Contract Programmer Seeks Job in Cambridge (£500 reward)

Anyone in Cambridge need a programmer? I'll give you £500 if you can find me a job that I take.

CV at http://www.aspden.com

I make my usual promise, which I have paid out on several times:

If, within the next six months, I take a job which lasts longer than one month, and that is not obtained through an agency, then on the day the first cheque from that job cashes, I'll give £500 to the person who provided the crucial introduction.

If there are a number of people involved somehow, then I'll apportion it fairly between them. And if the timing conditions above are not quite met, or someone points me at a shorter contract which the £500 penalty makes not worth taking, then I'll do something fair and proportional anyway.

And this offer applies even to personal friends, and to old contacts whom I have not got round to calling yet, and to people who are themselves offering work, because why wouldn't it?

And obviously if I find one through my own efforts then I'll keep the money. But my word is generally thought to be good, and I have made a public promise on my own blog to this effect, so if I cheat you you can blacken my name and ruin my reputation for honesty, which is worth much more to me than £500.



And I also make the following boast:

I know all styles of programming and many languages, and can use any computer language you're likely to use as it was intended to be used.

I have a particular facility with mathematical concepts and algorithms of all kinds. I can become very interested in almost any problem which is hard enough that I can't solve it easily.

I have a deserved reputation for being able to produce heavily optimised, but nevertheless bug-free and readable code, but I also know how to hack together sloppy, bug-ridden prototypes, and I know which style is appropriate when, and how to slide along the continuum between them.

I've worked in telecoms, commercial research, banking, university research, chip design, server virtualization, university teaching, sports physics, a couple of startups, and occasionally completely alone.

I've worked on many sizes of machine. I've written programs for tiny 8-bit microcontrollers and gigantic servers, and once upon a time every IBM machine in the Maths Department in Imperial College was running my partial differential equation solvers in parallel in the background.

I'm smart and I get things done. I'm confident enough in my own abilities that if I can't do something I admit it and find someone who can.

I know what it means to understand a thing, and I know when I know something. If I understand a thing then I can usually find a way to communicate it to other people. If other people understand a thing even vaguely I can usually extract the ideas from them and work out which bits make sense.

Answer to g

What if I was so convinced I was right that I started a 'Rational Thyroid Treatment Corporation'?

Actually there wouldn't be any point, since the bloody stuff is cheap as chips. I think that might be the problem. There's never been anyone to fight its corner for it.

---

Which is verging on conspiracy theory. Except that there's no conspiracy, just perverse incentives.

Which is what we say when we want to say 'conspiracy theory'.

---

I used to know some Socialist Workers. And one of them used to refer to people as 'lumpen'. One day I asked her if that was what Socialist Workers said when they meant 'common', and she went red and said 'yes' in a very small voice.

Which increased my respect for her a lot. Unfortunately she ruined it all about a month later when at the end of an argument about the correct method of determining wage levels for firemen she completely lost it with the immortal words 'Under Socialism there WOULDN'T BE FIRES'.

---

I wonder if she's still a Socialist? I wonder what she's doing? I wonder if she's still alive?

The follies of our youth are in retrospect glorious, when compared to the follies of our old age.

In Defence of Simple Ideas That Explain Everything But Are Wrong

I've been thinking, and writing, about The Impossible Question of the Thyroid for some while now.

I came up with what I thought was a good stab at an answer to its majestic mystery:

http://johnlawrenceaspden.blogspot.co.uk/2016/03/the-thyroid-madness-core-argument.html
http://lesswrong.com/r/discussion/lw/nef/the_thyroid_madness_core_argument_evidence/

This is a very simple and obvious explanation of an awful lot of otherwise confusing data, anecdotes, quackery, expert opinion and medical research.

People seem to hate it because it is so simple, and makes so many predictions, most of which are terrifying.

And it is obviously false! Of course medicine has tried using thyroid supplementation to fix 'tired all the time'. It doesn't work!

But there really is an awful lot unexplained about all this T4/T3 business, and why different people think it works differently. I refer you to the internet for all the unexplained things.

In just the endocrinological literature there is a long fight going on about T4/T3 ratios in thyroid supplementation, and about the question of whether or not to treat 'subclinical hypothyroidism'. Some people show symptoms with very low TSH values. Some people have extremely high TSH values and show no symptoms at all.

I've been trying various ways of explaining it all for nearly four months now. And I've found lots of magical thinking in conventional medicine, and lots of waving away of the reports of honest-sounding empiricists, real doctors, who have made no obvious errors of reasoning, most of whom are taking terrible risks with their own careers in order to, as they see it, help their patients.

I've read lots of people saying 'we tried this, and it works', and no people saying 'we tried this, and it makes no difference'. The explanation favoured by conventional medicine strongly predicts 'we tried this, and it makes no difference'. But they've never tried it!

It's really confusing. A lot of people are very confused.

I think that simple explanations are extra-worth looking at because they are simple.


Of course that doesn't mean they're right. Consequences and experiment are the only judge of that.

I do not think I am right! There is no way I can have got the whole picture. I can't explain, for instance: 'euthyroid sick syndrome'. But I don't predict that it doesn't exist either.

But you should look very carefully at the simple beautiful ideas that seem to explain everything, but that look untrue.

Firstly because Solomonoff induction looks like a good way to think about the world. Or call it Occam's Razor if you prefer. It is straightforward Bayesianism, as David Mackay points out in Information Theory, Inference, and Learning Algorithms.

Secondly because all the good ideas have turned out to be simple, and could have been spotted, (and often were) by the Ancient Greeks, and could have been demonstrated by them, if only they'd really thought about it.

Thirdly because experiments not done with the hypothesis in mind have likely neglected important aspects of the problem. (In this case T3 homeostasis, and possible peripheral resistance, and the difference between basal metabolic rate and waking rate, and the difference between core and peripheral temperature, and the possibility of a common DIO2 mutation causing people's systems to react differently to T4 monotherapy, and in general the hideous complexity of the thyroid system and its function in vertebrates in general).

Fourthly because the reason for the 'unreasonable effectiveness of mathematics' is that the simplest ideas tend to come up everywhere!

And so when a mathematician plays with a toy problem for fun, and reasons carefully about it, two thousand years later it can end up winning a major war in a way no one ever expected.

So that even if there are things you can't explain (I can't explain hot daytime fibro-turks...), you should keep plugging away, to see if you can explain them, if you think hard enough.

Good ideas should be given extra-benefit of the doubt. Not ignored because they prove (slightly) too much!

Do not believe them. Do not ever ever believe them. You will end up worse than Hitler. You will end up worse than Marx.

But give them the benefit of the doubt. Keep them in mind. Try safe experiments, ready to abort when they go wrong.

And if they're easy to refute (mine is), then if you're going to call yourself a scientist, damned well take the trouble to refute the things. You might learn something!

The Thyroid Madness : Core Argument, Evidence, Probabilities and Predictions

I've made a couple of recent blog posts about hypothyroidism:

http://johnlawrenceaspden.blogspot.co.uk/2016/02/thyroid-hormones-chronic-fatigue-and.html
http://johnlawrenceaspden.blogspot.co.uk/2016/01/a-medical-mystery.html

It appears that many of those who read them were unable to extract the core argument, and few people seem to have found them interesting.

They seem extremely important to me. Somewhere between a possible palliative for some cases of Chronic Fatigue Syndrome, and a panacea for most of the remaining unexplained diseases of the world.

So here I've made the core argument as plain as I can. But obviously it misses out many details. Please read the original posts to see what I'm really saying. They were written as I thought, and the idea has crystallised somewhat in the process of arguing about it with friends and contributors to Less Wrong. In particular I am indebted to the late Broda Barnes for the connection with diabetes, which I found in his book 'Hypothyroidism: The Unsuspected Illness', and which makes the whole thing look rather more plausible.

---

CORE ARGUMENT

(1.1) Hypothyroidism is a disease with very variable symptoms, which can present in many different ways.
It is an endocrine hormone disease, which causes the metabolism to run slow. A sort of general systems failure. Which parts fail first seems random.
It is extraordinarily difficult to diagnose by clinical symptoms.

(1.2) Chronic Fatigue Syndrome and Fibromyalgia look very like possible presentations of Hypothyroidism

(1.3) The most commonly used blood test (TSH) for Hypothyroidism is negative in CFS/FMS

=>

EITHER

(2.1) CFS/FMS/Hypothyroidism are extremely similar diseases which are nevertheless differently caused.

OR

(2.2) The blood test is failing to detect many cases of Hypothyroidism.

---

It seems that one is either forced to accept (2.1), or to believe that blood hormone levels can be normal in the presence of Hypothyroidism.

There is precedent for this:

Diabetes, another endocrine disorder (this time the hormone is insulin), comes in two forms:

type I : the hormone producing gland is damaged, the blood hormone levels go wrong.         (Classical Diabetes)
type II: the blood hormone levels are normal, but for some reason the hormone does not act. (Insulin Resistance)

I therefore hypothesize:

(3) That there is at least one mechanism interfering with the action of the thyroid hormones on the cells.

and

(4) The same, or similar mechanisms can interfere with the actions of other hormones.

A priori, I'd give these hypotheses a starting chance of 1%. They do not seem unreasonable. In fact they are obvious.
The strongest evidence against them is that they are so very obvious, and yet not believed by those whose job it is to decide.

---

CURRENT STATUS  (Estimated probability)

(1.1) Uncontroversial, believed by everyone involved (~100%)

(1.2) Similarly uncontroversial (~100%)

(1.3) By definition. With abnormal TSH, you'd have hypothyroidism (~100%)

(2.1) Universal belief of conventional medicine and medical science, some alternative medicine disagrees (~90%)

(2.2) The idea that the TSH test is inaccurate is widely believed in alternative medicine, and by thyroid patient groups, but largely rejected by conventional medicine (~10%)

(3) There is some evidence from alternative medicine that this might be true (~10%)

(4) My own idea. A wild stab in the dark. But if it happens twice, you bet it happens thrice (~0.000001%)

---

Some Details

(1.1) Clinical diagnosis of Hypothyroidism is very out of fashion, considered hopelessly unreliable, doctors are actually trained to ignore the symptoms. There is a famous medical sin of 'Overdiagnosing Hypothyroidism', and doctors who fall into sin are regularly struck off.

(1.2) I don't think you'll find anyone who knows about both diseases to dispute this.

(1.3) True by definition. CFS/FMS symptoms plus abnormal TSH would be Hypothyroidism proper, almost no-one would disagree.

(2.1) This is the belief of conventional medicine. But the cause of CFS/FMS is unknown.
Generally the symptoms are blamed on 'stress', but 'stress' seems to be 'that which causes disease'. This 'explanation' seems to be doing little explanatory work. In fact it looks like magical thinking to me.
Medical Scientists know much more about all this than I do, and they believe it.
On the other hand, scientific ideas without verified causal chains often turn out to be wrong.

(2.2) (The important bit: If the TSH test is not solid, there are a number of interesting consequences.)

I've been looking for a few months through the endocrinological literature for evidence that the sensitivity of the TSH test was properly checked before its introduction or since, and I can't find any. It seems to have been an unjustified assumption. At the very least, my medical literature search skillz are not up to it. I appeal for help to those with better skillz.

It is beyond doubt that atrophy or removal of the thyroid gland causes the TSH value to go extremely high, and such cases are uncontroversial.

The actual interpretation of the TSH test is curiously wooly.
It has proved very difficult to pin down the 'normal range' for TSH, and they have been arguing about it for nearly forty years, over which the 'normal range' has been repeatedly narrowed
The AACB report of 2012 concluded that the normal range was so narrow that huge numbers of people with no symptoms would be outside it, and this range is not widely accepted for obvious reasons

There are many other possible blood hormone tests for hypothyroidism. All are considered to be less accurate or less sensitive than the TSH test. It does seem to be the best available blood test. It does not correlate particularly well with clinical symptoms.

(3) Broda Barnes, a conventional endocrinologist working before the introduction of reliable blood tests, was convinced that the most accurate test was the peripheral basal body temperature on waking.
He considered measuring the basal metabolic rate, and rejected it for good reasons. He considered that desiccated thyroid was a good treatment for the disease, and thought the disease very common. He estimated its prevalence at 40% in the American population. His work is nowadays considered obsolete, and ignored. But he seems to have been a careful, thoughtful scientist, and the best arguments against his conclusions are placebo-effect and confirmation bias. He treated thousands of patients, his treatments were not controversial at the time, and he reported great success. He wrote a popular book 'Hypothyroidism: The Unsuspected Illness', and his conclusions have fathered a large and popular alternative medicine tradition.

John Lowe, a chiropractor who claimed that fibromyalgia could be cured with desiccated thyroid, found that many (25%) of his patients did not respond to the treatment. He hypothesised peripheral resistance, thought it genetic, and used very high doses of the thyroid hormone T3 on many of his patients, which should have killed them. I have read many of his writings, they seem thoughtful and sane. I am not aware of any case in which John Lowe is thought to have done harm. There must be some, even if he was right. But if he was wrong he should have killed many of his patients, including himself. He was either a liar, or a serial murderer, or he was right. He was likely seeing an extremely biased sample of patients, those who could not be helped by conventional approaches.

(4) I just made it up by analogy.
There is the curious concept of 'adrenal fatigue', widespread in alternative medicine but dismissed as fantasy outside it, where the adrenal glands (more endocrine things) are supposed to be 'tired out' by 'excessive stress'. That could concievably be explained by peripheral resistance to adrenal hormones.

---

CONSEQUENCES

If (3) is true but (4) is not:

There are a number of mysterious 'somatoform' disorders, collectively known as the central sensitivity syndromes, with many symptoms in common, which could be explained as type 2 hypothyroidism. Obvious cases are Chronic Fatigue Syndrome, Fibromyalgia Syndrome, Major Depressive Disorder, Irritable Bowel Syndrome, but there are many others. Taken together they would explain Broda Barnes' estimate of 40% of Americans.

If (4) is true:

Then we can probably explain most of the remaining unexplained human diseases as endocrine resistance disorders.

---

HOW CAN THIS BE TRUE, BUT HAVE BEEN MISSED?

This is the million-dollar question!

My favourite explanation is that in order to overwhelm 'peripheral resistance to thyroid hormones', one needs to give the patient both T4 and T3 in exactly the right proportions and dose.

Supplementation with T4 alone will not increase the levels of T3 in the system, since the conversion is under the body's normal control, and the body defends T3 levels.

But T3 is the 'active hormone'. Without significantly increasing the circulating levels of T3, the resistance cannot be overwhelmed.

On the other hand, any significant overdosing of T3 will massively overstimulate the body, causing the extremely unpleasant symptoms of hyperthyroidism.

This seems to me to be sufficient explanation for why various trials of T4 supplementation on the central sensitivity disorders have all failed. In almost all cases, the patients will either have seen no improvement, or have experienced the symptoms of over-treatment. Only in very few cases will any improvement have occured, and standard trials are not designed to detect such effects.

It is actually just luck that the T4/T3 proportion in desiccated thyroid is about right for some people.

Alternatively, there may just be some component in desiccated thyroid whose action we don't understand.

---

PERSONAL EXPERIENCE

I displayed symptoms of mild-to-moderate Chronic Fatigue Syndrome, and my wonderful NHS GP checked everything it could possibly be. All my blood tests normal, TSH=2.51. I was heading for a diagnosis of CFS.

After four months I mysteriously partially recovered after trying the iron/vitamin B supplement Floradix, even though I wasn't anaemic.

I started researching on the basis that things that go away on their own tend to come back on their own.

I noticed that I had recorded, in records kept at the time of the illness, thirty out of a list of forty possible symptoms of Hypothyroidism, drew the obvious conclusions as so many other have, and purchased a supply of desiccated thyroid in case it came back.

It did come back, and after one month, I began to self-treat with desiccated thyroid, very carefully titrating small doses against symptoms, and quickly noted immediate huge improvement in all symptoms. In fact I'd say they were gone.

My basal temperature rose over a few weeks from 36.1 to ~36.6 (average, rise slow over several weeks, noise ~ +-0.3 day to day).

One week, holding the dose steady in anticipation of more blood tests, I overdid it by the truly minute amount of 3mg/day of desiccated thyroid, which caused all of the symptoms of the manic phase of bipolar disorder (whose down phase is indistinguishable from CFS, and whose up phase looks terribly like the onset of hyperthyroidism), The manic symptoms disappeared within twelve hours of ceasing thyroid supplementation, to be replaced by overwhelming tiredness.

I resumed thyroid supplementation at a slightly lower dose, and feel as well as I have done for ten years. It's now been ten weeks and I am becoming reasonably confident that it is having some effect.

---

POSSIBLE CAUSATION

Such catastrophic failures of the body's central control system CANNOT be evolutionarily stable unless they are extremely rare or have compensating advantages.

I am thus drawn to the idea of either:

(a) recent environmental change (which seems to be the alternative medicine explanation)

(b) immune defence (which would explain why e.g. CFS often presents as extended version of the normal post-viral fatigue)

---

STRONG PREDICTIONS
Low Body Temperature

It is a very strong prediction of this theory that low basal metabolic rates, and thus low basal peripheral temperatures will be found in many sufferers of Chronic Fatigue Syndrome and Fibromyalgia.
If this is not true, then the idea is refuted unambiguously.

Thyroid Hormone Supplementation as Palliative
It is a less strong prediction, but still fairly strong, that supplementation of the hormones T4 and T3 in carefully titrated doses and proportions will relieve some of the symptoms of CFS/FMS.

Note that T4 supplementation alone is unlikely to work. And that unless the doses and proportions are carefully adjusted to relieve symptoms, the treatment is likely to either not work, or be worse than the disease!

---

SOME SELECTED POSSIBLE IMPLICATIONS / PREDICTIONS
I've been very reluctant to draw my wilder speculative conclusions in public, since they have the potential to do great harm whether or not the idea is true, but here are some of the less frightening ones that I feel safe stating:

I state them only to encourage people to believe that this problem is worth thinking about.

Endocrinology appears not to be too interested, and my crank emails to endocrinologists have gone unanswered.

One of the reasons that I feel safe stating these three in public is that Broda Barnes thought them obvious and published popular books about them, so they are unlikely to come as a surprise to anyone outside endocrinology:

Dieting/Exercise/Weight Loss

Dieting and Exercise don't work long term as treatments for weight loss. The function of the thyroid system is to adapt metabolism to available resources. Starvation will cause mild transient hypothyroidism as the body attempts to survive the famine it infers. This may be the explanation for Anorexia Nervosa.

Diabetes

Diagnosis of diabetes was once a death sentence. With the discovery of insulin, allowing diabetics to control their blood sugar levels, it became survivable.
However it still has terrible complications, a lot of which look like the complications of hypothyroidism.

If a hormone-resistance mechanism interferes with both insulin and thyroid hormones, the reason for this is obvious. Diabetics with well-controlled blood sugar are dying in their millions from a treatable condition.

Heart Disease

One of the very old tests for hypothyroidism was blood cholesterol. It was thought to be a reliable indicator of hypothyroidism if present, but it was not always present.

A known symptom of hypothyroidism is atherosclerosis and weakness of the heart.

I would imagine that hypothyroidism initially presents as low blood pressure, due to the weakness of the heart. As the arteries clog, the weakened heart is forced to work harder and harder. Blood pressure goes higher and higher, and eventually the heart collapses under the strain.

Blood pressure reducing medications may actually be doing harm. A promising treatment might be to correct the underlying hypothyroidism.

Smoking

Cigarettes are full of poisons, and smoking is correlated with very many diseases.

It could be that smoking causes amongst its effects peripheral resistance, which causes clinical hypothyroidism, which then causes everything it usually causes. And that would be my bet!

It could be that hypothyroidism causes a very great number of bad things, including depression, which then causes smoking.

Smoking may not actually be that dangerous, and it might be possible to mitigate its bad effects.

---

I'm going to stop there. There are quite a lot of similar conclusions to be drawn. Read Barnes.

I also have some novel ones of my own which I am not telling anyone about just yet.

What the hell do I, or any of the quacks who have been screaming about this for forty years, have to say in order that someone with real expertise in this area takes this idea seriously enough to have a go at refuting it?

Meta

OK, probably everything I've written recently is ravings.

Sorry about that!

Thyroid Hormones, Chronic Fatigue and Fibromyalgia: A Hypothesis and a Proposed Experiment

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]

A Medical Mystery : Chronic Fatigue, Fibromyalgia and the Thyroid Hormones

I'm sorry that I haven't posted much recently. I have been very ill. I am quite recovered now.

I believe that I've come across a genuine puzzle, and I wonder if you can help me solve it. This problem is complicated, and subtle, and has confounded and defeated good people for forty years. And yet there are huge and obvious clues. No-one seems to have conducted the simple experiments which the clues suggest, even though many clever people have thought hard about it, and the answer to the problem would be very valuable. And so I wonder what it is that I am missing.

I am going to tell a story which rather extravagantly privileges a hypothesis that I have concocted from many different sources, but a large part of it is from the work of the late Doctor John C Lowe, an American chiropractor who claimed that he could cure Fibromyalgia.

I myself am drowing in confirmation bias to the point where I doubt my own sanity. Every time I look for evidence to disconfirm my hypothesis, I find only new reasons to believe. But I am utterly unqualified to judge. Three months ago I didn't know what an amino acid was. And so I appeal to wiser heads for help.

Setting the Scene

Chronic Fatigue Syndrome, Myalgic Encephalitis, and Fibromyalgia are 'new diseases'. There is considerable dispute as to whether they even exist, and if so how to diagnose them. They all seem to have a large number of possible symptoms, and in any given case, these symptoms may or may not occur with varying severity.

As far as I can tell, if someone claims that they're 'Tired All The Time', then a competent doctor will first of all check that they're getting enough sleep and are not unduly stressed, then rule out all of the known diseases that cause fatigue (there are a very lot!), and finally diagnose one of the three 'by exclusion', which means that there doesn't appear to be anything wrong, except that you're ill.

If widespread pain is one of the symptoms, it's Fibromyalgia Syndrome (FMS). If there's no pain, then it's CFS or ME. These may or may not be the same thing, but Myalgic Encephalitis is preferred by patients because it's greek and so sounds like a disease. Unfortunately Myalgic Encephalitis means 'hurty muscles brain inflammation', and if one had hurty muscles, it would be Fibromyalgia, and if one had brain inflammation, it would be something else entirely.

Despite the widespread belief that these are 'somatoform' diseases (all in the mind), the severity of them ranges from relatively mild (tired all the time, can't think straight), to devastating (wheelchair bound, can't leave the house, can't open one eye because the pain is too great).

All three seem to have come spontaneously into existence in the 1970s, and yet searches for the responsible infective agent have proved fruitless. Neither have palliative measures been discovered, apart from the tried and true method of telling the sufferers that it's all in their heads.

The only treatments that have proved effective are Cognitive Behavioural Therapy / Graded Exercise. A Cochrane Review reckoned that they do around 15% over placebo in producing a measurable alleviation of symptoms. I'm not very impressed. CBT/GE sound a lot like 'sports coaching', and I'm pretty sure that if we thought of 'Not Being Very Good at Rowing' as a somatoform disorder, then I could produce an improvement over placebo in a measurable outcome in ten percent of my victims without too much trouble.

But any book on CFS will tell you that the disease was well known to the Victorians, under the name of neurasthenia. The hypothesis that God lifted the curse of neurasthenia from the people of the Earth as a reward for their courage during the wars of the early twentieth century, while well supported by the clinical evidence, has a low prior probability.

We face therefore something of a mystery, and in the traditional manner of my people, a mystery requires a Just-So Story:

How It Was In The Beginning

In the dark days of Victoria, the brilliant physician William Miller Ord noticed large numbers of mainly female patients suffering from late-onset cretinism.

These patients, exhausted, tired, stupid, sad, cold, fat and emotional, declined steeply, and invariably died.

As any man of decent curiosity would, Dr Ord cut their corpses apart, and in the midst of the carnage noticed that the thyroid, a small butterfly-shaped gland in the throat, was wasted and shrunken.

One imagines that he may have thought to himself: "What has killed them may cure them."

After a few false starts and a brilliant shot in the dark by the brave George Redmayne Murray, Dr Ord secured a supply of animal thyroid glands (cheaply available at any butcher, sautée with nutmeg and basil) and fed them to his remaining patients, who were presumably by this time too weak to resist.

They recovered miraculously, and completely.

I'm not sure why Dr Ord isn't better known, since this appears to have been the first time in recorded history that something a doctor did had a positive effect.

Dr Ord's syndrome was named Ord's Thyroiditis, and it is now known to be an autoimmune disease where the patient's own antibodies attack and destroy the thyroid gland. In Ord's thyroiditis, there is no goiter.

A similar disease, where the thyroid swells to form a disfiguring deformity of the neck (goiter), was described by Hakaru Hashimoto in 1912 (who rather charmingly published in German), and as part of the war reparations of 1946 it was decided to confuse the two diseases under the single name of Hashimoto's Thyroiditis. Apart from the goiter, both conditions share a characteristic set of symptoms, and were easily treated with animal thyroid gland, with no complications.

Many years before, in 1835, a fourth physician, Robert James Graves, had described a different syndrome, now known as Graves' Disease, which has as its characteristic symptoms irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhoea, and weight loss. Unfortunately Dr Graves could not think how to cure his eponymous horror, and so the disease is still named after him.

The Horror Spreads

Victorian medicine being what it was, we can assume that animal glands were sprayed over and into any wealthy person unwise enough to be remotely ill in the vicinity of a doctor. I seem to remember a number of jokes about "monkey glands" in PG Wodehouse, and indeed a man might be tempted to assume that chimpanzee parts would be a good substitute for humans. Supply issues seem to have limited monkey glands to a few millionaires worried about impotence, and it may be that the corresponding procedure inflicted on their wives has come down to us as Hormone Replacement Therapy.

Certainly anyone looking a bit cold, tired, fat, stupid, sad or emotional is going to have been eating thyroids. We can assume that in a certain number of cases, this was just the thing, and I think it may also be safe to assume that a fair number of people who had nothing wrong with them at all died as a result of treatment, although the fact that animal thyroid is still part of the human food chain suggests it can't be that dangerous.

I mean seriously, these people use high pressure hoses to recover the last scraps of meat from the floors of slaughterhouses, they're not going to carefully remove all the nasty gristly throat-bits before they make ready meals, are they?

The Armour Sausage company, owner of extensive meat-packing facilities in Chicago, Illinois, and thus in possession of a large number of pig thyroids which, if not quite surplus to requirements, at the very least faced a market sluggish to non-existent as foodstuffs, brilliantly decided to sell them in freeze-dried form as a cure for whatever ails you.


Some Sort of Sanity Emerges, in a Decade not Noted for its Sanity

Around the time of the second world war, doctors became interested in whether their treatments actually helped, and an effort was made to determine what was going on with thyroids and the constellation of sadness that I will henceforth call 'hypometabolism', which is the set of symptoms associated with Ord's thyroiditis. Jumping the gun a little, I shall also define 'hypermetabolism' as the set of symptoms associated with Graves' disease.

The thyroid gland appeared to be some sort of metabolic regulator, in some ways analogous to a thermostat. In hypometabolism, every system of the body is running slow, and so it produces a vast range of bad effects, affecting almost every organ. Different sufferers can have very different symptoms, and so diagnosis is very difficult.

Dr Broda Barnes decided that the key symptom of hypometabolism was a low core body temperature. By careful experiment he established that in patients with no symptoms of hypometabolism the average temperature of the armpit on waking was 98 degrees Fahrenheit (or 36.6 Celsius). He believed that temperature variation of +/- 0.2 degrees Fahrenheit was unusual enough to merit diagnosis. He also seems to have believed, in the manner of the proverbial man with a hammer, that all human ailments without exception were caused by hypometabolism, and to have given freeze-dried thyroid to almost everyone he came into contact with, to see if it helped. A true scientist. Doctor Barnes became convinced that fully 40% of the population of America suffered from hypometabolism, and recommended Armour's Freeze Dried Pig Thyroid to cure America's ills.

In a brilliant stroke, Freeze Dried Pig's Thyroid was renamed 'Natural Dessicated Thyroid', which almost sounds like the sort of thing you might take in sound mind. I love marketing. It's so clever.

America being infested with religious lunatics, and Chicago being infested with nasty useless gristly bits of cow's throat, led almost inevitably to a second form of 'Natural Dessicated Thyroid' on the market.

Dr Barnes' hypometabolism test never seems to have caught on. There are several ways your temperature can go outside his 'normal' range, including fever (too hot), starvation (too cold), alcohol (too hot), sleeping under too many duvets (too hot), sleeping under too few duvets (too cold). Also mercury thermometers are a complete pain in the neck, and take ten minutes to get a sensible reading, which is a long time to lie around in bed carefully doing nothing so that you don't inadvertently raise your body temperature. To make the situation even worse, while men's temperature is reasonably constant, the body temperature of healthy young women goes up and down like the Assyrian Empire.

Several other tests were proposed. One of the most interesting is the speed of the Achilles Tendon Reflex, which is apparently super-fast in hypermetabolism, and either weirdly slow or has a freaky pause in it if you're running a bit cold. Drawbacks of this test include 'It's completely subjective, give me something with numbers in it', and 'I don't seem to have one, where am I supposed to tap the hammer-thing again?'.

By this time, neurasthenia was no longer a thing. In the same way that spiritualism was no longer a thing, and the British Empire was no longer a thing.

As far as we know, Chronic Fatigue Syndrome was not a thing either, and neither was Fibromyalgia (which is just Chronic Fatigue Syndrome but it hurts), nor Myalgic Encephalitis. There was something called 'Myalgic Neurasthenia' in 1934, but it seems to have been a painful infectious disease and they thought it was polio.


Finally, Science

It turned out that the purpose of the thyroid gland is to make hormones which control the metabolism. It takes in the amino acid tyrosine, and it takes in iodine. It releases Thyroglobulin, mono-iodo-tyrosine (MIT), di-iodo-tyrosine (DIT), thyroxine (T4) and triiodothyronine (T3) into the blood. The chemistry is interesting but too complicated to explain in a just-so story.

I believe that we currently think that thyroglobulin, MIT and DIT are simply by-products of the process that makes T3 and T4.

T3 is the hormone. It seems to control the rate of metabolism in all cells. T4 has something of the same effect, but is much less active, and called a 'prohormone'. Its main purpose seems to be to be deiodinated to make more T3. This happens outside the thyroid gland, in the other parts of the body ('peripheral conversion'). I believe mainly in the liver, but to some extent in all cells.

Our forefathers knew about thyroxine (T4, or thyronine-with-four-iodines-attached), and triiodothyronine (T3, or thyronine-with-three-iodines-attached)

It seems to me that just from the names, thyroxine was the first one to be discovered. But I'm not sure about that. You try finding a history-of-endocrinology website. At any rate they seem to have known about T4 and T3 fairly early on.

The mystery of Graves', Ord's and Hashimoto's thyroid diseases was explained.

Ord's and Hashimoto's are diseases where the thryoid gland under-produces (hypothyroidism). The metabolism of all cells slows down. As might be expected, this causes a huge number of effects, which seem to manifest differently in different sufferers.

Graves' disease is caused by the thyroid gland over-producing (hyperthyroidism). The metabolism of all cells speeds up. Again, there are a lot of possible symptoms.

All three are thought to be autoimmune diseases. Some people think that they may be different manifestations of the same disease. They are all fairly common.

Dessicated thryoid cures hypothyroidism because the ground-up thyroids contain T4 and T3, as well as lots of thyroglobulin, MIT and DIT, and they are absorbed by the stomach. They get into the blood and speed up the metabolism of all cells. By titrating the dose carefully you can restore roughly the correct levels of the thyroid hormones in all tissues, and the patient gets better. (Titration is where you change something carefully until you get it right)

The theory has considerable explanatory power. It explains cretinism, which is caused either by a genetic disease, or by iodine deficiency in childhood. If you grow up in an iodine deficient area, then your growth is stunted, your brain doesn't develop properly, and your thyroid gland may become hugely enlarged. Presumably because the brain is desperately trying to get it to produce more thyroid hormones, and it responds by swelling.

Once upon a time, this swelling (goitre) was called 'Derbyshire Neck'. I grew up near Derbyshire, and I remember an old rhyme: "Derbyshire born, Derbyshire bred, strong in the arm, and weak in the head". I always thought it was just an insult. Maybe not. Cretinism was also popular in the Alps, and there is a story of an English traveller in Switzerland of whom it was remarked that he would have been quite handsome if only he had had a goitre. So it must have been very common there.

But at this point I am *extremely suspicious*. The thyroid/metabolic regulation system is ancient (universal in vertebrates, I believe), crucial to life, and it really shouldn't just go wrong. We should suspect either an infectious cause, or a recent environmental influence which we haven't had time to adjust to, an evolved defence against an infectious disease, or just possibly, a recently evolved but as yet imperfect defence against a less recent environmental change.

(Cretinism in particular is very strange. Presumably animals in iodine-deficient areas aren't cretinous, and yet they should be. Perhaps a change to a farming from a hunter-gatherer lifestyle has increased our dependency on iodine from crops, which crops have sucked what little iodine occurs naturally out of the soil?)

It's also not entirely clear to me what the thyroid system is *for*. If there's just a particular rate that cells are supposed to run at, then why do they need a control signal to tell them that? I could believe that it was a literal thermostat, designed to keep the body temperature constant at the best speed for the various biological reactions, but it's universal in *vertebrates*. There are plenty of vertebrates which don't keep a constant temperature.


The Fall of Dessicated Thyroid

There turned out to be some problems with Natural Dessicated Thyroid (NDT).

Firstly, there were many competing brands and types, and even if you stuck to one brand the quality control wasn't great, so the dose you'd be taking would have been a bit variable.

Secondly, it's fucking pig's thyroid from an abattoir. It could have all sorts of nasty things in it. Also, ick.

Thirdly, it turned out that pigs made quite a lot more T3 in their thyroids than humans do. It also seems that T3 is better absorbed by the gut than T4 is, so someone taking NDT to compensate for their own underproduction will have too much of the active hormone compared to the prohormone. That may not be good news.

With the discovery of 'peripheral conversion', and the possibility of cheap clean synthesis, it was decided that modern scientific thyroid treatment would henceforth be by synthetic T4 (thyroxine) alone. The body would make its own T3 from the T4 supply.

Alarm bells should be ringing at this point. Apart from the above points, I'm not aware of any great reason for the switch from NDT to thyroxine in the treatment of hypothyroidism, but it seems to have been pretty much universal, and it seems to have worked.

Aware of the lack of T3, doctors compensated by giving people more T4 than was in their pig-thyroid doses. And there don't seem to have been any complaints.

Over the years, NDT seems to have become a crazy fringe treatment despite there not being any evidence against it. It's still a legal prescription drug, but in America it's only prescribed by eccentrics. In England a doctor prescribing it would be, at the very least, summoned to explain himself before the GMC.

However, since it was (a) sold over the counter for so many years, and (b) part of the food chain, it is still perfectly legal to sell as a food supplement in both countries, as long as you don't make any medical claims for it. And the internet being what it is, the prescription-only synthetic hormones T3 and T4 are easily obtained without a prescription. These are extremely powerful hormones which have an effect on metabolism. If 'body-builders' and sports cheats aren't consuming all three in vast quantities, I am a Dutchman.

The Clinical Diagnosis of Hypothyroidism

We pass now to the beginning of the 1970s.

Hypothyroidism is ferociously difficult to diagnose. People complain of 'Tired All The Time' well, ... all the time, and it has literally hundreds of causes.

And it must be diagnosed correctly! If you miss a case of hypothyroidism, your patient is likely to collapse and possibly die at some point in the medium-term future. If you diagnose hypothyroidism where it isn't, you'll start giving the poor bugger powerful hormones which he doesn't need and *cause* hypermetabolism.

The last word in 'diagnosis by symptoms' was the absolutely excellent paper:

Statistical Methods Applied To The Diagnosis Of Hypothyroidism by W. Z. Billewicz et al.

Connoisseurs will note the clever and careful application of 'machine learning' techniques, before there were machines to learn!

One important thing to note is that this is a way of separating hypothyroid cases from other cases of tiredness at the point where people have been referred by their GP to a specialist at a hospital on suspicion of hypothyroidism. That changes the statistics remarkably. This is *not* a way of diagnosing hypothyroidism in the general population. But if someone's been to their GP (general practitioner, the doctor that a British person likely makes first contact with) and their GP has suspected their thryoid function might be inadequate, this test should probably still work.

For instance, they consider Physical Tiredness, Mental Lethargy, Slow Cerebration, Dry Hair, and Muscle Pain, the classic symptoms of hypothyroidism, present in most cases, to be indications *against* the disease.

That's because if you didn't have these things, you likely wouldn't have got that far. So in the population they're seeing (of people whose doctor suspects they might be hypothyroid), they're not of great value either way, but their presence is likely the reason why the person's GP has referred them even though they've really got iron-deficiency anaemia or one of the other causes of fatigue.

In their population, the strongest indicators are 'Ankle Jerk' and 'Slow Movements', subtle hypothyroid symptoms which aren't likely to be present in people who are fatigued for other reasons.

But this absolutely isn't a test you should use for population screening! In the general population, the classic symptoms are strong indicators of hypothyroidism.

Probability Theory is weird, huh?

Luckily, there were lab tests for hypothyroidism too, but they were expensive, complicated, annoying and difficult to interpret. Billewicz et al used them to calibrate their test, and recommend them for the difficult cases where their test doesn't give a clear answer.

And of course, the final test is to give them thyroid treatment and see whether they get better. If you're not sure, go slow, watch very carefully and look for hyper symptoms.

Overconfidence is definitely the way to go. If you don't diagnose it and it is, that's catastrophe. If it isn't, but you diagnose it anyway, then as long as you're paying attention the hyper symptoms are easy enough to spot, and you can pull back with little harm done.

A Better Way

It should be obvious from the above that the diagnosis of hypothyroidism by symptoms is absolutely fraught with complexity, and very easy to get wrong, and if you get it wrong the bad way, it's a disaster. Doctors were absolutely screaming for a decisive way to test for hypothyroidism.

Unfortunately, testing directly for the levels of thyroid hormones is very difficult, and the tests of the 1960s weren't accurate enough to be used for diagnosis.

The answer came from an understanding of how the thyroid regulatory system works, and the development of an accurate blood test for a crucial signalling hormone.

Three structures control the level of thyroid hormones in the blood.

The thyroid gland produces the hormones and secretes them into the blood.

Its activity is controlled by the hormone thyrotropin, or Thyroid Signalling Hormone (TSH). Lots of TSH works the thyroid hard. In the absence of TSH the thyroid relaxes but doesn't switch off entirely. However the basal level of thyroid activity in the absence of TSH is far too low.

TSH is controlled by the pituitary gland, a tiny structure attached to the brain.

The pituitary itself is controlled, via Thyroid Releasing Hormone (TRH), by the hypothalamus, which is part of the brain.

This was thought to be a classic example of a feedback control system.

hypothalamus->pituitary->thyroid

It turns out that the level of thyrotropin TSH in the blood is exquisitely sensitive to the levels of thyroid hormones in the blood.

Administer thyroid hormone to a patient and their TSH level will rapidly adjust downwards by an easily detectable amount.

So:

In hypothyroidism, where the thyroid has failed, the body will be desperately trying to produce more thyroid hormones, and the TSH level will be extremely high.

In Graves' Disease, this theory says, where the thyroid has grown too large, and the metabolism is running damagingly fast, the body will be, like a central bank trying to stimulate growth in a deflationary economy by reducing interest rates, 'pushing on a piece of string'. TSH will be undetectable.

The original TSH test was developed in 1965, by the startlingly clever method of radio-immuno-assay.

[For reasons that aren't clear to me, rather than being expressed in grams/litre, or mols/litre, the TSH test is expressed in 'international units/liter'. But I don't think that that's important]

A small number of people in whom there was no suspicion of thyroid disease were assessed, and the 'normal range' of TSH was calculated.

Again, 'endocrinology history' resources are not easy to find, but the first test was not terribly sensitive, and I think originally hyperthyroidism was thought to result in a complete absence of TSH, and that the highest value considered normal was about 4 (milli-international-units/liter).

This apparently pretty much solved the problem of diagnosing thyroid disorders.

Forgetfulness

It's no longer necessary to diagnose hypo- and hyper-thyroidism by symptoms. It was error prone anyway, and the question is easily decided by a cheap and simple test.

Natural Dessicated Thyroid is one with Nineveh and Tyre.

No doctor trained since the 1980s knows much about hypothyroid symptoms.

Medical textbooks mention them only in passing, as an unweighted list of classic symptoms. You couldn't use that for diagnosis of this famously difficult disease.

If you suspect hypothyroidism, you order a TSH test. If the value of TSH is very low, that's hyperthyroidism. If the value is very high then that's hypothyroidism. Otherwise you're 'euthyroid' (greek again, good-thyroid), and your symptoms are caused by some other problem.

The treatment for hyperthyroidism is to damage the thyroid gland. There are various ways. This often results in hypothyroidism. *For reasons that are not terribly well understood*.

The treatment for hypothyroidism is to give the patient sufficient thyroxine (T4) to cause TSH levels to come back into their normal range.

The conditions hyperthyroidism and hypothyroidism are now *defined* by TSH levels.

Hypothyroidism, in particular, a fairly common disease, is considered to be such a solved problem that it's usually treated by the GP, without involving any kind of specialist.


Present Day

It was found that the traditional amount of thyroxine (T4) administered to cure hypothyroid patients, was in fact too high. The amount of T4 that had always been used to replace the hormones that had once been produced by a thyroid gland now dead, destroyed, or surgically removed appeared now to be too much. That amount causes suppression of TSH to below its normal range. The brain, theory says, is asking for the level to be reduced.

The amount of T4 administered in such cases (there are many) has been reduced by a factor of around two, to the level where it produces 'normal' TSH levels in the blood. Treatment is now titrated to produce the normal levels of TSH.

TSH tests have improved enormously since their introduction, and are on their third or fourth generation. The accuracy of measurement is very good indeed.

It's now possible to detect the tiny remaining levels of TSH in overtly hyperthyroid patients, so hyperthyroidism is also now defined by the TSH test.

In England, the normal range is 0.35 to 5.5. This is considered to be the definition of 'euthyroidism'. If your levels are normal, you're fine.

If you have hypothyroid symptoms but a normal TSH level, then your symptoms are caused by something else. Look for Anaemia, look for Lyme Disease. There are hundreds of other possible causes. Once you rule out all the other causes, then it's the mysterious CFS/FMS/ME, for which there is no cause and no treatment.

If your doctor is very good, very careful and very paranoid, he might order tests of the levels of T4 and T3 directly. But actually the direct T4 and T3 tests, although much more accurate than they were in the 1960s, are quite badly standardised, and there's considerable controversy about what they actually measure. Different assay techniques can produce quite different readings. They're expensive. It's fairly common, and on the face of it perfectly reasonable, for a lab to refuse to conduct the T3 and T4 tests if the TSH level is normal.

It's been discovered that quite small increases in TSH actually predict hypothyroidism. Minute changes in thyroid hormone levels, which don't produce symptoms, cause detectable changes in the TSH levels. Normal, but slightly high values of TSH, especially in combination with the presence of thyroid related antibodies (there are several types), indicate a slight risk of one day developing hypothyroidism.

There's quite a lot of controversy about what the normal range for TSH actually is. Many doctors consider that the optimal range is 1-2, and target that range when administering thyroxine. Many think that just getting the value in the normal range is good enough. None of this is properly understood, to understate the case rather dramatically.

There are new categories, 'sub-clinical hypothyroidism' and 'sub-clinical hyperthyroidism', which are defined by abnormal TSH tests in the absence of symptoms. There is considerable controversy over whether it is a good idea to treat these, in order to prevent subtle hormonal imbalances which may cause difficult-to-detect long term problems.

Everyone is a little concerned about accidentally over-treating people, (remember that hyperthyroidism is now defined by TSH<0.35).

Hyperthyroidism has long been associated with Atrial Fibrillation (a heart problem), and Osteoporosis, both very nasty things. A large population study in Denmark recently revealed that there is a greater incidence of Atrial Fibrillation in sub-clinical hyperthyroidism, and that hypothyroidism actually has a 'protective effect' against Atrial Fibrillation.

It's known that TSH has a circadian rhythm, higher in the early morning, lower at night. This makes the test rather noisy, as your TSH level can be doubled or halved depending on what time of day you have the blood drawn.

But the big problems of the 1960s and 1970s are completely solved. We are just tidying up the details.

Doubt

Many hypothyroid patients complain that they suffer from 'Tired All The Time', and have some of the classic hypothyroid symptoms, even though their TSH levels have been carefully adjusted to be in the normal range.

I've no idea how many, but opinions range from 'the great majority of patients are perfectly happy' to 'around half of hypothyroid sufferers have hypothyroid symptoms even though they're being treated'.

The internet is black with people complaining about it, and there are many books and alternative medicine practitioners trying to cure them, or possibly trying to extract as much money as possible from people in desperate need of relief from an unpleasant, debilitating and inexplicable malaise.

THE PLURAL OF ANECDOTE IS DATA.

Not good data, to be sure. But if ten people mention to you in passing that the sun is shining, you are a damned fool if you think you know nothing about the weather.

It's known that TSH ranges aren't 'normally distributed' (in the sense of Gauss/the bell curve distribution) in the healthy population.

If you log-transform them, they do look a bit more normal.

The American Academy of Clinical Biochemists, in 2003, decided to settle the question once and for all. They carefully screened out anyone with even the slightest sign that there might be anything wrong with their thyroid at all, and measured their TSH very accurately.

In their report, they said (this is a direct quote):

In the future, it is likely that the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L because >95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.

Many other studies disagree, and propose wider ranges for normal TSH.

But if the AACB report were taken seriously, it would lead to diagnosis of hypothyroidism in vast numbers of people who are perfectly healthy! In fact the levels of noise in the test would put people whose thyroid systems are perfectly normal in danger of being diagnosed and inappropriately treated.

For fairly obvious reasons, biochemists have been extremely, and quite properly, reluctant to take the report of their own professional body seriously. And yet it is hard to see where the AACB have gone wrong in their report.

Neurasthenia is back.

A little after the time of the introduction of the TSH test, new forms of 'Tired All The Time' were discovered.

As I said, CFS and ME are just two names for the same thing. Fibromyalgia Syndrome (FMS) is much worse, since it is CFS with constant pain, for which there is no known cause and from which there is no relief. Most drugs make it worse.

But if you combine the three things (CFS/ME/FMS), then you get a single disease, which has a large number of very non-specific symptoms.

These symptoms are the classic symptoms of 'hypometabolism'. Any doctor who has a patient who has CFS/ME/FMS and hasn't tested their thyroid function is *de facto* incompetent. I think the vast majority of medical people would agree with this statement.

And yet, when you test the TSH levels in CFS/ME/FMS sufferers, they are perfectly normal.

All three/two/one are appalling, crippling, terrible syndromes which ruin people's lives. They are fairly common. You almost certainly know one or two sufferers. The suffering is made worse by the fact that most people believe that they're psychosomatic, which is a polite word for 'imaginary'.

And the people suffering are mainly middle-aged women. Middle-aged women are easy to ignore. Especially stupid middle-aged women who are worried about being overweight and obviously faking their symptoms in order to get drugs which are popularly believed to induce weight loss. It's clearly their hormones. Or they're trying to scrounge up welfare benefits. Or they're trying to claim insurance. Even though there's nothing wrong with them and you've checked so carefully for everything that it could possibly be.

But it's not all middle aged women. These diseases affect men, and the young. Sometimes they affect little children. Exhaustion, stupidity, constant pain. Endless other problems as your body rots away. Lifelong. No remission and no cure.

And I have Doubts of my Own

And I can't believe that careful, numerate Billewicz and his co-authors would have made this mistake, but I can't find where the doctors of the 1970s checked for the sensitivity of the TSH test.

Specificity, yes. They tested a lot of people who hadn't got any sign of hypothyroidism for TSH levels. If you're well, then your TSH level will be in a narrow range, which may be 0-6, or it may be 1-2. Opinions are weirdly divided on this point in a hard to explain way.

But Sensitivity? Where's the bit where they checked for the other arm of the conditional?

The bit where they show that no-one who's suffering from hypometabolism, and who gets well when you give them Dessicated Thyroid, had, on first contact, TSH levels outside the normal range.

If you're trying to prove A <=> B, you can't just prove A => B and call it a day. You couldn't get that past an A-level maths student. And certainly anyone with a science degree wouldn't make that error. Surely? I mean you shouldn't be able to get that past anyone who can reason their way out of a paper bag.

I'm going to say this a third time, because I think it's important and maybe it's not obvious to everyone.

If you're trying to prove that two things are the same thing, then proving that the first one is always the second one is not good enough.

IF YOU KNOW THAT THE KING OF FRANCE IS ALWAYS FRENCH, YOU DO *NOT* KNOW THAT ANYONE WHO IS FRENCH IS KING OF FRANCE.

It's possible, of course, that I've missed this bit. As I say, 'History of Endocrinology' is not one of those popular, fashionable subjects that you can easily find out about.

I wonder if they just assumed that the thyroid system was a thermostat. The analogy is still common today.

But it doesn't look like a thermostat to me. The thyroid system with its vast numbers of hormones and transforming enzymes is insanely, incomprehensibly complicated. And very poorly understood. And evolutionarily ancient. It looks as though originally it was the system that coordinated metamorphosis. Or maybe it signalled when resources were high enough to undergo metamorphosis. But whatever it did originally in our most ancient ancestors, it looks as though the blind watchmaker has layered hack after hack after hack on top of it on the way to us.

Only the thyroid originally, controlling major changes in body plan in tiny creatures that metamorphose.

Of course, humans metamorphose too, but it's all in the womb, and who measures thyroid levels in the unborn when they still look like tiny fish?

And of course, humans undergo very rapid growth and change after we are born. Especially in the brain. Baby horses can walk seconds after they're born. Baby humans take months to learn to crawl. I wonder if that's got anything to do with cretinism.

And I'm told that baby humans have very high hormone levels. I wonder why they need to be so hot? If it's a thermostat, I mean.

But then on top of the thyroid, the pituitary. I wonder what that adds to the system? If the thyroid's just a thermostat, or just a device for keeping T4 levels constant, why can't it just do the sensing itself?

What evolutionary process created the pituitary control over the thyroid? Is that the thermostat bit?

And then the hypothalamus, controlling the pituitary. Why? Why would the brain need to set the temperature when the ideal temperature of metabolic reactions is always 37C in every animal? That's the temperature everything's designed for. Why would you dial it up or down, to a place where the chemical reactions that you are don't work properly?

I can think of reasons why. Perhaps you're hibernating. Many of our ancestors must have hibernated. Maybe it's a good idea to slow the metabolism sometimes. Perhaps to conserve your fat supplies. Your stored food.

Perhaps it's a good idea to slow the metabolism in times of famine?

Perhaps the whole calories in/calories out thing is wrong, and people whose energy expenditure goes over their calorie intake have slow metabolisms, slowly sacrificing every bodily function including immune defence in order to avoid starvation.

I wonder at the willpower that could keep an animal sane in that state. While its body does everything it can to keep its precious fat reserves high so that it can get through the famine.

And then I remember about Anorexia Nervosa, where young women who want to lose weight starve themselves to the point where they no longer feel hungry at all. Another mysterious psychological disease that's just put down to crazy females. We really need some female doctors.

And I remember about Seth Robert's Shangri-La Diet, that I tried, to see if it worked, some years ago, just because it was so weird, where by eating strange things, like tasteless oil and raw sugar, you can make your appetite disappear, and lose weight. It seemed to work pretty well, to my surprise. Seth came up with it while thinking about rats. And apparently it works on rats too. I wonder why it hasn't caught on.

It seems, my female friends tell me, that a lot of diets work well for a bit, but then after a few weeks the effect just stops. If we think of a particular diet as a meme, this would seem to be its infectious period, where the host enthusiastically spreads the idea.

And I wonder about the role of the thyronine de-iodinating enzymes, and the whole fantastically complicated process of stripping the iodines and the amino acid bits from thyroxine in various patterns that no-one understands, and what could be going on there if the thyroid system were just a simple thermostat.

And I wonder about reports I am reading where elite athletes are finding themselves suffering from hypothyroidism in numbers far too large to be credible, if it wasn't, say, a physical response to calorie intake less than calorie output.

I've been looking ever so hard to find out why the TSH test, or any of the various available thyroid blood tests are a good way to assess the function of this fantastically complicated and very poorly understood system.

But every time I look, I just come up with more reasons to believe that they don't tell you very much at all.


The Mystery

Can anyone convince me that the converse arm has been carefully checked?

That everyone who's suffering from hypometabolism, and who gets well when you give them Dessicated Thyroid, has, before you fix them, TSH levels outside the normal range.

In other words, that we haven't just thrown, though carelessness, a long standing, perfectly safe, well tested treatment, for a horrible disabling disease that often causes excruciating pain, that the Victorians knew how to cure, and that the people of the 1950s and 60s routinely cured, away.