidence against 'it's widespread and treatable with thyroxine', and very weak evidence against 'CFS is thyroidy'. A test is allowed to produce weak evidence one way and strong evidence the other. Imagine rolling a dice. If it comes out 5, you've not learned much. If it comes out 7, that's a big surprise, and enough to smash the 'six-sided' theory into the very long grass. If a fair number of the normal-TSH patient group had nevertheless had a thyroid problem amenable to thyroxine 100mg/day, then I'd have expected that to make a difference between healthy controls and patients. Which appears to be what happened. I think that's actually fairly strong evidence in favour of 'common and treatable with thyroxine'. Nowhere near proof, but it strengthens Skinner's paper, which is already strong evidence, rather than weakening it. I'm actually really surprised by that. That thyroxine made any difference at all. I believed it was thyroidy just on the argument in 'A medical mystery'. (Looks like hypothyroidism, existed in Victorian times, didn't exist 1900-1970 when hypothyroidism was diagnosed by symptoms and treated with desiccated thyroid, which has too much T3 in it, validity of TSH test never checked) I've been saying for a while that it must be to do with T4/T3 balance, because I couldn''t believe that if it was amenable to thyroxine that wouldn't already be known. Because I literally couldn't believe that medical science could have been that careless and stupid. But now I'm looking at the only two papers I've ever been able to find on the subject, and thinking, 'they both imply that thyroxine works'. It might not be optimal, but it seems to do something! And sure, it's nowhere near proof, and I wouldn't want public health policy changed on this
2Lumifer5yBy the way, what's you definition of hypothyroidism? Since you are doubtful of the TSH test and point out that diagnosis by clinical symptoms is very hard (with the relevant implication that there will be a lot of mistakes), which exactly condition of the human body do you call hypothyroidism? It's not "that which is made better by consuming dessicated thyroid", is it?
0johnlawrenceaspden5yActually I think it was only 'very hard' for GPs. It seems that most endocrinologists back in the day just ruled in or ruled out the obvious cases, and experimented with small amounts of thyroid on the rest. That doesn't look like a bad approach to me. Small amounts of thyroid with someone competent watching you won't hurt you.
2Lumifer5yI don't know about that. Let's try s/thyroid/bloodletting. Why, that looks just like what the doctors used to do a few centuries ago. I don't think this was a resounding success.
0johnlawrenceaspden5yWell sure, and as an advocate of 'Traditional Western Medicine', I suppose I should be equally hurt by the disappearance of that once beloved (by doctor and patient alike!) treatment, so well supported by the humorous theories of Aristotle and Galen. So I suggest that we appeal to Almighty God to show to us His Wille, by using the ritual of randomised controlled augury, as our fathers have shown us. We should carefully select our patients using the strategems of Billewicz, and we should have three treatment arms, one with desiccated thyroid, one with leechwork and lancettry, and one with that flower of the modern schoole, graded exercise therapy. I have a feeling that thryoid will come out well in the comparison. I am somewhat unclear as to GET vs leeches. Let the best quackery win!
0johnlawrenceaspden5ySomething like 'inadequate thyroid-hormone-mediated regulation of metabolism'. Certainly that would include primary, secondary, and tertiary hypothyroidism, as well as the various forms of 'peripheral resistance', and the conversion disorders. (TSH probably detects the primary form. The question is 'how widespread are the other things.') A good clinical correlate for all of those would probably be the Billewicz score from '68. Which he pretty much did work out by 'that which is made better by consuming desiccated thyroid'. We might want to call all that 'easily-treatable clinical hypothyroidism', or 'twimbbcdt'. Congratulations, trope-namer! But actually there are consistent reports of people with all the usual symptoms who don't respond to the sane use of T4/T3 or NDT, but who do improve on insanely high levels of T3. So I'd actually want to draw 'hypothyroidism' a bit wider than "that which is made better by consuming desiccated thyroid". And I bet you can get all sorts of 'dysthyroidism' too, where there are some resistant tissues but some are fine, and you or your system raises levels of this or that to compensate, and makes some bits of you hyper and some bits hypo at the same time. If there's that, we might actually need to understand how it works to treat it. Imagine... And then, I bet if there are two acquired hormone resistances then there are others, and I bet they're all horribly intertwined, and lots of nasty pathogens either taking advantage of or causing them, so there's probably a whole swamp of horrors that get a bit better with thyroid but that no-one would call 'hypothyroidism'. We'd probably need to call those 'acquired generalised hormone resistance disorders', which gives the pleasantly onomatopoeic "aghrd". And we're not going to nail those without actually rolling up our sleeves and playing around. At the current rate of progress it should all be sorted out well after we've destroyed the universe by careless use of computers. Unless
2Lumifer5yThat's wonderfully vague. I bet I can diagnose half the population with having "inadequate" regulation. A definition should allow easy classification of observed phenomena into two classes: "fits the definition" and "doesn't fit the definition". This one... struggles. Yes, I have such a suspicion, too. And this I can probably diagnose 90% of the population with? See above. The meta issue is whether you want to medicalise deviations from the theoretical optimum. On the one hand, sure, it's nice to move closer to the optimum, on the other hand this means that no one is "healthy", everyone is "sick" and under care of doctors.
0johnlawrenceaspden5yWell, 'hypothyroidism' was a very difficult and polymorphic badger in its day. But a thing that is difficult to detect can still be a thing. Consider neutrinos and gravity waves and unicornes, which no man nowadays doubts of. And as for 'medicalise deviations from the theoretical optimum', most chronic fatigue people are already bothering their poor doctors incessantly, and being given (with the best will in the world) a selection of nasty things that mildly alleviate some of their symptoms. CFS is a horrible thing. As Hitler says in the film Downfall: "'Chronic Fatigue Syndrome' ? they might as well call Leprosy : 'Chronic Dandruff Syndrome'".
2Lumifer5yIsn't it still "its day"? Think of it this way. There is a set of people with some clinical symptoms which look maybe-possibly like hypothyroidism. There is a another set of people with abnormal TSH. These sets partially intersect and form three subsets. Subset one is the intersection: people with both clinical symptoms and abnormal TSH. They are a clear case and there are no problems here. Subset two is abnormal TSH and absence of clinical symptoms. We interpret that as thyroid gland falling apart and expect clinical symptoms to appear in the near future. We are not concerned with people either. Subset three is the one you are interested in: people with normal TSH and clinical symptoms. What about them? Well, as you mention diagnosing hypothyroidism solely on the basis of clinical symptoms is difficult. So in this subset some but not all people will have a thyroid malfunction, and some will have other problems, maybe instead or maybe in addition to thyroid issues. By the way, the people who you insist on calling "fat, tired, and with dry skin" are in subset three. They exhibit clinical symptoms of hypothyroidism. Your suggestion is that we give some dessicated thyroid to subset three and see if it helps. Well, it's pretty clear that it will help some people and will not help other people (for example, those fat and tired ones). However that is true of many medical interventions. For example, there are probably males in subset three with low testosterone. So giving testosterone to subset three males will also help some people and not help others. There also probably people with low-grade systemic infections in there. Giving broad-spectrum antibiotics to subset three might well help some people and not help others. There are likely people with autoimmune disorders there... Basically, if you have little idea about what's wrong, trying a variety of drugs hoping for a lucky hit is not necessarily a horrible strategy (depends on the side-effects of the drugs and t
0johnlawrenceaspden5yP.S. Note the awe-inspiring lack of smugness with which I present: IMPAIRED ACTION OF THYROID HORMONE ASSOCIATED WITH SMOKING IN WOMEN WITH HYPOTHYROIDISM BEAT MÜLLER , M.D., HENRYK ZULEWSKI , M.D., PETER HUBER , P H .D., JOHN G. RATCLIFFE , M.D., AND JEAN -JACQUES STAUB , M.D. I bloody said it would turn out to be the reason smoking's bad for you, didn't I? And at the same time it's evidence that acquired hormone resistance exists, and this one fingers an environmental cause.
0johnlawrenceaspden5yOpinions are divided. There's me and some dead guys, and everyone else. Everyone else thinks it's a solved problem. They absolutely do! Back in the day, they would have been referred to endocrinologists on suspicion of hypothyroidism, who would have (if they were very sophisticated and modern endocrinologists) used Billewicz' test to sort them into definite, definitely not, and 'therapeutic trial' groups. His test didn't rate these three symptoms, or lethargy or stupidity, because most everyone he saw had them, so he would look at all their other symptoms to make the diagnosis, looking for things like slow reflexes that are characteristic of hypothyroidism, and weight them to get a score. It really is a very careful piece of work, that test. He would treat the 'definites' without further ado, send the 'definitely nots' off to people who were into diabetes etc, and be careful with the rest. Including all sorts of unreliable lab tests and therapeutic trials. Luckily the therapeutic trials are not difficult to do, because with desiccated thyroid/T3 you seem to get either get a fairly rapid improvement, or you get hyper symptoms. (you might get both of course, in which case dose probably too high) Other popular ways of trying to work it out involved cholesterol and basal metabolic rate. Broda Barnes thought waking armpit temperature beat all this and just handed it out to anyone who woke up cold. And the fact that it has been sprayed around at random for a hundred years without anyone having a word to say against it implies that it's pretty damned safe. If you give yourself a massive overdose, then sure, you can probably give yourself a heart attack, but you'd need to be way way more criminally careless than I can imagine any (modern) doctor being. Osteoporosis and atrial fibrillation (both ghastly things) are associated with low TSH, so it's doubtless not a good idea to induce hyperthyroidism in people. And I think we should be careful not do that. Barnes mig

What do you think about the notion that rising perchlorate levels in food in North America in recent decades could be contributing to thyroid problems in the population? It inhibits iodide pumps throughout the body, not just the thyroid, and has a particular effect on babies getting iodine through these iodide pumps in breast tissue making milk.

4johnlawrenceaspden5yI'm afraid I don't have the faintest idea. It certainly fits in the general 'pathogen, immune defense, recent environmental' bag, and if it interferes with iodine chemistry then it sounds more likely than 'randomly chosen thing in that bag'. If it's true, it should be a simple experiment to inflict the stuff on rats and cause thyroid problems. If it doesn't sod up the rats (even in small amounts) then there doesn't seem to be a strong reason to believe that it would do anything nasty to us. It all works pretty much the same way. Do you know of any relevant experiments? The central problem seems to be to get medicine to pay attention to the existence of thyroid problems with 'normal' TSH. At the moment they seem to be being run ragged by witch-doctors, but I'm not sure I trust the witch-doctors to do the job properly either. They seem to have convinced themselves that it's mercury fillings or PCBs or fluoride in the water, or anything else they can think of. If medicine can be persuaded to find out whether there's a real problem, rather than just a weird information cascade from Broda Barnes that's somehow hoodwinking thousands of people into believing they've got better by trying things that should harm them, then I kind of semi-trust it to investigate the possible causes. But perhaps I am being naive.
1CellBioGuy5yHere's a more or less randomly chosen talk on the subject of environmental perchlorate and iodide, for what it's worth (from Seti Talks, of all places): https://m.youtube.com/watch?v=r-p55WLXAEI [https://m.youtube.com/watch?v=r-p55WLXAEI] A study that saw statistically significant hormone effects at 10 micrograms per kilogram per day: http://www.ncbi.nlm.nih.gov/pubmed/10966512 [http://www.ncbi.nlm.nih.gov/pubmed/10966512]
1Lumifer5yFirst, 10 mg/kg/day is a LOT (that's mg, not mcg). Second, while there were morphological changes ("significantly increased thyroid weights and thyroid histopathology") and some changes in the TSH/T3/T4, the study notes that "No toxicologically meaningful differences were observed between the control and AP-treated groups" which means there were no clinical symptoms whatsoever.
2CellBioGuy5y10 mg was what showed thyroid enlargement, but they saw hormone changes without definitive toxicological effects at all doses down to the minimum they tried, ten micrograms per kg per day. Quote: "Statistically significant changes in TSH and thyroid hormones were observed at all AP dosage levels tested; however, no thyroid organ weight or histopathological effects were observed at AP dosage levels < or = 1.0 mg/kg/day. In the absence of thyroid organ weight and histopathological effects, the toxicological significance of TSH and thyroid hormone changes at AP dosage levels < or = 1.0 mg/kg/day remains to be determined." I have little strong opinion here, just noting that they saw subtle hormone changes at very low doses and it's hard to ask a mouse how they feel.
4Lumifer5yIs it normal in a study like this to report the results separately for males and females? At low intervention levels what's significant for males is not significant for females and vice versa, so there's some potential for statistical shenanigans.
0johnlawrenceaspden5yAgree with this too. On the one hand, Simpson's Paradox, on the other hand, Simpson's Paradox. But if you don't expect male/female confounder, it just gives you three goes at the magic p<0.05. Frequentism. It's just broken.
0johnlawrenceaspden5yThis is absolutely evidence that huge doses of this stuff knacker your thyroid. But huge doses of most nasty chemicals probably do that. There's no particular reason to finger this as a significant cause unless it's in the environment in huge doses.
0johnlawrenceaspden5yI totally concur. 10mg/kg/day is a gram a day. If I took that amount of thyroid hormone, which I believe to be one of the safest drugs ever used, and of huge benefit to a large subset of the population, I would confidently expect to give myself an immediate heart attack. At the very least it would make me spectacularly ill. So it's not buggered them up too badly. For comparison, if you took the poor wee things' thyroids out, then you'd expect them to display horrible symptoms and die off in droves.
2CellBioGuy5yOh the effect is definitely small. They do however note observable differences in the hormones down to a thousandth the dose that caused histological changes, albeit without being able to see secondary effects on quantifiable health outcomes. No idea at all if that's significant but figured I'd contribute it to the discussion of subtle thyroid dysfunction.
2johnlawrenceaspden5yWell, I don't want to sound like an endocrinologist, but there aren't many chemicals which don't have some sort of effect on thyroid hormones, and if this one screwed up the system in a way measurable by hormone blood tests, it would just cause ordinary hypothyroidism, and that would get treated. As far as I can see, the evidence for it causing any sort of subtle dysfunction is non-existent. All I've seen is the one study, but it sounds from that as though it would be safe to ingest in small doses.

Oh, and a postscript.

Gordon Skinner wrote a book: Diagnosis and Management of Hypothyroidism

It's digressive, irreverent, and gloriously politically incorrect. I love it, but I recognise a certain British sense of self-deprecating humour which will not go down terribly well with everyone.

In my reading of it, he is full of self-doubt, and finds the behaviour of his own profession ridiculous and is hiding behind his jokes and raw language.

He describes many years of treating hypothyoidism by its symptoms, pretty much ignoring lab tests. As he describes it, it... (read more)

I got a reply from an actual endocrinologist! I'm not going to use his name because ethics, and because it was kind of him to reply at all, and more than any of his colleagues have done, but am I wrong to detect a certain lack of curiosity? Or do you think they're all too busy beavering away at the problem to bother answering e-mails from cranks?

to: subject: crank-trap

Dear [First Name],

Is there any reason why people think that thyroid hormone resistance is only congenital and never acquired?

Given the widespread acquired resistance to insulin it seems an o... (read more)

1Lumifer5yYou are falling prey to the typical mind fallacy. The meaning you ascribe to your words in not how a stranger would read them. You asked about thyroid hormone resistance. The "actual endocrinologist" knows what that is -- it is a genetic condition. So he assumes you are talking about the genetic problem (RTH) but you are terribly confused because you somehow think that genetic conditions can be acquired after birth. At this point he probably stopped reading because why bother.
0johnlawrenceaspden5yOh, well spotted! Can anyone suggest a better crank e-mail? This is actually the only one I've sent since I found Skinner's paper, which is the thing that made me go from 'dark suspicion' to 'bloody hell, this is probably true'.
2Lumifer5yI would suggest that your first two paragraphs should be (1) a hook, to make the reader interested; and (2) establishing your bona fides in the sense that you've read the literature and not just a random bloke who saw a programme on the BBC and now knows everything about thyroids. Also don't be so bloody apologetic about intruding on their time and write more than a few lines. They always have the option to stop reading.
0johnlawrenceaspden5yActually I wrote back once you pointed that out, and we've swapped a few e-mails since, but now he's gone silent too. It is hard, this crankery. I explained the whole bloody thing to him, with papers attached, and said: and he said: -------------------------------------------------------------------------------- Am I reading too much into this, or are those the words of a man trying not to get his name mixed up in a massive scandal? Are there in fact lots of people perfectly well aware that there is something dreadful going on but no-one wants to be the first to say it out loud in public?
[-][anonymous]5y 0

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