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

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

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

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

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

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

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

Chronic Fatigue Syndrome often seems to start with an infection.

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

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

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

The first:

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

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

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

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

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

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

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

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

He mentions no adverse effects whatsoever.

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

This prompted a small trial:

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

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

This trial looks very well designed and established that:

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

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

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

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

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

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

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

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

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

The criteria for the formal trial were:

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

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

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

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

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

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

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

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

Can anyone explain these two studies in any other way?

Conclusion

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

At the very least, this should be investigated.

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

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

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

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