Why is the Pollock trial evidence supporting your hypothesis? What outcome from the trial would you have considered to be evidence against it?
Also, what part suggests that the healthy controls could distinguish the treatment from placebo? From Table 4, it seems that the reverse is true.
At first glance, the results from that study look like straightforward evidence that this treatment is actively harmful. I’d also point out that RCTs need to be standardized across patients. I can’t say whether the inclusion criteria should have been different, but choosing a single dose is normal procedure. There are always better options, but it’s a weak argument on its own, in part because it can be applied in almost any circumstances.
Everyone who’s ever tried fixing the clinical diagnosis of hypothyroidism with any kind of thyroid therapy either seems to think it works, or hasn’t written about it on the internet or in the medical literature.
I admit I’m not an endocrinologist, but from what I’m reading I don’t think there is any recognized clinical diagnosis of hypothyroidism. The TSH test is the gold standard. That would suggest those who talk about it are primarily cranks and such.
That’s a big claim. I’m making it in bold on Less Wrong. I expect someone to turn up some evidence against it. I would love to see that evidence.
Less Wrong might not be the best place for this, since there aren’t many biologists here. You have the burden of proof (i.e., the prior for arbitrary hypotheses is very low), so you shouldn’t be asking other people to disprove it. Could you summarize your support for this claim? Are these the only two peer-reviewed articles?
Assuming he’s not just making up his data it’s hard to explain his results.
There are lots of ways that data can be wrong without being made up. 90% of medical research findings are false, etc.
Thank you so much, intelligent and careful criticism like this is exactly what I started posting on Less Wrong for!
Why is the Pollock trial evidence supporting your hypothesis?
Well, it’s only fairly weak evidence, but it does seem that the healthy controls reacted differently to the patient group.
What it really proves is that thyroxine isn’t just a nice recreational drug that everyone likes. Healthy people dislike it.
But it seems to have been less bad for the patients on average. So I imagine there were some people in the patient group who reacted well.
What I’m saying is that Skinner got strong evidence for the idea, and wanted it confirmed by PCRT (and I agree, that’s necessary).
So they did a PCRT, but not very well because they didn’t find patients carefully. And yet they seem to have supported him anyway, but everyone thinks that they refuted him, because they didn’t quite understand what he was saying.
What outcome from the trial would you have considered to be evidence against it?
If none of the patients had had any sort of thyroid problem, I’d have expected it to be equally bad for everyone. If that had been the result, then I’d have had to think that ‘type 2 hypothyroidism’ is rare, or that ‘fixed doses of thyroxine don’t fix it’. For a long time that’s exactly what I did think! I was assuming you might need T3 as well and you might need to adust the ratio carefully. Skinner and Pollock together make me think that it might be fairly common, and mostly fixable with T4 alone.
Also, what part suggests that the healthy controls could distinguish the treatment from placebo? From Table 4, it seems that the reverse is true.
That shows that when they were asked which was the active preparation, they couldn’t tell. They appear to have had a ‘nocebo’ effect, where they interpreted everything they felt as an effect of the drug. That’s as expected.
What makes me think that they felt bad on thyroxine is table 2, where all the ‘self-reported’ psychological scores have got worse from thyroxine. In particular p=0.007 for the decline in Vitality. Since, as you point out, they really didn’t know which was which, it’s hard to see how they could have faked that.
At first glance, the results from that study look like straightforward evidence that this treatment is actively harmful.
Absolutely this treatment is harmful to healthy people. It should cause ‘hypermetabolism’, which is unpleasant. And severe hypermetabolism is awful. Very like the manic phase of manic depression. You should be careful not to give drugs to people who don’t need them. That’s why in the old days, if they weren’t sure, they’d give you a bit and watch to see what effect it had. That was pretty much their test, except in the obvious cases.
but choosing a single dose is normal procedure.
Yes, but that does mean that anything that needs careful dose control will get rejected. In this case I think it might have made the treatment less effective, but it shouldn’t have ruined it. I’m not making any criticism of the people who did this trial, I think it was a brave try and they did it well. I just don’t think it’s enough to refute Skinner. In fact I think it was supportive.
From what I’m reading I don’t think there is any recognized clinical diagnosis of hypothyroidism. The TSH test is the gold standard.
There was once. The 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
was the last word in ‘clinical diagnosis’. It was very very difficult to do, and GPs tended to refer suspected cases to experts. In doubtful cases they just tried treating it with small amounts of thyroid and checked that people improved rather than being made anxious and hyper.
The TSH test replaced that around 1970. But they never seem to have checked that clinical and biochemical diagnoses detected the same things, and after that there was the slow emergence of all sorts of nasty diseases that look very like hypothyroidism in the clinical sense but have normal TSH.
The TSH test seems to have been accepted (and then ruthlessly enforced) on the basis of theoretical arguments that weren’t checked experimentally.
I do think that the TSH test detects gland failure quite well, in fact I think that if your thyroid gland gets destroyed, your TSH value will become huge. My (excellent) GP tells me that he sees people with TSH 30 with no symptoms at all (yet! Their thyroids are obviously on the way out...).
In fact the original ‘normal range’ for TSH was very wide indeed. And I think that’s probably right too. Over the years the ‘normal range’ has got narrowed to the point where it’s now so narrow people with abnormal TSH usually don’t have any symptoms, and the noise in the test can put you outside the range. That’s kind of weird. See recent AACB study where they thought the upper limit of normal should be 2.5.
There was a recent attempt to define a new clinical score (Zulewski et al), but the authors of the paper who’d constructed it refused to endorse it because the symptoms didn’t correlate with TSH. That says to me that the test isn’t detecting the disease it’s supposed to detect.
You have the burden of proof
Absolutely accept that! And if Skinner was right, it should be dead easy to prove. Just re-run the Scottish trial using Billewicz as the entry criterion. It would be better if you could adjust the dose, but it should work quite well with a fixed dose, if you accept you’re going to under-treat some people and over-treat others. Actually I’d rather use titrated doses of desiccated thyroid, since that’s what they used to do, or T4/T3 combinations, but if I believe Skinner then they should all work, and it’s just a question of which works best.
Could you summarize your support for this claim? Are these the only two peer-reviewed articles?
These are the only ones I can find through google scholar / pubmed. That in itself is really surprising and one of the things I can’t explain! Why has such an obvious thing not been ruled out? Real doctors seem to try it all the time, find it works, and then get persecuted for trying it.
All the rest of it is anecdotal, from alternative sources, but there’s a mountain of it. Just google. If people have tried this and it didn’t work, they’re keeping very quiet. All I’ve heard against is ‘it helps, but it doesn’t fix it entirely’. And the alternative people say exactly that themselves, and reckon that there’s usually something adrenal going on as well.
I’d point primarily to Broda Barnes, John Lowe, Kenneth Blanchard, Gordon Skinner, Sarah Myhill, Barry Durrant-Peatfield, the various thyroid activist groups, Kent Holtorf, and ‘Wilson’s syndrome’, off the top of my head, but there’s plenty more where that came from. And a lot of those guys are actual medical doctors. The big exception is John Lowe, who was a chiropractor. But I’ve read a lot of his stuff and he was a very careful, thoughtful man.
90% of medical research findings are false
Indeed. The whole thing is a disaster. John Ioannides said ‘Evidence Based Medicine Has Been Hijacked’. But I think it’s worse than that. By saying that you’re going to ignore the experience of doctors, and only accept very expensive evidence that can only be provided by wealthy sources, and even then using methods so bad that they’re practically guaranteed to produce false answers, you’ve completely cut yourselves off from the truth.
I’d go further and say ‘Evidence Based Medicine Has Been A Catastrophe’. I’m not more than half-convinced this thryoid-craziness is true, but I think the fact that it’s never been properly investigated is a complete scandal.
I’m not against “evidence based medicine” because it’s based on evidence. I’m against “evidence based medicine” precisely because it’s based on ignoring most of the evidence. -- GK Chesterton’s Homeopath.
I was helping a consultant friend revise for an interview the other day, and one of the practice questions was ‘describe the hierarchy of evidence’. He put ‘expert opinion’ bottom.
Really? Forty years of experience in treating patients is less valuable than a single anecdote published in a journal? Really?
And of course, it doesn’t actually work that way. The TSH test ruling out hypothyroidism is expert opinion. Its reliability is unfounded dogma. I can’t find any evidence for it as the sole measure of thyroid system function at all.
If none of the patients had had any sort of thyroid problem, I’d have expected it to be equally bad for everyone.
I’m talking about conservation of expected evidence. If X is positive evidence, then ~X is negative evidence. An experiment only supports a hypothesis if it was possible for it to come out another way that refutes it. And if an experiment that could have supported the hypothesis actually didn’t, then it’s evidence against.
What makes me think that they felt bad on thyroxine is table 2, where all the ‘self-reported’ psychological scores have got worse from thyroxine. In particular p=0.007 for the decline in Vitality. Since, as you point out, they really didn’t know which was which, it’s hard to see how they could have faked that.
Terminology then. When you said “Thyroxine is very strongly disliked by the healthy controls (they could tell it from placebo and hated it),” it suggests they could identify the active treatment.
Absolutely this treatment is harmful to healthy people.
The people in the study had symptoms. Even if you think their symptoms were mild or unrepresentative, you shouldn’t call them healthy. It’s fair to extend the conclusion to cover people without those symptoms, but I think that’s an important difference.
Yes, but that does mean that anything that needs careful dose control will get rejected.
It’s more that you need an easily followed protocol. Anything else, especially anything subjective, is unlikely to be practically feasible, and will probably not be reproducible.
The TSH test replaced that around 1970. But they never seem to have checked that clinical and biochemical diagnoses detected the same things, and after that there was the slow emergence of all sorts of nasty diseases that look very like hypothyroidism in the clinical sense but have normal TSH.
This is normal. Clinical presentations often have many causes, which makes it almost impossible to progress. Eventually we break them down based on their causal mechanisms so we can treat them individually. Each time we find a new cause, some of the cases will be left unexplained.
These are the only ones I can find through google scholar / pubmed. That in itself is really surprising and one of the things I can’t explain! Why has such an obvious thing not been ruled out?
There are a lot of interesting hypotheses competing for resources, and we have to decide which ones are worth considering. I can’t say what the reason might be here, but there are a lot of possibilities. For example, it might not be possible to design a study like the one you want that could effectively answer the question.
Really? Forty years of experience in treating patients is less valuable than a single anecdote published in a journal? Really?
Yes. Expert opinion (i.e., the opinion of individual experts, not expert consensus) is the lowest level because you can find an expert to support pretty much any proposition that isn’t obviously ridiculous, and sometimes even if it is. In fact, this is true higher in the hierarchy as well, which is why we use syntheses of evidence so much. I can’t stress this enough: in biology, you can use peer-reviewed evidence to make plausible arguments for arbitrary hypotheses.
All the rest of it is anecdotal, from alternative sources, but there’s a mountain of it.
The point of evidence-based medicine is that perceptions are unreliable. That includes the perceptions we call clinical experience (which once said that bloodletting was an important medical treatment). Keep in mind that doctors aren’t scientists and usually don’t even qualify as experts. EBM is unreliable too, but less so, just like science is unreliable but is still better than ancestral wisdom.
The TSH test ruling out hypothyroidism is expert opinion. Its reliability is unfounded dogma.
This sounds like you’re saying the TSH test doesn’t actually measure TSH, but I think you mean to say you disagree with the conclusions that it’s used for. But since hypothyroidism is defined as low thyroid hormone levels, some of this will be a dispute over definitions.
I can’t find any evidence for it as the sole measure of thyroid system function at all.
I don’t think anyone who understands it would say it is. It measures TSH levels, and the question is what we do with that measurement. But we’re often limited by what we’re able to (easily) measure, and it might even be the only objective measurement we have.
in biology, you can use peer-reviewed evidence to make plausible arguments for arbitrary hypotheses.
Et tu, Brut? That is obviously true for humanities and for things like observational studies of nutrition, but do you think it extends to most / all of biology? “For any hypothesis there is a mouse strain which proves it true”? :-/
...we face a replication crisis in the field of biomedicine, not unlike the one we’ve seen in psychology but with far more dire implications. Sloppy data analysis, contaminated lab materials, and poor experimental design all contribute to the problem.
...Freedman and his co-authors guessed that fully half of all results rest on shaky ground, and might not be replicable in other labs. These cancer studies don’t merely fail to find a cure; they might not offer any useful data whatsoever.
In most ways biology is intermediate between the hard and soft sciences, with all that implies. It’s usually impossible to identify all the confounders, most biologists are not trained in statistics, experiments are complex and you can get different results from slight variations in protocol, we’re trying to generalize from imperfect models, many high-profile results don’t get tested by other labs, … all these factors come together and we get something that people call a “replication crisis.”
Oh God, where will this end? Is it really only physics and chemistry that aren’t sloppy cargo-cults, or are they broken too?
A lot of this, I think is to do with taking tenure away from young academics. Once upon a time once you’d proved basic competence and cleverness, you could spend your whole career being careful about stuff. These days you’ve just got to turn out crap as fast as possible. And you spend most of your time applying for grants.
I’m talking about conservation of expected evidence.
Sure, this experiment is evidence against ‘all fat, tired people with dry hair get better with thryoxine’. No problem there.
Terminology then. When you said “Thyroxine is very strongly disliked by the healthy controls (they could tell it from placebo and hated it),” it suggests they could identify the active treatment.
Yes, it is kind of odd isn’t it? One of the pills apparently made them a bit unwell, and yet they couldn’t tell which one. I notice that I am confused.
The people in the study had symptoms.
You’re right. I think I should have said “This treatment is harmful to most people”.
This is normal...
But that’s awful! Once, there was a diagnostic method, and a treatment that worked fine, that everyone thought was brilliant. Then they invented a test, which is very clever, and a good test for what it tests, and the result of that is that lots of people are ill and don’t get the treatment any more and have to suffer horribly and die early.
If that’s normal then there’s something badly wrong with normal. A new way of measuring things should help!
we have to decide which ones are worth considering.
Sure, I’m trying to make a case that this one is worth considering.
it might not be possible to design a study ..
I think the Scottish study with stricter entry criteria for the patient group would do. If that failed, I would be quite surprised.
If someone did the same thing with stricter entry criteria and used desiccated thyroid and titrated doses and it failed I would be so surprised that I would give up.
Seriously, if ‘start off with low doses and keep raising the dose until you get a response’ is inaccessible to testing, then something is broken.
But in fact, just ‘low basal metabolic rate in CFS’ would be good evidence in favour, I think. We can work out optimal treatments later.
And if it turned out that there wasn’t a subset of CFS patients with high Billewicz scores and low basal metabolic rates, I’d give up. No study needed.
I can’t stress this enough: in biology, you can use peer-reviewed evidence to make plausible arguments for arbitrary hypotheses.
At that point, we’re all post-modernists aren’t we? The truth is socially determined.
science is unreliable but is still better than ancestral wisdom
Science is not unreliable. If I can surprise a physicist or a chemist about something he is sure of, he will be very very interested, and science will quickly rearrange itself around the new fact. It took about five years to completely overturn classical physics and replace it with something we haven’t managed to surprise yet, even though everyone knows that the new theories are broken and is actively trying to find things that happen that they don’t predict. And classical physics is still damned good in the domains that it used to work in.
There’s at least a possibility here that medical science is getting beaten hollow by chiropractors and quack doctors and internet loonies, none of whom have any resources or funding at all.
Even the possibility is enough to make me think that there’s something appallingly badly wrong with the methods and structure of medical science.
Sure, this experiment is evidence against ‘all fat, tired people with dry hair get better with thryoxine’. No problem there.
Okay, but you said it was evidence in favor of your own hypothesis. That’s what my question was about.
Yes, it is kind of odd isn’t it? One of the pills apparently made them a bit unwell, and yet they couldn’t tell which one. I notice that I am confused.
Suppose they’re measuring on a 10-point scale, and we get ordered pairs of scores for time A and time B. One person might have 7 and 6, another has (4,3), another has (5,6), then (9,7), (7,7), (4,5), (3,2)...Even if they’re aware of their measurements (which they might not be), all sorts of things affect their scores and it’s unlikely that any one person would be able to make a conclusion. You’re basically asking an untrained patient to draw a conclusion from an n of 1.
But that’s awful! Once, there was a diagnostic method, and a treatment that worked fine, that everyone thought was brilliant. Then they invented a test, which is very clever, and a good test for what it tests, and the result of that is that lots of people are ill and don’t get the treatment any more and have to suffer horribly and die early.
There are several assumptions here that I think are probably incorrect, the biggest being the causal link between introducing the test and people suffering. But what I described before is just the application of reductionism to better distinguish between disease states based on their causal mechanism.
If that’s normal then there’s something badly wrong with normal. A new way of measuring things should help!
Sometimes, but replacing an objective measurement with a subjective one isn’t usually a step forward.
Seriously, if ‘start off with low doses and keep raising the dose until you get a response’ is inaccessible to testing, then something is broken.
Problems with this include: you can’t justify the parameters of the dose increase, you still have to agree on how to measure the response, and you also have a multiple testing issue. It isn’t inaccessible, but it’s a complication (potentially a major one), and that’s just in the abstract. Practically, in any one situation there might be another half dozen issues that wouldn’t be apparent to anyone who isn’t an expert.
But in fact, just ‘low basal metabolic rate in CFS’ would be good evidence in favour, I think. We can work out optimal treatments later.
Not knowing anything about the subject, I would expect to observe a low basal metabolic rate in CFS regardless of its ultimate cause or causes.
At that point, we’re all post-modernists aren’t we? The truth is socially determined.
No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.
Science is not unreliable...
You’re talking about the overall process and how science moves in the direction of truth, which I agree with. I’m talking on the level of individual papers and how our current best knowledge may still be overturned in the future. But you can leave out “just like..wisdom” from the paragraph without losing the main points.
There’s at least a possibility here that medical science is getting beaten hollow by chiropractors and quack doctors and internet loonies, none of whom have any resources or funding at all.
The alt med people have a lot of funding. It’s a multi-billion-dollar industry.
Even the possibility is enough to make me think that there’s something appallingly badly wrong with the methods and structure of medical science.
A few things, not just one, but it’s the best we have at the moment.
No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.
So, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p.
Is the only way we learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?
And nothing done outside the system is worth anything at all?
And the opinions of patients and doctors are ‘placebo effect?’.
And the patients’ obvious symptoms are ‘psychosomatic/somatoform/hypochondriac/malingering’? All the same bloody word, changed every decade or so when people realise what they mean.
And someone invents a wonderful new measurement technique that bears on a hard problem, and it’s used to make things worse?
No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.
So, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p.
Is the only way you learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?
Not knowing anything about the subject, I would expect to observe a low basal metabolic rate in CFS regardless of its ultimate cause or causes.
Ooh, why? I thought that was thyroid and starvation?
I mean, low once you adjust for all the known predictive factors, e.g. age, sex, height, weight and exercise. Obviously people who have trouble standing up are going to show low BMR in absolute terms. But I mean ‘even after adjusting for sedentary lifestyle’.
The alt med people have a lot of funding. It’s a multi-billion-dollar industry.
OK, but none of that funding is going in favour of the likes of John Lowe or Gordon Skinner or Barry Durrant-Peatfield or Sarah Myhill, in fact those people are losing/risking their licences and livelihoods in order to try to help people. They may or may not be right about their methods, but they’re not doing it for the money!
Ken Blanchard appears to have built an endocrinology practice out of treating hypothyroidism ‘functionally’, but I’m sure he could have done just as well doing it ‘conventionally’, and been risking far less legal trouble.
Okay, but you said it was evidence in favor of your own hypothesis. That’s what my question was about.
I must be confused here. Sorry, I’m not deliberately evading your (good!) question.
If none of the patients had had any sort of thyroid problem, I’d have expected it to be equally bad for everyone. That would be strong evidence against ‘it’s widespread and treatable with thyroxine’, and very weak evidence against ‘CFS is thyroidy’.
A test is allowed to produce weak evidence one way and strong evidence the other. Imagine rolling a dice. If it comes out 5, you’ve not learned much. If it comes out 7, that’s a big surprise, and enough to smash the ‘six-sided’ theory into the very long grass.
If a fair number of the normal-TSH patient group had nevertheless had a thyroid problem amenable to thyroxine 100mg/day, then I’d have expected that to make a difference between healthy controls and patients. Which appears to be what happened. I think that’s actually fairly strong evidence in favour of ‘common and treatable with thyroxine’. Nowhere near proof, but it strengthens Skinner’s paper, which is already strong evidence, rather than weakening it.
I’m actually really surprised by that. That thyroxine made any difference at all.
I believed it was thyroidy just on the argument in ‘A medical mystery’. (Looks like hypothyroidism, existed in Victorian times, didn’t exist 1900-1970 when hypothyroidism was diagnosed by symptoms and treated with desiccated thyroid, which has too much T3 in it, validity of TSH test never checked)
I’ve been saying for a while that it must be to do with T4/T3 balance, because I couldn″t believe that if it was amenable to thyroxine that wouldn’t already be known. Because I literally couldn’t believe that medical science could have been that careless and stupid.
But now I’m looking at the only two papers I’ve ever been able to find on the subject, and thinking, ‘they both imply that thyroxine works’. It might not be optimal, but it seems to do something!
And sure, it’s nowhere near proof, and I wouldn’t want public health policy changed on this kind of evidence. But it’s worth a good look. And the level of carelessness implied is just staggering.
If they’d just made a terrible mistake and then ignored millions screaming for help for forty years, that would be criminal, but John Lowe and lots of medical doctors had/have been asking, perfectly clearly and sanely, for endocrinology to check its beliefs, for decades.
And they’ve been marginalised, ridiculed, and persecuted for it. “TSH tests normal, therefore it can’t be a thyroid issue.” Over and over and over again. No evidence whatsoever.
Even if CFS turns out to be caused by magic space pixies who deliberately confuse all the experiments, medical science has my utter contempt.
Six months ago I would have said: “There’s no point to alternative medicine, if they had anything that worked it would just be real medicine.”. In fact my friends (and the chiropractor I used to go and see even though I believed her treatments didn’t really help and I was allowing myself to buy a placebo) tell me I used to say that quite a lot.
Because I trusted something extravagantly publicly funded, that called itself a science, to use the scientific method.
After taking a (fairly brief) look at this one problem, I’m now thinking “How many lives have these morons fucked up through their arrogance and carelessness?”.
“How much of the random crap in Holland and Barrett actually works, and how much public money is being shoved down the drain buying chemical poisons for the ill on dodgy evidence produced by drugs companies when they could be fixed with cheap treatments that have been known for years?”
By the way, what’s you definition of hypothyroidism?
Since you are doubtful of the TSH test and point out that diagnosis by clinical symptoms is very hard (with the relevant implication that there will be a lot of mistakes), which exactly condition of the human body do you call hypothyroidism?
It’s not “that which is made better by consuming dessicated thyroid”, is it?
Actually I think it was only ‘very hard’ for GPs. It seems that most endocrinologists back in the day just ruled in or ruled out the obvious cases, and experimented with small amounts of thyroid on the rest. That doesn’t look like a bad approach to me. Small amounts of thyroid with someone competent watching you won’t hurt you.
just ruled in or ruled out the obvious cases, and experimented with small amounts of thyroid on the rest. That doesn’t look like a bad approach to me.
I don’t know about that. Let’s try s/thyroid/bloodletting. Why, that looks just like what the doctors used to do a few centuries ago. I don’t think this was a resounding success.
Well sure, and as an advocate of ‘Traditional Western Medicine’, I suppose I should be equally hurt by the disappearance of that once beloved (by doctor and patient alike!) treatment, so well supported by the humorous theories of Aristotle and Galen.
So I suggest that we appeal to Almighty God to show to us His Wille, by using the ritual of randomised controlled augury, as our fathers have shown us.
We should carefully select our patients using the strategems of Billewicz, and we should have three treatment arms, one with desiccated thyroid, one with leechwork and lancettry, and one with that flower of the modern schoole, graded exercise therapy.
I have a feeling that thryoid will come out well in the comparison. I am somewhat unclear as to GET vs leeches.
Something like ‘inadequate thyroid-hormone-mediated regulation of metabolism’.
Certainly that would include primary, secondary, and tertiary hypothyroidism, as well as the various forms of ‘peripheral resistance’, and the conversion disorders. (TSH probably detects the primary form. The question is ‘how widespread are the other things.’)
A good clinical correlate for all of those would probably be the Billewicz score from ’68. Which he pretty much did work out by ‘that which is made better by consuming desiccated thyroid’.
We might want to call all that ‘easily-treatable clinical hypothyroidism’, or ‘twimbbcdt’. Congratulations, trope-namer!
But actually there are consistent reports of people with all the usual symptoms who don’t respond to the sane use of T4/T3 or NDT, but who do improve on insanely high levels of T3.
So I’d actually want to draw ‘hypothyroidism’ a bit wider than “that which is made better by consuming desiccated thyroid”.
And I bet you can get all sorts of ‘dysthyroidism’ too, where there are some resistant tissues but some are fine, and you or your system raises levels of this or that to compensate, and makes some bits of you hyper and some bits hypo at the same time.
If there’s that, we might actually need to understand how it works to treat it. Imagine...
And then, I bet if there are two acquired hormone resistances then there are others, and I bet they’re all horribly intertwined, and lots of nasty pathogens either taking advantage of or causing them, so there’s probably a whole swamp of horrors that get a bit better with thyroid but that no-one would call ‘hypothyroidism’. We’d probably need to call those ‘acquired generalised hormone resistance disorders’, which gives the pleasantly onomatopoeic “aghrd”. And we’re not going to nail those without actually rolling up our sleeves and playing around.
At the current rate of progress it should all be sorted out well after we’ve destroyed the universe by careless use of computers.
Unless it is all being caused by nasty chemicals in the environment, in which case we’ll probably make ourselves so stupid that we just blunder straight back into Malthus’ trap in a few generations. And that should sort it all out ‘the natural way’
Something like ‘inadequate thyroid-hormone-mediated regulation of metabolism’.
That’s wonderfully vague. I bet I can diagnose half the population with having “inadequate” regulation.
A definition should allow easy classification of observed phenomena into two classes: “fits the definition” and “doesn’t fit the definition”. This one… struggles.
we might actually need to understand how it works to treat
And this I can probably diagnose 90% of the population with? See above.
The meta issue is whether you want to medicalise deviations from the theoretical optimum. On the one hand, sure, it’s nice to move closer to the optimum, on the other hand this means that no one is “healthy”, everyone is “sick” and under care of doctors.
Well, ‘hypothyroidism’ was a very difficult and polymorphic badger in its day. But a thing that is difficult to detect can still be a thing. Consider neutrinos and gravity waves and unicornes, which no man nowadays doubts of.
And as for ‘medicalise deviations from the theoretical optimum’, most chronic fatigue people are already bothering their poor doctors incessantly, and being given (with the best will in the world) a selection of nasty things that mildly alleviate some of their symptoms. CFS is a horrible thing. As Hitler says in the film Downfall:
“‘Chronic Fatigue Syndrome’ ? they might as well call Leprosy : ‘Chronic Dandruff Syndrome’”.
Well, ‘hypothyroidism’ was a very difficult and polymorphic badger in its day.
Isn’t it still “its day”?
Think of it this way. There is a set of people with some clinical symptoms which look maybe-possibly like hypothyroidism. There is a another set of people with abnormal TSH. These sets partially intersect and form three subsets. Subset one is the intersection: people with both clinical symptoms and abnormal TSH. They are a clear case and there are no problems here. Subset two is abnormal TSH and absence of clinical symptoms. We interpret that as thyroid gland falling apart and expect clinical symptoms to appear in the near future. We are not concerned with people either.
Subset three is the one you are interested in: people with normal TSH and clinical symptoms. What about them? Well, as you mention diagnosing hypothyroidism solely on the basis of clinical symptoms is difficult. So in this subset some but not all people will have a thyroid malfunction, and some will have other problems, maybe instead or maybe in addition to thyroid issues.
By the way, the people who you insist on calling “fat, tired, and with dry skin” are in subset three. They exhibit clinical symptoms of hypothyroidism.
Your suggestion is that we give some dessicated thyroid to subset three and see if it helps. Well, it’s pretty clear that it will help some people and will not help other people (for example, those fat and tired ones). However that is true of many medical interventions.
For example, there are probably males in subset three with low testosterone. So giving testosterone to subset three males will also help some people and not help others. There also probably people with low-grade systemic infections in there. Giving broad-spectrum antibiotics to subset three might well help some people and not help others. There are likely people with autoimmune disorders there...
Basically, if you have little idea about what’s wrong, trying a variety of drugs hoping for a lucky hit is not necessarily a horrible strategy (depends on the side-effects of the drugs and the consequences of doing nothing), but it’s not much advancement from the good old times.
Back in the good old days, Charles II, age 53, had a fit one Sunday evening, while fondling two of his mistresses.
Monday they bled him (cupping and scarifying) of eight ounces of blood. Followed by an antimony emetic, vitriol in peony water, purgative pills, and a clyster. Followed by another clyster after two hours. Then syrup of blackthorn, more antimony, and rock salt. Next, more laxatives, white hellebore root up the nostrils. Powdered cowslip flowers. More purgatives. Then Spanish Fly. They shaved his head and stuck blistering plasters all over it, plastered the soles of his feet with tar and pigeon-dung, then said good-night.
Tuesday. ten more ounces of blood, a gargle of elm in syrup of mallow, and a julep of black cherry, peony, crushed pearls, and white sugar candy.
Wednesday. Things looked good:: only senna pods infused in spring water, along with white wine and nutmeg.
Thursday. More fits. They gave him a spirituous draft made from the skull of a man who had died a violent death. Peruvian bark, repeatedly, interspersed with more human skull. Didn’t work.
Friday. The king was worse. He tells them not to let poor Nelly starve. They try the Oriental Bezoar Stone, and more bleeding. Dies at noon.
P.S. Note the awe-inspiring lack of smugness with which I present:
IMPAIRED ACTION OF THYROID HORMONE ASSOCIATED WITH SMOKING IN WOMEN WITH HYPOTHYROIDISM
BEAT MÜLLER , M.D., HENRYK ZULEWSKI , M.D., PETER HUBER , P H .D., JOHN G. RATCLIFFE , M.D., AND JEAN -JACQUES STAUB , M.D.
I bloody said it would turn out to be the reason smoking’s bad for you, didn’t I? And at the same time it’s evidence that acquired hormone resistance exists, and this one fingers an environmental cause.
Opinions are divided. There’s me and some dead guys, and everyone else. Everyone else thinks it’s a solved problem.
By the way, the people who you insist on calling “fat, tired, and with dry skin” are in subset three. They exhibit clinical symptoms of hypothyroidism.
They absolutely do! Back in the day, they would have been referred to endocrinologists on suspicion of hypothyroidism, who would have (if they were very sophisticated and modern endocrinologists) used Billewicz’ test to sort them into definite, definitely not, and ‘therapeutic trial’ groups. His test didn’t rate these three symptoms, or lethargy or stupidity, because most everyone he saw had them, so he would look at all their other symptoms to make the diagnosis, looking for things like slow reflexes that are characteristic of hypothyroidism, and weight them to get a score. It really is a very careful piece of work, that test.
He would treat the ‘definites’ without further ado, send the ‘definitely nots’ off to people who were into diabetes etc, and be careful with the rest. Including all sorts of unreliable lab tests and therapeutic trials.
Luckily the therapeutic trials are not difficult to do, because with desiccated thyroid/T3 you seem to get either get a fairly rapid improvement, or you get hyper symptoms. (you might get both of course, in which case dose probably too high)
Other popular ways of trying to work it out involved cholesterol and basal metabolic rate.
Broda Barnes thought waking armpit temperature beat all this and just handed it out to anyone who woke up cold.
And the fact that it has been sprayed around at random for a hundred years without anyone having a word to say against it implies that it’s pretty damned safe. If you give yourself a massive overdose, then sure, you can probably give yourself a heart attack, but you’d need to be way way more criminally careless than I can imagine any (modern) doctor being.
Osteoporosis and atrial fibrillation (both ghastly things) are associated with low TSH, so it’s doubtless not a good idea to induce hyperthyroidism in people. And I think we should be careful not do that.
Barnes might have been deluded. I certainly started off thinking that he was, but one thing he was into was records and statistics. He thought his patients healthier than the general population. Including low rates of heart trouble. Which is just bizarre if what he was seeing was today’s CFS etc population, who seem to be really ill and then go on to be even more ill. Unless his treatments actually helped.
Hell, let’s do all four! If there’s a subset of fat tired stupid lethargic CFS patients with dry skin and high Billewicz scores, low basal metabolic rates, high cholesterol, and low waking temperatures all at the same time, then let’s run the Scottish trial on them and see what happens. That should be enough to break the TSH test, at which point, I imagine there will be an absolute explosion of research.
I couldn’t agree more that it’s really really important to understand mechanism. I’m into ‘explanations’ and ‘causes’. I think you are too. I get the impression that they’re a bit out of fashion in medicine.
Well, it’s pretty clear that it will help some people
Ooh, is it me and you and some dead guys now? Welcome! Sorry some of us aren’t that talkative. Damnit, that means I need another opponent. Devil’s advocate isn’t good enough. It needs to be someone who hates the idea.
Dies at noon.
Oh dear, poor Charles. The English crown was a bit of a poisoned chalice for the Stuarts wasn’t it? Still, he made it to 53 and they did call him the Merry Monarch. Anyone who dies in office of excessive mistress-related-activity hasn’t had a totally wasted life.
Why is the Pollock trial evidence supporting your hypothesis? What outcome from the trial would you have considered to be evidence against it?
Also, what part suggests that the healthy controls could distinguish the treatment from placebo? From Table 4, it seems that the reverse is true.
At first glance, the results from that study look like straightforward evidence that this treatment is actively harmful. I’d also point out that RCTs need to be standardized across patients. I can’t say whether the inclusion criteria should have been different, but choosing a single dose is normal procedure. There are always better options, but it’s a weak argument on its own, in part because it can be applied in almost any circumstances.
I admit I’m not an endocrinologist, but from what I’m reading I don’t think there is any recognized clinical diagnosis of hypothyroidism. The TSH test is the gold standard. That would suggest those who talk about it are primarily cranks and such.
Less Wrong might not be the best place for this, since there aren’t many biologists here. You have the burden of proof (i.e., the prior for arbitrary hypotheses is very low), so you shouldn’t be asking other people to disprove it. Could you summarize your support for this claim? Are these the only two peer-reviewed articles?
There are lots of ways that data can be wrong without being made up. 90% of medical research findings are false, etc.
Thank you so much, intelligent and careful criticism like this is exactly what I started posting on Less Wrong for!
Well, it’s only fairly weak evidence, but it does seem that the healthy controls reacted differently to the patient group. What it really proves is that thyroxine isn’t just a nice recreational drug that everyone likes. Healthy people dislike it. But it seems to have been less bad for the patients on average. So I imagine there were some people in the patient group who reacted well.
What I’m saying is that Skinner got strong evidence for the idea, and wanted it confirmed by PCRT (and I agree, that’s necessary). So they did a PCRT, but not very well because they didn’t find patients carefully. And yet they seem to have supported him anyway, but everyone thinks that they refuted him, because they didn’t quite understand what he was saying.
If none of the patients had had any sort of thyroid problem, I’d have expected it to be equally bad for everyone. If that had been the result, then I’d have had to think that ‘type 2 hypothyroidism’ is rare, or that ‘fixed doses of thyroxine don’t fix it’. For a long time that’s exactly what I did think! I was assuming you might need T3 as well and you might need to adust the ratio carefully. Skinner and Pollock together make me think that it might be fairly common, and mostly fixable with T4 alone.
That shows that when they were asked which was the active preparation, they couldn’t tell. They appear to have had a ‘nocebo’ effect, where they interpreted everything they felt as an effect of the drug. That’s as expected.
What makes me think that they felt bad on thyroxine is table 2, where all the ‘self-reported’ psychological scores have got worse from thyroxine. In particular p=0.007 for the decline in Vitality. Since, as you point out, they really didn’t know which was which, it’s hard to see how they could have faked that.
Absolutely this treatment is harmful to healthy people. It should cause ‘hypermetabolism’, which is unpleasant. And severe hypermetabolism is awful. Very like the manic phase of manic depression. You should be careful not to give drugs to people who don’t need them. That’s why in the old days, if they weren’t sure, they’d give you a bit and watch to see what effect it had. That was pretty much their test, except in the obvious cases.
Yes, but that does mean that anything that needs careful dose control will get rejected. In this case I think it might have made the treatment less effective, but it shouldn’t have ruined it. I’m not making any criticism of the people who did this trial, I think it was a brave try and they did it well. I just don’t think it’s enough to refute Skinner. In fact I think it was supportive.
There was once. The 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
was the last word in ‘clinical diagnosis’. It was very very difficult to do, and GPs tended to refer suspected cases to experts. In doubtful cases they just tried treating it with small amounts of thyroid and checked that people improved rather than being made anxious and hyper.
The TSH test replaced that around 1970. But they never seem to have checked that clinical and biochemical diagnoses detected the same things, and after that there was the slow emergence of all sorts of nasty diseases that look very like hypothyroidism in the clinical sense but have normal TSH.
The TSH test seems to have been accepted (and then ruthlessly enforced) on the basis of theoretical arguments that weren’t checked experimentally.
I do think that the TSH test detects gland failure quite well, in fact I think that if your thyroid gland gets destroyed, your TSH value will become huge. My (excellent) GP tells me that he sees people with TSH 30 with no symptoms at all (yet! Their thyroids are obviously on the way out...).
In fact the original ‘normal range’ for TSH was very wide indeed. And I think that’s probably right too. Over the years the ‘normal range’ has got narrowed to the point where it’s now so narrow people with abnormal TSH usually don’t have any symptoms, and the noise in the test can put you outside the range. That’s kind of weird. See recent AACB study where they thought the upper limit of normal should be 2.5.
There was a recent attempt to define a new clinical score (Zulewski et al), but the authors of the paper who’d constructed it refused to endorse it because the symptoms didn’t correlate with TSH. That says to me that the test isn’t detecting the disease it’s supposed to detect.
Absolutely accept that! And if Skinner was right, it should be dead easy to prove. Just re-run the Scottish trial using Billewicz as the entry criterion. It would be better if you could adjust the dose, but it should work quite well with a fixed dose, if you accept you’re going to under-treat some people and over-treat others. Actually I’d rather use titrated doses of desiccated thyroid, since that’s what they used to do, or T4/T3 combinations, but if I believe Skinner then they should all work, and it’s just a question of which works best.
These are the only ones I can find through google scholar / pubmed. That in itself is really surprising and one of the things I can’t explain! Why has such an obvious thing not been ruled out? Real doctors seem to try it all the time, find it works, and then get persecuted for trying it.
All the rest of it is anecdotal, from alternative sources, but there’s a mountain of it. Just google. If people have tried this and it didn’t work, they’re keeping very quiet. All I’ve heard against is ‘it helps, but it doesn’t fix it entirely’. And the alternative people say exactly that themselves, and reckon that there’s usually something adrenal going on as well.
I’d point primarily to Broda Barnes, John Lowe, Kenneth Blanchard, Gordon Skinner, Sarah Myhill, Barry Durrant-Peatfield, the various thyroid activist groups, Kent Holtorf, and ‘Wilson’s syndrome’, off the top of my head, but there’s plenty more where that came from. And a lot of those guys are actual medical doctors. The big exception is John Lowe, who was a chiropractor. But I’ve read a lot of his stuff and he was a very careful, thoughtful man.
Indeed. The whole thing is a disaster. John Ioannides said ‘Evidence Based Medicine Has Been Hijacked’. But I think it’s worse than that. By saying that you’re going to ignore the experience of doctors, and only accept very expensive evidence that can only be provided by wealthy sources, and even then using methods so bad that they’re practically guaranteed to produce false answers, you’ve completely cut yourselves off from the truth.
I’d go further and say ‘Evidence Based Medicine Has Been A Catastrophe’. I’m not more than half-convinced this thryoid-craziness is true, but I think the fact that it’s never been properly investigated is a complete scandal.
I’m not against “evidence based medicine” because it’s based on evidence. I’m against “evidence based medicine” precisely because it’s based on ignoring most of the evidence. -- GK Chesterton’s Homeopath.
I was helping a consultant friend revise for an interview the other day, and one of the practice questions was ‘describe the hierarchy of evidence’. He put ‘expert opinion’ bottom.
Really? Forty years of experience in treating patients is less valuable than a single anecdote published in a journal? Really?
And of course, it doesn’t actually work that way. The TSH test ruling out hypothyroidism is expert opinion. Its reliability is unfounded dogma. I can’t find any evidence for it as the sole measure of thyroid system function at all.
I’m talking about conservation of expected evidence. If X is positive evidence, then ~X is negative evidence. An experiment only supports a hypothesis if it was possible for it to come out another way that refutes it. And if an experiment that could have supported the hypothesis actually didn’t, then it’s evidence against.
Terminology then. When you said “Thyroxine is very strongly disliked by the healthy controls (they could tell it from placebo and hated it),” it suggests they could identify the active treatment.
The people in the study had symptoms. Even if you think their symptoms were mild or unrepresentative, you shouldn’t call them healthy. It’s fair to extend the conclusion to cover people without those symptoms, but I think that’s an important difference.
It’s more that you need an easily followed protocol. Anything else, especially anything subjective, is unlikely to be practically feasible, and will probably not be reproducible.
This is normal. Clinical presentations often have many causes, which makes it almost impossible to progress. Eventually we break them down based on their causal mechanisms so we can treat them individually. Each time we find a new cause, some of the cases will be left unexplained.
There are a lot of interesting hypotheses competing for resources, and we have to decide which ones are worth considering. I can’t say what the reason might be here, but there are a lot of possibilities. For example, it might not be possible to design a study like the one you want that could effectively answer the question.
Yes. Expert opinion (i.e., the opinion of individual experts, not expert consensus) is the lowest level because you can find an expert to support pretty much any proposition that isn’t obviously ridiculous, and sometimes even if it is. In fact, this is true higher in the hierarchy as well, which is why we use syntheses of evidence so much. I can’t stress this enough: in biology, you can use peer-reviewed evidence to make plausible arguments for arbitrary hypotheses.
The point of evidence-based medicine is that perceptions are unreliable. That includes the perceptions we call clinical experience (which once said that bloodletting was an important medical treatment). Keep in mind that doctors aren’t scientists and usually don’t even qualify as experts. EBM is unreliable too, but less so, just like science is unreliable but is still better than ancestral wisdom.
This sounds like you’re saying the TSH test doesn’t actually measure TSH, but I think you mean to say you disagree with the conclusions that it’s used for. But since hypothyroidism is defined as low thyroid hormone levels, some of this will be a dispute over definitions.
I don’t think anyone who understands it would say it is. It measures TSH levels, and the question is what we do with that measurement. But we’re often limited by what we’re able to (easily) measure, and it might even be the only objective measurement we have.
Et tu, Brut? That is obviously true for humanities and for things like observational studies of nutrition, but do you think it extends to most / all of biology? “For any hypothesis there is a mouse strain which proves it true”? :-/
Hmmm
This piece claims that
This open-access article discusses some of the issues in cancer research.
In most ways biology is intermediate between the hard and soft sciences, with all that implies. It’s usually impossible to identify all the confounders, most biologists are not trained in statistics, experiments are complex and you can get different results from slight variations in protocol, we’re trying to generalize from imperfect models, many high-profile results don’t get tested by other labs, … all these factors come together and we get something that people call a “replication crisis.”
tl;dr It’s complicated.
Yes, I know. But it would be nice if people recognized that it is complicated and not pretend that we know more than we actually do.
Oh God, where will this end? Is it really only physics and chemistry that aren’t sloppy cargo-cults, or are they broken too?
A lot of this, I think is to do with taking tenure away from young academics. Once upon a time once you’d proved basic competence and cleverness, you could spend your whole career being careful about stuff. These days you’ve just got to turn out crap as fast as possible. And you spend most of your time applying for grants.
Vocative!
Sure, this experiment is evidence against ‘all fat, tired people with dry hair get better with thryoxine’. No problem there.
Yes, it is kind of odd isn’t it? One of the pills apparently made them a bit unwell, and yet they couldn’t tell which one. I notice that I am confused.
You’re right. I think I should have said “This treatment is harmful to most people”.
But that’s awful! Once, there was a diagnostic method, and a treatment that worked fine, that everyone thought was brilliant. Then they invented a test, which is very clever, and a good test for what it tests, and the result of that is that lots of people are ill and don’t get the treatment any more and have to suffer horribly and die early.
If that’s normal then there’s something badly wrong with normal. A new way of measuring things should help!
Sure, I’m trying to make a case that this one is worth considering.
I think the Scottish study with stricter entry criteria for the patient group would do. If that failed, I would be quite surprised.
If someone did the same thing with stricter entry criteria and used desiccated thyroid and titrated doses and it failed I would be so surprised that I would give up.
Seriously, if ‘start off with low doses and keep raising the dose until you get a response’ is inaccessible to testing, then something is broken.
But in fact, just ‘low basal metabolic rate in CFS’ would be good evidence in favour, I think. We can work out optimal treatments later.
And if it turned out that there wasn’t a subset of CFS patients with high Billewicz scores and low basal metabolic rates, I’d give up. No study needed.
At that point, we’re all post-modernists aren’t we? The truth is socially determined.
Science is not unreliable. If I can surprise a physicist or a chemist about something he is sure of, he will be very very interested, and science will quickly rearrange itself around the new fact. It took about five years to completely overturn classical physics and replace it with something we haven’t managed to surprise yet, even though everyone knows that the new theories are broken and is actively trying to find things that happen that they don’t predict. And classical physics is still damned good in the domains that it used to work in.
There’s at least a possibility here that medical science is getting beaten hollow by chiropractors and quack doctors and internet loonies, none of whom have any resources or funding at all.
Even the possibility is enough to make me think that there’s something appallingly badly wrong with the methods and structure of medical science.
Okay, but you said it was evidence in favor of your own hypothesis. That’s what my question was about.
Suppose they’re measuring on a 10-point scale, and we get ordered pairs of scores for time A and time B. One person might have 7 and 6, another has (4,3), another has (5,6), then (9,7), (7,7), (4,5), (3,2)...Even if they’re aware of their measurements (which they might not be), all sorts of things affect their scores and it’s unlikely that any one person would be able to make a conclusion. You’re basically asking an untrained patient to draw a conclusion from an n of 1.
There are several assumptions here that I think are probably incorrect, the biggest being the causal link between introducing the test and people suffering. But what I described before is just the application of reductionism to better distinguish between disease states based on their causal mechanism.
Sometimes, but replacing an objective measurement with a subjective one isn’t usually a step forward.
Problems with this include: you can’t justify the parameters of the dose increase, you still have to agree on how to measure the response, and you also have a multiple testing issue. It isn’t inaccessible, but it’s a complication (potentially a major one), and that’s just in the abstract. Practically, in any one situation there might be another half dozen issues that wouldn’t be apparent to anyone who isn’t an expert.
Not knowing anything about the subject, I would expect to observe a low basal metabolic rate in CFS regardless of its ultimate cause or causes.
No, it just means we put very little weight on individual studies. We don’t pay much attention to results that haven’t been replicated a few times, and rely heavily on summaries like meta-analyses.
You’re talking about the overall process and how science moves in the direction of truth, which I agree with. I’m talking on the level of individual papers and how our current best knowledge may still be overturned in the future. But you can leave out “just like..wisdom” from the paragraph without losing the main points.
The alt med people have a lot of funding. It’s a multi-billion-dollar industry.
A few things, not just one, but it’s the best we have at the moment.
So, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p.
Is the only way we learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?
And nothing done outside the system is worth anything at all?
And the opinions of patients and doctors are ‘placebo effect?’.
And the patients’ obvious symptoms are ‘psychosomatic/somatoform/hypochondriac/malingering’? All the same bloody word, changed every decade or so when people realise what they mean.
And someone invents a wonderful new measurement technique that bears on a hard problem, and it’s used to make things worse?
So, for instance, Skinner, who may or may not have demonstrated and published something really important and blindingly obvious in hindsight, gets ignored and then eventually pretty much struck off for it, even though his results could have been put to formal trial for about 50p.
Is the only way you learn anything new if seven different people do the necessary research at their own expense and get their lives destroyed as a consequence?
Ooh, why? I thought that was thyroid and starvation?
I mean, low once you adjust for all the known predictive factors, e.g. age, sex, height, weight and exercise. Obviously people who have trouble standing up are going to show low BMR in absolute terms. But I mean ‘even after adjusting for sedentary lifestyle’.
Surely the ‘stress’ theory predicts high BMR?
OK, but none of that funding is going in favour of the likes of John Lowe or Gordon Skinner or Barry Durrant-Peatfield or Sarah Myhill, in fact those people are losing/risking their licences and livelihoods in order to try to help people. They may or may not be right about their methods, but they’re not doing it for the money!
Ken Blanchard appears to have built an endocrinology practice out of treating hypothyroidism ‘functionally’, but I’m sure he could have done just as well doing it ‘conventionally’, and been risking far less legal trouble.
I must be confused here. Sorry, I’m not deliberately evading your (good!) question.
If none of the patients had had any sort of thyroid problem, I’d have expected it to be equally bad for everyone. That would be strong evidence against ‘it’s widespread and treatable with thyroxine’, and very weak evidence against ‘CFS is thyroidy’.
A test is allowed to produce weak evidence one way and strong evidence the other. Imagine rolling a dice. If it comes out 5, you’ve not learned much. If it comes out 7, that’s a big surprise, and enough to smash the ‘six-sided’ theory into the very long grass.
If a fair number of the normal-TSH patient group had nevertheless had a thyroid problem amenable to thyroxine 100mg/day, then I’d have expected that to make a difference between healthy controls and patients. Which appears to be what happened. I think that’s actually fairly strong evidence in favour of ‘common and treatable with thyroxine’. Nowhere near proof, but it strengthens Skinner’s paper, which is already strong evidence, rather than weakening it.
I’m actually really surprised by that. That thyroxine made any difference at all.
I believed it was thyroidy just on the argument in ‘A medical mystery’. (Looks like hypothyroidism, existed in Victorian times, didn’t exist 1900-1970 when hypothyroidism was diagnosed by symptoms and treated with desiccated thyroid, which has too much T3 in it, validity of TSH test never checked)
I’ve been saying for a while that it must be to do with T4/T3 balance, because I couldn″t believe that if it was amenable to thyroxine that wouldn’t already be known. Because I literally couldn’t believe that medical science could have been that careless and stupid.
But now I’m looking at the only two papers I’ve ever been able to find on the subject, and thinking, ‘they both imply that thyroxine works’. It might not be optimal, but it seems to do something!
And sure, it’s nowhere near proof, and I wouldn’t want public health policy changed on this kind of evidence. But it’s worth a good look. And the level of carelessness implied is just staggering.
If they’d just made a terrible mistake and then ignored millions screaming for help for forty years, that would be criminal, but John Lowe and lots of medical doctors had/have been asking, perfectly clearly and sanely, for endocrinology to check its beliefs, for decades. And they’ve been marginalised, ridiculed, and persecuted for it. “TSH tests normal, therefore it can’t be a thyroid issue.” Over and over and over again. No evidence whatsoever. Even if CFS turns out to be caused by magic space pixies who deliberately confuse all the experiments, medical science has my utter contempt. Six months ago I would have said: “There’s no point to alternative medicine, if they had anything that worked it would just be real medicine.”. In fact my friends (and the chiropractor I used to go and see even though I believed her treatments didn’t really help and I was allowing myself to buy a placebo) tell me I used to say that quite a lot. Because I trusted something extravagantly publicly funded, that called itself a science, to use the scientific method. After taking a (fairly brief) look at this one problem, I’m now thinking “How many lives have these morons fucked up through their arrogance and carelessness?”. “How much of the random crap in Holland and Barrett actually works, and how much public money is being shoved down the drain buying chemical poisons for the ill on dodgy evidence produced by drugs companies when they could be fixed with cheap treatments that have been known for years?”By the way, what’s you definition of hypothyroidism?
Since you are doubtful of the TSH test and point out that diagnosis by clinical symptoms is very hard (with the relevant implication that there will be a lot of mistakes), which exactly condition of the human body do you call hypothyroidism?
It’s not “that which is made better by consuming dessicated thyroid”, is it?
Actually I think it was only ‘very hard’ for GPs. It seems that most endocrinologists back in the day just ruled in or ruled out the obvious cases, and experimented with small amounts of thyroid on the rest. That doesn’t look like a bad approach to me. Small amounts of thyroid with someone competent watching you won’t hurt you.
I don’t know about that. Let’s try s/thyroid/bloodletting. Why, that looks just like what the doctors used to do a few centuries ago. I don’t think this was a resounding success.
Well sure, and as an advocate of ‘Traditional Western Medicine’, I suppose I should be equally hurt by the disappearance of that once beloved (by doctor and patient alike!) treatment, so well supported by the humorous theories of Aristotle and Galen.
So I suggest that we appeal to Almighty God to show to us His Wille, by using the ritual of randomised controlled augury, as our fathers have shown us.
We should carefully select our patients using the strategems of Billewicz, and we should have three treatment arms, one with desiccated thyroid, one with leechwork and lancettry, and one with that flower of the modern schoole, graded exercise therapy.
I have a feeling that thryoid will come out well in the comparison. I am somewhat unclear as to GET vs leeches.
Let the best quackery win!
Something like ‘inadequate thyroid-hormone-mediated regulation of metabolism’.
Certainly that would include primary, secondary, and tertiary hypothyroidism, as well as the various forms of ‘peripheral resistance’, and the conversion disorders. (TSH probably detects the primary form. The question is ‘how widespread are the other things.’)
A good clinical correlate for all of those would probably be the Billewicz score from ’68. Which he pretty much did work out by ‘that which is made better by consuming desiccated thyroid’.
We might want to call all that ‘easily-treatable clinical hypothyroidism’, or ‘twimbbcdt’. Congratulations, trope-namer!
But actually there are consistent reports of people with all the usual symptoms who don’t respond to the sane use of T4/T3 or NDT, but who do improve on insanely high levels of T3.
So I’d actually want to draw ‘hypothyroidism’ a bit wider than “that which is made better by consuming desiccated thyroid”.
And I bet you can get all sorts of ‘dysthyroidism’ too, where there are some resistant tissues but some are fine, and you or your system raises levels of this or that to compensate, and makes some bits of you hyper and some bits hypo at the same time.
If there’s that, we might actually need to understand how it works to treat it. Imagine...
And then, I bet if there are two acquired hormone resistances then there are others, and I bet they’re all horribly intertwined, and lots of nasty pathogens either taking advantage of or causing them, so there’s probably a whole swamp of horrors that get a bit better with thyroid but that no-one would call ‘hypothyroidism’. We’d probably need to call those ‘acquired generalised hormone resistance disorders’, which gives the pleasantly onomatopoeic “aghrd”. And we’re not going to nail those without actually rolling up our sleeves and playing around.
At the current rate of progress it should all be sorted out well after we’ve destroyed the universe by careless use of computers.
Unless it is all being caused by nasty chemicals in the environment, in which case we’ll probably make ourselves so stupid that we just blunder straight back into Malthus’ trap in a few generations. And that should sort it all out ‘the natural way’
That’s wonderfully vague. I bet I can diagnose half the population with having “inadequate” regulation.
A definition should allow easy classification of observed phenomena into two classes: “fits the definition” and “doesn’t fit the definition”. This one… struggles.
Yes, I have such a suspicion, too.
And this I can probably diagnose 90% of the population with? See above.
The meta issue is whether you want to medicalise deviations from the theoretical optimum. On the one hand, sure, it’s nice to move closer to the optimum, on the other hand this means that no one is “healthy”, everyone is “sick” and under care of doctors.
Well, ‘hypothyroidism’ was a very difficult and polymorphic badger in its day. But a thing that is difficult to detect can still be a thing. Consider neutrinos and gravity waves and unicornes, which no man nowadays doubts of.
And as for ‘medicalise deviations from the theoretical optimum’, most chronic fatigue people are already bothering their poor doctors incessantly, and being given (with the best will in the world) a selection of nasty things that mildly alleviate some of their symptoms. CFS is a horrible thing. As Hitler says in the film Downfall:
“‘Chronic Fatigue Syndrome’ ? they might as well call Leprosy : ‘Chronic Dandruff Syndrome’”.
Isn’t it still “its day”?
Think of it this way. There is a set of people with some clinical symptoms which look maybe-possibly like hypothyroidism. There is a another set of people with abnormal TSH. These sets partially intersect and form three subsets. Subset one is the intersection: people with both clinical symptoms and abnormal TSH. They are a clear case and there are no problems here. Subset two is abnormal TSH and absence of clinical symptoms. We interpret that as thyroid gland falling apart and expect clinical symptoms to appear in the near future. We are not concerned with people either.
Subset three is the one you are interested in: people with normal TSH and clinical symptoms. What about them? Well, as you mention diagnosing hypothyroidism solely on the basis of clinical symptoms is difficult. So in this subset some but not all people will have a thyroid malfunction, and some will have other problems, maybe instead or maybe in addition to thyroid issues.
By the way, the people who you insist on calling “fat, tired, and with dry skin” are in subset three. They exhibit clinical symptoms of hypothyroidism.
Your suggestion is that we give some dessicated thyroid to subset three and see if it helps. Well, it’s pretty clear that it will help some people and will not help other people (for example, those fat and tired ones). However that is true of many medical interventions.
For example, there are probably males in subset three with low testosterone. So giving testosterone to subset three males will also help some people and not help others. There also probably people with low-grade systemic infections in there. Giving broad-spectrum antibiotics to subset three might well help some people and not help others. There are likely people with autoimmune disorders there...
Basically, if you have little idea about what’s wrong, trying a variety of drugs hoping for a lucky hit is not necessarily a horrible strategy (depends on the side-effects of the drugs and the consequences of doing nothing), but it’s not much advancement from the good old times.
Let me quote from West Hunter:
P.S. Note the awe-inspiring lack of smugness with which I present:
IMPAIRED ACTION OF THYROID HORMONE ASSOCIATED WITH SMOKING IN WOMEN WITH HYPOTHYROIDISM
BEAT MÜLLER , M.D., HENRYK ZULEWSKI , M.D., PETER HUBER , P H .D., JOHN G. RATCLIFFE , M.D., AND JEAN -JACQUES STAUB , M.D.
I bloody said it would turn out to be the reason smoking’s bad for you, didn’t I? And at the same time it’s evidence that acquired hormone resistance exists, and this one fingers an environmental cause.
Opinions are divided. There’s me and some dead guys, and everyone else. Everyone else thinks it’s a solved problem.
They absolutely do! Back in the day, they would have been referred to endocrinologists on suspicion of hypothyroidism, who would have (if they were very sophisticated and modern endocrinologists) used Billewicz’ test to sort them into definite, definitely not, and ‘therapeutic trial’ groups. His test didn’t rate these three symptoms, or lethargy or stupidity, because most everyone he saw had them, so he would look at all their other symptoms to make the diagnosis, looking for things like slow reflexes that are characteristic of hypothyroidism, and weight them to get a score. It really is a very careful piece of work, that test.
He would treat the ‘definites’ without further ado, send the ‘definitely nots’ off to people who were into diabetes etc, and be careful with the rest. Including all sorts of unreliable lab tests and therapeutic trials.
Luckily the therapeutic trials are not difficult to do, because with desiccated thyroid/T3 you seem to get either get a fairly rapid improvement, or you get hyper symptoms. (you might get both of course, in which case dose probably too high)
Other popular ways of trying to work it out involved cholesterol and basal metabolic rate.
Broda Barnes thought waking armpit temperature beat all this and just handed it out to anyone who woke up cold.
And the fact that it has been sprayed around at random for a hundred years without anyone having a word to say against it implies that it’s pretty damned safe. If you give yourself a massive overdose, then sure, you can probably give yourself a heart attack, but you’d need to be way way more criminally careless than I can imagine any (modern) doctor being.
Osteoporosis and atrial fibrillation (both ghastly things) are associated with low TSH, so it’s doubtless not a good idea to induce hyperthyroidism in people. And I think we should be careful not do that.
Barnes might have been deluded. I certainly started off thinking that he was, but one thing he was into was records and statistics. He thought his patients healthier than the general population. Including low rates of heart trouble. Which is just bizarre if what he was seeing was today’s CFS etc population, who seem to be really ill and then go on to be even more ill. Unless his treatments actually helped.
Hell, let’s do all four! If there’s a subset of fat tired stupid lethargic CFS patients with dry skin and high Billewicz scores, low basal metabolic rates, high cholesterol, and low waking temperatures all at the same time, then let’s run the Scottish trial on them and see what happens. That should be enough to break the TSH test, at which point, I imagine there will be an absolute explosion of research.
I couldn’t agree more that it’s really really important to understand mechanism. I’m into ‘explanations’ and ‘causes’. I think you are too. I get the impression that they’re a bit out of fashion in medicine.
Ooh, is it me and you and some dead guys now? Welcome! Sorry some of us aren’t that talkative. Damnit, that means I need another opponent. Devil’s advocate isn’t good enough. It needs to be someone who hates the idea.
Oh dear, poor Charles. The English crown was a bit of a poisoned chalice for the Stuarts wasn’t it? Still, he made it to 53 and they did call him the Merry Monarch. Anyone who dies in office of excessive mistress-related-activity hasn’t had a totally wasted life.