Random Thoughts: March 2016

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!

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?

Random Thoughts

Wednesday, March 23, 2016

Answer to g

Tuesday, March 22, 2016

In Defence of Simple Ideas That Explain Everything But Are Wrong

Monday, March 14, 2016

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

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