[For background see: http://lesswrong.com/lw/n8u/a_medical_mystery_thyroid_hormones_chronic/

I thought of a class of solutions, I went looking for possible evidence, someone's already proposed what looks like a perfect answer, and the problem is much bigger than I originally thought.]

[ Epistemic Status 1: Gather Underpants  2: ? 3: Profit! ]

Suppose that:

 

(1) Some common mechanism(s) can interfere with the reception of the endocrine hormones by the cells on which they should act.

 

There would be a high genetic load on such a mechanism, so we should look for recent environmental change, immune defence, or incomplete adaptation to less recent environmental change for the causes.[1] [2]

 

Seek, and you will find: Such a mechanism was proposed in 2003 in:

 

A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone R. L. Garrison, P. C. Breeding

 

These authors may have seen the whole of the truth for all I know, it looks terribly plausible to me, but I don't understand any of the interesting words in their paper. Hyaluronic. Now there is an interesting word. I wonder what it means. Nevertheless, this is exactly the sort of thing we should be looking for. I would imagine that there might be more than one such mechanism.

 

Then we would expect to see something like the classical presentations of endocrine disorders without any evident disturbance of the endocrine hormone levels in the blood.

 

Consider for instance Hypothyroidism / Hypometabolism / Myxoedema, a form of general metabolic collapse disease with famously many symptoms which appear almost at random, famously difficult to diagnose.

 

Pick a symptom of Hypometabolism and suppose it your primary symptom: For instance T3 deprivation in cells reduces the ability of mitochondria to recycle ATP, resulting in complete, shattering exhaustion from the mildest exercise.

 

Take this to your doctor. If competent she will test you for hypothyroidism (and all other common causes of fatigue). Your test will show that your blood hormone levels are normal. At this point, you have a mysterious unexplained syndrome in which the primary symptom is chronic fatigue, but which overall shows similarities to hypothyroidism. You have Chronic Fatigue Syndrome.

 

Suppose that the symptom that bothers you most is widespread pain. Then you will eventually be diagnosed with Fibromyalgia.

 

Should you complain mostly about alternating constipation and diarrhoea, then you have Irritable Bowel Syndrome.

 

Hypothyroidism, being a general collapse of the metabolism, can present with about forty different symptoms.

 

We would expect to see a number of overlapping 'syndromes', all with different primary symptoms, but all with great overlap with one another, and with the ancient and no longer understood metabolic collapse syndrome associated with Hypothyroidism, once familiar to doctors but no more.

 

We should also see various other overlapping clusters of syndromes, associated with random tissue deprivation of different endocrine hormones.

 

We should see that these syndromes have exploded in prevalence since 1970, when diagnosis of endocrine disorder by clinical symptoms went out of fashion in favour of diagnosis by blood hormone level tests.

 

We should see low levels of abnormal thyroid blood tests in these populations of sufferers, because some diagnoses of classical hypothyroidism will have been missed. But on the assumption that most doctors are competent, these levels should be above the general population levels, but not nearly high enough to indicate that the symptoms are caused by thyroid disorders.

 

If one of the obstructing mechanisms is immune in nature, then we should see these various disorders occasionally appearing shortly after infections. Particular types of infections should be more likely to cause them than others.

 

I believe that that is exactly what we see. They are known as the 'somatoform' disorders, because they are thought to be all in the mind. By those who have never had one.

 

I have a feeling that the air of crankiness around Lyme Disease, and the belief that its chronic-fatigue-like symptoms get worse long after the known infective agent has gone, might be explained in this sort of way.

 

But I am tempted also to include other mysterious diseases without known causes and with symptoms plausibly explained by endocrine hormone abnormalities, such as Bipolar Disorder, Depression, and the 'Metabolic Syndrome', which may do exactly what it says on the tin.

 

In particular, it is known that the principal characteristic of Chronic Fatigue Syndrome is Mitochondrial Dysfunction [4] . I contend that this is principally caused by lack of the hormone T3 in cells, for reason or reasons currently unclear.

 

The TSH test in particular is suspect, since it appears to have been justified on the basis of a simplistic model of the thyroid hormone system which had very little explanatory power even at the time, and which is now known to be a hopeless oversimplification. Even allowing for this context, the sensitivity of the TSH test never seems to have been investigated.

 

It is well known in the alternative medicine community that thyroid hormone treatment can alleviate Fibromyalgia and Chronic Fatigue. Some put this down to the 'stimulant action' of the thyroid hormones, believing that a similar effect would be achieved with amphetamines. But this is known to be untrue. A 2001 trial by some brave Scottish GPs proved conclusively that thyroid hormones have perceived harmful effects on healthy people [5].

 

The fact that this has been taken as a refutation of the alternative medicine idea of treating Chronic Fatigue Syndrome with Desiccated Thyroid is most unfortunate.

 

 

We therefore see that (1) =>

 

(2) There is a huge, generalized, common disorder with many names, which is caused by inadequate thyroid hormone stimulation of peripheral tissue.

 

(3) There are further clusters of disorders corresponding to other hormones.

 

(4) These clusters themselves may overlap. Whatever interfering mechanisms there are may interfere with many hormones at the same time.

 

Following the suggestion of Garrison and Breeding, by analogy with the situation in diabetes, I call the disorder in (2) type II hypothyroidism. It is not to be confused with central hypothyroidism, which is detectable by blood hormone tests, although not by the TSH test. John Lowe called this disorder 'peripheral resistance to thyroid hormone'.

 

Since (2) would be such a good explanation of observed patterns of mysterious diseases, it becomes urgent to refute the hypothesis (1)

 

How to Refute the Central Hypothesis

 

We seek sufferers of type II hypothyroidism amongst the sufferers of Chronic Fatigue Syndrome and Fibromyalgia.

 

I choose Chronic Fatigue Syndrome because I have had it myself, and thyroid hormones have so far had an excellent effect on me, including raising my basal temperature to normal levels.

 

I choose Fibromyalgia because John Lowe dedicated his life to establishing that the symptoms of Fibromyalgia and Hypothyroidism were one and the same, and to apparently successfully treating sufferers of Fibromyalgia with thyroid hormones.

 

We filter out all those with abnormal blood hormone levels. They are classically hypothyroid and should be treated as such, although the possible presence of interfering mechanisms must be remembered, and the treatment should be by symptoms and not by hormone levels.

 

In our remaining population of CFS/FMS sufferers with normal lab values, I expect to find many people with the classical symptoms of hypothyroidism.

 

We could score them with the Billewicz test [6], the last word in clinical diagnosis. Although note that by design this test does not take account of the most obvious hypothyroid symptoms!

 

Or we could score them by what John Lowe considered the principal symptom of hypothyroidism, the ratio of measured basal metabolic rate to the metabolic rate predicted from such factors as weight, age, and sex.

 

I propose that we do both and I expect that:

 

(5) In the CFS/FMS population, there is a proportion of sufferers with abnormally low metabolic rate and abnormal hypothyroidism scores.

 

If (5) is not true, (1) is refuted. My beautiful if somewhat disturbing hypothesis refuted by an ugly fact, I shall shut up about it and start thinking about another way to explain the mystery.

 

If (5) is true, then we may wish to consider attempting to treat these conditions with desiccated thyroid, since that is what everyone who cares about these diseases has been telling us works since about 1940.

 

 

References

[1] Infectious causation of disease: an evolutionary perspective Gregory M. Cochran, Paul W. Ewald, and Kyle D. Cochran

[2] Is rheumatoid arthritis a consequence of natural selection for enhanced tuberculosis resistance? James L. Mobley

[3] A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone R. L. Garrison, P. C. Breeding

[4] Chronic fatigue syndrome and mitochondrial dysfunction Sarah Myhill, Norman E. Booth, John McLaren-Howard

[5] 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

[6] Statistical Methods Applied to the Diagnosis of Hypothyroidism by W. Z. Billewicz, R. S. Chapman, J. Crooks, M. E. Day, J. Gossage, Sir Edward Wayne, and J. A. Young

 

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I have a couple of questions about your hypothesis.

First, as I understand it, you are hypothesizing that there are people who have symptoms of CFS/etc. but normal blood levels of T3, T4, and TSH, who can nevertheless be helped by taking thyroid extract. And your hypothesized explanation for why these people are having symptoms of CFS/etc. is that, even though there are normal levels of T3 and T4 in their bloodstream, those hormones are not getting into their cells where they are actually needed. But if that is the case, how will putting more T3 and T4 into their bloodstream help? It still won't be getting into the cells. It seems to me that, if your hypothesized cause were correct, the indicated treatment would be to somehow inject T3/T4 directly into the cells--or else to figure out what is blocking the hormones from getting into the cells, and fix that. But just putting more T3/T4 into the bloodstream, ISTM, should not work if your hypothesized cause were correct.

Second, as I understand it, you are taking the fact that treating these people with thyroid extract appears to help them, as evidence that your hypothesis is correct. But it seems to me that this fact is actually evidence for a different hypothesis: the hypothesis that the definition of "normal" levels of T3, T4, and TSH is incorrect. More specifically, that "normal" levels should be defined, not in a "one size fits all" fashion, but specifically for each person based on some set of factors that can vary from person to person. (Obvious candidates would be body weight/BMI and genetic factors.)

Hi Peter, I don't want to claim credit for this, it's mostly the work of John Lowe/Broda Barnes (and now Gordon Skinner). I've just put their ideas into what I think is a fairly compelling order, and connected them to some ideas of Greg Cochran and Sarah Myhill. I'm seeing myself more as a speaker for the dead.

I was definitely starting off thinking about 'something wrong with those tests, a few cases missed, maybe', and I absolutely agree that if we take the anecdotal evidence that T3/T4/NDT help in CFS at face value, then this is definitely evidence for that. Two different hypotheses can make a similar prediction.

I've ended up thinking about the 'hormone resistance' idea, because it seems like the sort of thing that might well be true, (once you've realised that it works that way in diabetes), and it's the simplest explanation for what's going on. Sometimes you'll see people with symptoms and a TSH of 2, sometimes you'll see people with a TSH of 30 (in whom something is obviously going wrong), but no symptoms at all yet.

As for 'hormone resistance' as an idea, you're right that if the action of the hormones was completely blocked, adding extra stuff to the bloodstream wouldn't make any difference. And also, those people should be very ill indeed with really obvious hypothyroidism. (Severe cases are easy to recognise).

But there's no reason why resistance should be an on/off thing. There are all sorts of chemical reactions taking place between hormones in the blood and their effect on the mitochondria. All it would need is for something to mysteriously slow one of the reactions down.

John Lowe was forced into inventing the idea of 'peripheral resistance to thyroid hormone' by noticing that a lot (about 25%) of his patients didn't get better (or in fact notice) his attempts to fix them with T4/T3. They should have been made quite ill by this if hormone deficiency wasn't the problem. So he tried higher and higher doses of T3, and found that that worked. He never seems to have connected it to diabetes or to have wondered if it was present in the other cases. I think he thought that 'central hypothyroidism' was the principal problem (another thing that's missed by TSH)

It would make sense as an immune response. Something nasty (virus most likely) might be trying to get into the cells, and in order to avoid being eaten alive, the body somehow tries to wall off the cells so it's harder for things to get in and out. It's a very scorched-earth defense, but those sorts of things happen. Often in bacterial diseases, your body takes most of the iron out of your bloodstream. That's bad for you, but worse for the bacteria. Fever's the same. It does you a lot of harm but it does the enemy more harm.

We have very little idea how the immune system works, or how pathogens try to get round it, but it's a very strange and cruel world down there, and there's group-selection on both sides, so I think it's best viewed as a billion year war, with strategies, tricks, camouflage, and even cleverness involved.

Alternative medicine seems to be much more into the idea of 'toxins', by which they mean chemicals that weren't around when we were evolving. That might well work too, but then you'd expect that there'd be a specific chemical which could reliably induce the resistance, and thus the symptoms of hypothyroidism. I don't know of one.

Conventional medicine seems to mostly revolve around the idea of making up new chemicals and seeing what they do. And they seem to refuse to consider any evidence that doesn't come from very careful formal trials (which are very expensive). I don't think that's a terribly good approach, myself, but it seems to be the best we've got.

All credit to them for wanting to avoid fooling themselves, but I think they've swapped 'bad data' for 'no data', when what they should have done is 'been careful'.

I wish they'd spend more time thinking about cause and effect and what all these systems are 'for', and accepting that millions screaming in pain is not just a big placebo effect or a 'psychological problem'

Ok, so the "hormone resistance" hypothesis is really something more like: the rate of some key reaction involving T3/T4 is being slowed down by some unknown factor; since we don't know what the factor is, we can't fix it directly, but we can increase the reaction rate by increasing the concentration of T3/T4 in the bloodstream to above normal levels, to compensate for the damping effect of the unknown factor.

This hypothesis makes an obvious testable prediction: that when people with CFS/etc. who are treated with thyroid extract feel better, the T3/T4 levels in their bloodstream should be above normal. Or, conversely, if their bloodstream T3/T4 levels are within the normal range, they should not feel better, even though they are being treated with thyroid extract. I don't know if any existing data has this information.

Absolutely, hormone levels would have to be higher than they were, in order to make any difference.

Whether that means 'out of the normal range' for any particular hormone, I don't know. Nobody seems to have the faintest idea what 'normal range' means for these things. But if there are serious cases of resistance, the level of the thing resisted should have to be way high in order to make any difference.

And it should probably cause TSH suppression. In my own case, I had TSH 2.51 when I first started complaining of symptoms, it was 4.06 when they came back, and with a tiny bit of thyroid which was nevertheless enough to get rid of all manifestations of CFS and cause some hyper symptoms it was 2.31, so looks like it pushed TSH down, but still not even as far as some people say is optimal.

And all of that could be noise in the test. Circadian cycle means TSH results can vary by a factor of two depending on when the blood is drawn. Go figure!

What would be ideal would be to figure out the cause of the 'hormone resistance', and fix it, rather than trying to overwhelm it.

It might even be a bad idea to fix it, if it's performing some vital immune defence function.

Whether that means 'out of the normal range' for any particular hormone, I don't know. Nobody seems to have the faintest idea what 'normal range' means for these things.

Yes, a better way to put it would be that the bloodstream levels of T3/T4 should be significantly higher when the person is treated and feels better than they were before treatment.

it should probably cause TSH suppression

That would be expected, yes.

What would be ideal would be to figure out the cause of the 'hormone resistance', and fix it, rather than trying to overwhelm it.

Yes, agreed. See below.

It might even be a bad idea to fix it, if it's performing some vital immune defence function.

If this is true, it might also be a bad idea to overwhelm it. The "immune defense" hypothesis says that, if a person is feeling symptoms of CFS/etc., it's because some pathogen is trying to attack their cells, so the immune defense kicks in, but as a side effect it also depresses normal cell metabolism. If thyroid therapy increases normal cell metabolism by overwhelming the immune defense, it might also increase the ability of the pathogen to infect cells. The only real fix in this case would be to find the pathogen and eliminate it.

Agreed. All I'm really saying is "For God's sake, people, there's enough evidence here to have a look, surely?"

We do have Broda Barnes' word that taking desiccated thyroid long-term isn't that bad for people. He really does seem to have put people on thyroid at the slightest excuse, and he reckoned that his patient records showed them being healthier than the general population, especially for things like heart disease. Which is kind of weird given that his patients were the sort of people who went to see a doctor and got put on lifetime medication.

Maybe only the really healthy could survive his methods and everyone else scurried back to more conventional doctors who would sensibly tell them it was all their fault for fancying their parents? Increasingly I think that psychiatry has the same advantage as homeopathy, in that it can't possibly have any effect so they're not going to hurt people.

I don't know how seriously to take Barnes. Originally I thought he must have been a bit of a lunatic, until I ended up coming up with the idea above, which pretty much makes his observations as predictions. Then I read his book, and it said exactly what I thought it would say.

I disagree with his 'origin story', that the strange widespread hypothyroidism of modern times is because people aren't dying of infections any more. (He thought that hypothyroid children were prone to infections and so they'd have all died of tuberculosis before they became adults. I think that a 'genetic proneness to infection' would have bred out very quickly.)

But again, if he was handing out thyroid meds to people who already had enough of the stuff naturally, that should have hurt them, not made them less prone to illness.

He might have been a fraud, but it seems a weird thing to do..... Even if he was just disregarding his patients' complaints because he had given them thyroid and so they were damned well better, whatever they thought, he should have noticed them dying of heart attacks.

But I don't really trust anyone medical any more. And Barnes was an endocrinologist.

You're doing a lot of reasoning based on dodgy inferences.

I think you're trying to have it both ways: when it comes to deflecting criticism, you admit that your ideas are unlikely and based on dodgy inferences. But when it comes to promoting your ideas, you forget that you were using dodgy inferences and suddenly you think there's a mountain of evidence and good reasoning behind them.

I admit both charges. Where do I go from here?

Stop doing that?

No way! It doesn't matter how I came up with the idea.

The original mystery is sound. CFS/FMS/hypothyroidism are ridiculously similar. That needs explaining unless you believe in awesome coincidences.

One explanation would be: Something makes it so that hormones in the blood don't act on the cells.

That would explain a spectacular number of medical facts. There really is a mountain of evidence there. Did you know that doctors are trained to ignore the symptoms of endocrine diseases because they're everywhere? It's a major sin: Overdiagnosing Hypothyroidism. Learn what the symptoms are and go for a walk.

It would all be explained if we could find a something.

So it might be worth looking for a something. Cochran tells us where to look. And wow, here is one possibility. I bet there are loads once you start looking.

And here I am a couple of weeks later, trying my little experiment to fix chronic fatigue with tiny amounts of thyroid hormones, and the fatigue's gone, and been replaced by the manic state from manic-depression, which looks like one of the symptoms of hyperthyroidism? And the depressive state looks exactly like chronic fatigue. And I can balance in between by carefully titrating the dose?

It scared the shit out of me. I wasn't expecting that at all, despite having come up with an idea that strongly suggests it might happen not a week before.

What exactly is the difference between CFS/hypothyroidism/FMS/bipolar disorder? Are they all just words for the same thing? And the only difference is some stupid test that no one should ever have expected to work in the first place?

Aren't you even curious?!

It doesn't matter how I came up with the idea.

Right now, you're saying "I use dodgy inferences" to deflect criticism, but then saying "all my inferences are great!" the rest of the time. That is not good rationality, and it is certainly not just "how I came up with the idea".

CFS/FMS/hypothyroidism are ridiculously similar.

Your perception of similarity is based on dodgy inferences, and as such, I have no reason to care about it.

There really is a mountain of evidence there.

Evidence based on dodgy inferences is not evidence worth paying attention to.

CFS/FMS/hypothyroidism are ridiculously similar.

Your perception of similarity is based on dodgy inferences, and as such, I have no reason to care about it.

That's a good point, and it's the heart of my argument (well, that and the TSH test).

So I propose a test for that. Ask a doctor you trust: "Can you tell CFS and hypothyroidism apart by clinical symptoms rather than by blood test?"

I have done this, and I think it's not possible. But you are right not to take my word for it.

If it is, I'd love to know, and it would be a great blow to this argument, which I am trying to defeat, so thank you both for the question and for the answer.

Ask a doctor you trust: "Can you tell CFS and hypothyroidism apart by clinical symptoms rather than by blood test?"

I have no idea if he could, but even assuming he can't, that wouldn't prove anything. "Have similar symptoms" isn't the same thing as "are similar". Many symptoms are produced by lots of different conditions.

Yes indeed! And if the only way to tell them apart is a blood test that shouldn't work, then....

I'm not sure why you think the blood test shouldn't work. If you mean that it shouldn't be able to tell apart two different conditions, of course it should--being able to tell apart two conditions is the whole point.

No, I mean that the blood test shouldn't be able to tell the difference between hypothyroidism (shows hypothyroid symptoms, gets better when given thyroid hormones) and not-hypothyroidism.

The TSH test measures one variable in a very complicated system full of feedback loops. It's a bit like if your aeroplane keeps crashing, and you take it to the mechanic and he says "The rudder wires are fine, so there's nothing wrong with it". And you say "But why do you think the rudder wire is all you need to test?", And he says, "Whenever an aeroplane is good, and doesn't crash, we check the rudder wires and they're always fine".

Except the TSH test isn't even that good! Because for forty years they've been arguing about what blood levels of TSH fine people have, and the latest answer is "such a narrow range that huge numbers of people who aren't ill are outside of the range".

So it diagnoses lots of people who seem perfectly healthy as ill, and it tells lots of people who are obviously ill that they're fine. I call bullshit!

But the real problem is that they never checked whether it worked or not. You're supposed to check these things. And they didn't.

Where is the evidence that (shows hypothyroid symptoms, gets better when given thyroid) is the same as (TSH in whatever the normal range is)?

Why did they ever believe that? Why did they not check to see whether it was true?

for forty years they've been arguing about what blood levels of TSH fine people have, and the latest answer is "such a narrow range that huge numbers of people who aren't ill are outside of the range".

Rephrased a bit, this says "Healthy people have such a narrow range of TSH that huge numbers of healthy people are outside of this range". I trust you see the problem.

the real problem is that they never checked whether it worked or not

What do you mean by "worked"? As you yourself point out, it's just one variable in a complicated system with feedback loops. If you mean "necessary and sufficient to give a clinical diagnosis", then no, it never "worked". Doesn't mean the number is not useful.

Absolutely I see the problem! Thank you for phrasing it more elegantly than I did. And absolutely TSH is a useful number. It's a very fine measure of the hormone thought to control the T4->T3 conversion rate, as well as the thyroid output.

Now can you tell me (a) What the AACB did wrong in their report, or (b) why, when someone goes to their doctor with many of the symptoms of hypothyroidism, they do this test, and they find the number to be within a very broad range, and then they say "your problems can't be anything to do with thyroid hormones".

Especially in the context of diabetes, another endocrine disorder, where we know that you can have normal levels of hormones, but for some reason they aren't working, and you have high blood-sugar that is killing you anyway? No one in their right mind would tell a type-2 diabetic that they weren't diabetic because they had a normal amount of insulin.

What the AACB did wrong in their report

I don't know, haven't looked at it. I suspect that the underlying issue is that for one variable in a complicated process the concept of unconditional "normal range" might be too simplistic.

why

For the usual reasons :-/ Find a better doctor.

Except that all the better doctors have been struck off! Who takes hypothyroidism to a chiropractor?

Because for forty years they've been arguing about what blood levels of TSH fine people have, and the latest answer is "such a narrow range that huge numbers of people who aren't ill are outside of the range".

Tests are Bayseian evidence. If people outside the range disproportionately have a condition, a test is evidence for that condition, even if not every person outside the range has the condition, and not every person with the condition is outside the range.

Absolutely agree, what I'm saying is that this test isn't very strong evidence. And that they decided to use it without considering how strong it was. They did check specificity, by measuring TSH levels in some healthy people. As far as I can tell, they didn't check sensitivity, and they never have.

I think you've just nicely summed up my argument for me. Thank you.

If you can find the bit where they checked sensitivity, and it's sound, then I'm flat wrong and I'll shut up!

They say:

(? (hypothyroid symptoms, gets better with T4) [in the Aristotelian sense]

I say they've shown:

(unambiguously healthy) => (0<TSH<2.5) [In the sense of plausible reasoning]

And that's all they've shown. Ever.

I am avid for evidence that they've done more than that.

My counsellor tells me that he literally cannot believe that they would have forgotten, it must be buried in the literature somewhere, and that's why we can't find it. I am perfectly happy to believe that it was a careless mistake.

[-]gjm10

... maybe the reasoning that led you to the conclusion that the blood test "shouldn't work" was wrong.

g, see answer to Jiro above. I agree that I am probably wrong. I would like to see evidence that I am wrong.

CFS/FMS/hypothyroidism are ridiculously similar.

Your perception of similarity is based on dodgy inferences, and as such, I have no reason to care about it.

That's a good point, and it's the heart of my argument (well, that and the TSH test).

So I propose a test for that. Ask a doctor you trust: "Can you tell CFS and hypothyroidism apart by clinical symptoms rather than by blood test?"

I have done this, and I think it's not possible. But you are right not to take my word for it.

If it is, I'd love to know, and it would be a great blow to this argument, which I am trying to defeat, so thank you both for the question and for the answer.

If I understand what you're saying, you think that some subset of people with chronic fatigue syndrome and fibromyalgia have undiagnosed thyroid problems that do not show up on standard tests, therefore treating them with dessicated thyroid could help.

I think that is plausible, and more reasonable than something like "all CFS and fibromyalgia can be explained by endocrine problems". It also seems to match the experience of some doctors who treat a lot of patients with these conditions.

There is also a difference between "helps to some extent" and "is enough to completely cure".

I would add to that:

The manufacturer of dessicated thyroid in the United States a few years ago added different fillers to the pills that can interfere with the medication. So if you are thinking of experimenting with that, check up on the non-active ingredients used, and precisely who manufactures it. There are differences between the pills from different manufacturers, they are not all the same, even if it looks like they ought to be interchangeable at first glance.

There are a number of doctors treating people with bioidentical hormones, that is, hormones in the same format that the body uses, not synthetic hormones that have similar, but not identical, structures. Bioidentical hormone supplementation seems to help some people. If you want to read up on that, Dr. Alvin Pettle has some lectures and books available where he goes into why, for example, horse hormones, derived from horse's urine, are problematic when in human women's bodies. In the context of thyroid problems, an alternative to dessicated thyroid would be bioidentical T3 and T4.

I agree with all of that, although I haven't read Pettle (yet!). My current best guess would be synthetic T3:T4 1:10 as a good starting point for adjustments, but I really think that the alternative people may be making some good points, and I think we should try what they say, see whether it works, and then start fiddling.

We should see that these syndromes have exploded in prevalence since 1970, when diagnosis of endocrine disorder by clinical symptoms went out of fashion in favour of diagnosis by blood hormone level tests.

How do you know about the timeline?

I don't know a great deal about the timeline.

As I remember from writing the first essay, Billewicz' paper seems to have been the last word in clinical diagnosis, and that was late 60s/early 70s, I think. After that they went over to TSH tests. Before that the tests weren't trusted and were only used for the hard cases, according to Billewicz.

A book on CFS recommended to me as the bible of the only successful standard treatment told me that the disease was widely thought to be recent, but that 'neurasthenia' existed in Victorian times, and seems to have been similar. I think her point was supposed to be that it wasn't anything new. But that made me really suspicious.

I remember reading about the 'yuppie flu' in the 1980s, and a friend of mine at college came down with it in about 1992, and I still remember how it poleaxed him, so I reckon CFS must have kicked off about then.

Apart from that I know nothing, but it's a fairly strong prediction of mine that it wouldn't have existed much before 1970, because any serious investigation would have ended in deciding that it was hypothyroidism, and they'd have treated it with desiccated thyroid.

Since, whatever Broda Barnes and my own experience says, I don't think dessicated thyroid is a priori that good a treatment, there might have been some strangely resistant cases, but I imagine they'd have got lost in the noise.

A book on CFS recommended to me as the bible of the only successful standard treatment told me that the disease was widely thought to be recent

In general it would help if you would name the book in cases like that to make it easier for other people to follow your reasoning.

I looked up Chronic Fatigue Syndrome and Fibromyalgia on Google Ngrams.

There a huge uptick in the late 1980's but not in 1970. Very interestingly there's a fall of both. To me that suggests that while your prediction of it not existing before 1970 happens to be true, your overall representation of the history isn't and it happened later than the timeline you are presenting. That in turn raises the question whether you are similary imprecise about other issues.

Amazon tells me that the book was Overcoming Chronic Fatigue by Mary Burgess, and it was recommended to me as the best book for CFS by a close friend who's a consultant psychiatrist.

As I remember, the first half of it describes what was happening to me so well that I could have written it myself, and the second half (the treatment) seemed weirdly irrelevant. I gave it to Oxfam in the end (the usual fate of my books) so I can't check what she actually said about neurasthenia.

The ngrams technique is brilliant! Actually Fibromyalgia seems to have started in '66. I am very interested in the fact that both things have fallen since 2000, any idea what that would mean?

Also, could you try some of the other things I'm claiming? I have done, and found what I expected, but if I say what to search for, that will look like I'm leading you.

I am certain to have been imprecise about other issues. I've only been thinking about this for three months, and I was writing what I thought, and now I can't distinguish my own writing from my memories or the truth! And in my original narrative I glossed over any details that detracted from the story, while being careful not to say anything I knew to be untrue or miss out anything I thought relevant. If I have been deliberately imprecise in misleading ways you have my word that it was unconscious bias, for what that's worth.

All changes will have happened slowly, and new 'syndromes' take a while to be accepted and given names, so the raw ngrams graph you link to looks as I'd expect up until 2000. The fall after, I can't explain, and the existence of Fibromyalgia in 1966 is a surprise too.

Looked up Billewicz' paper and it was published in 1969.

Take this to your doctor. If competent she will test you for hypothyroidism (and all other common causes of fatigue). Your test will show that your blood hormone levels are normal. At this point, you have a mysterious unexplained syndrome in which the primary symptom is chronic fatigue, but which overall shows similarities to hypothyroidism. You have Chronic Fatigue Syndrome. Suppose that the symptom that bothers you most is widespread pain. Then you will eventually be diagnosed with Fibromyalgia. Should you complain mostly about alternating constipation and diarrhoea, then you have Irritable Bowel Syndrome.

Or you have a psychiatric, inflammatory, genetic or other cause of fatigue, pain or bowel disturbance. Yes, undiagnosed thyroid issues could cause this but why is this more likely than other possibilities?

We should see that these syndromes have exploded in prevalence since 1970, when diagnosis of endocrine disorder by clinical symptoms went out of fashion in favour of diagnosis by blood hormone level tests.

This is weak evidence, where strong or at least more numerous arguments are needed.

In particular, it is known that the principal characteristic of Chronic Fatigue Syndrome is Mitochondrial Dysfunction [4] . I contend that this is principally caused by lack of the hormone T3 in cells, for reason or reasons currently unclear.

Why? Why not an alternative cause, such as a combination of thousands of genes, mostly unrelated to the thyroid?

I believe that that is exactly what we see. They are known as the 'somatoform' disorders, because they are thought to be all in the mind. By those who have never had one.

Not true. Plenty of people have and diagnose somatoform disorders.

But I am tempted also to include other mysterious diseases without known causes and with symptoms plausibly explained by endocrine hormone abnormalities, such as Bipolar Disorder, Depression, and the 'Metabolic Syndrome', which may do exactly what it says on the tin.

But plenty is already known about the pathophysiology of bipolar disorder, depression and so on. e.g. depression seems likely to be caused by many thousands of genes (either that or some unidentified environmental stimulus, though we tend to have looked quote closely for those) (1)

Why not learn about the conditions and the evidence about their causes and then argue forward to some hypothesis rather than priveleging your thyroid-based hypothesis and trying to apply it to all available diseases?

At least an experiment is proposed here, but if you wanted to actually implement it, you would need a placebo control design, and you would approach disease interest groups or elsewhere for participants.

1) http://www.ncbi.nlm.nih.gov/pubmed/22472876

Ryan, here's an argument that might make sense to you:

No-one in their right mind would tell a type 2 diabetic that they were fine because their insulin levels were normal.

There is a mysterious mechanism that interferes with the cellular action of insulin, even when the blood hormones are normal.

Imagine if that mechanism also interfered with the other endocrine hormones.

For one thing, it would explain why even diabetics in good control of their blood-sugar suffer terrible complications, which look awfully like the complications of hypothyroidism.

Wikipedia says that "elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise" are associated with the complications of diabetes. These four things are known consequences of hypothyroidism. So much so that elevated cholesterol was once a test for hypothyroidism.

Also, thank you for all your help. Your questions have clarified my thoughts immensely.

Why? Why not an alternative cause, such as a combination of thousands of genes, mostly unrelated to the thyroid?

Ryan, caused by a combination of thousands of genes is exactly what I'm saying. Likely immune defence genes.

The shadows of the great killers of the past lie across our genes

Must lie across our genes! Defense against pathogens is the most important thing a human does. We have no other predators. The strongest selection pressures on us are the pathogens.

And nothing else can plausibly explain why our ancient master control system often just seems to go wrong for no reason. Except recent environmental change. I think it's likely both.

In fact the selection pressure on the endocrine system is likely so strong that it's got to be defences against recent diseases. That's why I'm thinking about tuberculosis and syphilis and the black death. Things that killed huge numbers in the last few hundred years. Which modern 'genetic' diseases correspond to which recent mass killer diseases?

That's got to be true even for the well understood forms of thyroiditis, Ord's and Hashimoto's and Graves'.

I also have CFS, I got it after a viral illness when I was 18, so I'd be very interested to see what this line of reasoning leads to.

It's a shame metamed went bust, because this is right up their street.

It sounds extremely plausible to me that CFS is mainly caused by a viral infection doing damage to one of the hormone glands in the HPA-axis, in fact when I seriously researched my own illness this is the conclusion I came to. Nothing else out there makes any sense.

The problem is that I am merely one man, and not a medic either, so I gave up and tried the CBT approach on myself. I have found that occasional zolpidem use really helps me get to sleep and maintain a normal routine. I avoid alcohol and go to bed early, I avoid stress.

The HPA-axis is extremely complex. It seems to me that the only way to prove/disprove its involvement in CFS would be to record the hormone levels of a large number of CFS sufferers over the course of the day, along with controls. I even toyed with the idea of trying to organise such an RCT as part of a charity.

We need more good quality data, really.

I finally realised that I should read Broda Barnes, rather than dismissing him as a lunatic.

I ordered 'Hypothyroidism: The Unsuspected Illness', and read it through in one sitting the evening it arrived.

He doesn't have the idea of type 2 endocrine disorders, everything he claims is from his own observations, which I'd assumed were placebo-effect and confirmation bias.

His observations are a subset of my predictions. If you need supporting evidence, read his book, then look around.