A Medical Mystery: Thyroid Hormones, Chronic Fatigue and Fibromyalgia

johnlawrenceaspden14 Feb 2016 13:14 UTC
43 points
166 comments23 min readLW linkArchive

Summary:

  • Chronic Fatigue and Fibromyalgia look very like Hypothyroidism.

  • Thyroid Patients aren’t happy with either the diagnosis or treatment of Hypothyroidism.

  • It is possible that lots of FMS/​CFS cases are ‘something wrong with the thyroid system that doesn’t show up on laboratory hormone level tests’.

  • It’s possible that it’s not too difficult to fix these CFS/​FMS cases with thyroid hormones.

  • I believe that there may have been a stupendous cock-up that’s hurt millions.

  • Less Wrong should be interested, because it could be a real example of how bad inference can cause the sciences to come to false conclusions, as well as a good practice problem for the things we really care about.

Edit:

I found a possible answer here: http://​​lesswrong.com/​​lw/​​nbm/​​thyroid_hormones_chronic_fatigue_and_fibromyalgia/​​
I do not believe it, because I do not understand it, but contemplation of it seems to be enlightening. In particular, the problem is much broader than I originally thought.

A summary of the argument in the first two posts, together with links to lots of evidence in the literature:

http://​​lesswrong.com/​​r/​​discussion/​​lw/​​nef/​​the_thyroid_madness_core_argument_evidence/​​

And this is pretty much proof, I think:

http://​​lesswrong.com/​​lw/​​nhs/​​the_thyroid_madness_two_apparently_contradictory/​​

At this point, I think I’m as confident as I can be without some sort of formal trial (so 25% maybe?)

But certainly, if you’re suffering from Chronic Fatigue Syndrome/​Fibromyalgia/​Major Depression/​Irritable Bowel Syndrome, or any of the many similar disorders which just seem to be different names for ‘hypothyroidism with normal TSH’, I reckon this is worth trying!

I have done, and it worked for me. For about four months now...

Original Post:

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 drowning 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.

Crocker’s Rules on this. I suspect that I am being the most spectacular fool, but I can’t see why, and I’d like to know.

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 Desiccated 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 Desiccated 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.

Desiccated 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 Desiccated Thyroid

There turned out to be some problems with Natural Desiccated 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, R. S. Chapman, J. Crooks, M. E. Day, J. Gossage, Sir Edward Wayne, and J. A. Young

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 Desiccated 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 Desiccated 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 Desiccated 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.

johnlawrenceaspden14 Feb 2016 13:14 UTC
43 points
166 comments23 min readLW linkArchive