Hypothyroidism, Euthyroidism and Hyperthyroidism can be regarded as differently regulated entities

[helvella]

Today’s blog is an abstract of a paper which seems to be doing what I believe is an essential step in understanding thyroid hormone disorders. They are using computerised modelling.

I believe there is no other way to really understand because when you try to deal with all the variables (even keeping them as simple as TRH, TSH, FT4 and FT3), the interactions are beyond most human minds.

Their conclusions suggest that being Hyper, Hypo or with decent thyroid hormone levels cause three distinct ways in which these parameters interact. So the traditional simplistic ideas need to be reconsidered and they should not carry on as they have done for so long.

Such a pity that this level of understanding was not applied when first the TSH tests became available.

Nice to see it is a paper from (West) Yorkshire. We don’t see very many from there…

J Clin Pathol. 2013 Feb 19. [Epub ahead of print]

Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: in vivo and in silico data suggest a hierarchical model.

Midgley JE, Hoermann R, Larisch R, Dietrich JW.

Source

North Lakes Clinical, North Lakes Clinical, Ilkley, UK.

Abstract

AIMS:

Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) is a prerequisite for improving diagnostic reliability and clinical decision making.

METHODS:

We (1) retrospectively studied the relationship between TSH and FT(4) in a large unselected clinical sample (n=6641) of primary hypothyroid, euthyroid and hyperthyroid subjects, and (2) applied a mathematical model of thyroid hormone feedback control to assess the relation between structural parameters and TSH levels in the different functional states.

RESULTS:

When separately analysing total sample and untreated subjects, the correlation slope for logTSH versus FT(4) for hypothyroid subjects was significantly different from that of the euthyroid panel and hyperthyroid subjects (the latter being compromised by reaching the TSH assay's lower detection limit). As trends between functional states changed, each functional segment appeared to become differently regulated. Theoretical modelling and sensitivity analysis revealed that the influence of various structural parameters on TSH levels also depends on the overall function of the feedback loop.

CONCLUSIONS:

Our data suggest that the states of hypothyroidism, euthyroidism and hyperthyroidism can be regarded as differently regulated entities. The apparent complexity could be replicated by mathematical modelling suggesting a hierarchical type of feedback regulation involving patterns of operative mechanisms unique to each condition. For clinical purposes and assay evaluation, neither the standard model relating logTSH with FT(4), nor an alternative model based on non-competitive inhibition can be reliably represented by a single correlation comparing all samples for both hormones in one all-inclusive group.

PMID: 23423518 [PubMed - as supplied by publisher]

ncbi.nlm.nih.gov/pubmed/234...

Rod

Picture is, inevitably, Ilkley Moor.

[PinkNinja]

Excellent news! Hopefully doctors will start listening!

Carolyn x

[PR4NOW]

Rod, R. Hoermann seems to be doing a lot of good work, wish there were more like him.

Thanks for the link, almost tempted to buy the article. Now I really wonder what Lyn is working out with him. PR

[NBob]

JE Midgely has co-written and co-written other papers in a similar vein. Such as

Spurious conclusions on analog free thyroxine assay performance.

ncbi.nlm.nih.gov/pubmed/177...

As a Yorkshire person it gladdens my heart that good research is coming out of my home county.

[helvella Administrator in reply to NBob]

It heartens to see that at least some scientists are doing their best to improve the situation.

But disheartening how long it will take to get something relevant from papers like that into clinical understanding.

Still, the positive outlook is that research is getting from the lab to the patient in record time - as here!

(My birth county too.)

[NBob in reply to helvella]

I think that this could be his most important paper (for us)

TSH Measurement and Its Implications for Personalised Clinical Decision-Making Journal of Thyroid Research Volume 2012 (2012), Article ID 438037, 9 pages doi:10.1155/2012/438037

if I've read this correctly it says that individuals have a set point for TSH the is narrower than the reference range and that each individual's set point is different for that individual.

this should blow the "you're OK because you are in the reference range" statement out of the water.

This paper is particularly important when combined with Good Medical Practice which says in the preamble that a doctor MUST treat patients as individuals and respect their dignity and reiterated at paragraph 21 (c) where it says a doctor MUST treat each patient as an individual.

[helvella Administrator in reply to NBob]

I certainly agreed back in January!

thyroiduk.healthunlocked.co...

And still do.

I am still regularly amazed at the dreadful lack of understanding, and appalling misuse of statistics in medicine.

[NBob in reply to helvella]

Your link is where I got it from!

As you may have picked up, I think that patients should start complaining about their poor treatment, most of which starts with the reference range nonsense.

if we can get GPs past that we have achieved a massive amount. Any ideas how we can get this to GPs in a way that they will accept?

Perhaps a letter to the BMJ?

I am starting to get a "How to Complain" package together for patients and some form of CPD for GPs. A carrot and stick approach.

[helvella Administrator in reply to NBob]

Ho ho!

I think that a lot of people feel that individual GPs are all too often, and in their own ways, victims as well. Of a system which does not equip them to handle thyroid issues, does not take their referred patients and treat them properly, even cuts off the hands of those who try to request blood tests such as FT4 and FT3.

(Though it also appears that some GPs really don't even do what they clearly are allowed and able to do.)

I think a letter/article to the BMJ is well worth considering. They are not averse to publishing things that get attention.

I can't help feeling that those responsible for CPD - e.g. the doctors who produce the units for Pulse - should be taking patients on board in the development of the materials.

But, except in the most egregious cases, I do not think that targeting individual doctors is a productive line to take.

[NBob in reply to helvella]

Any responsible body can write or provide Continuous Professional Development documents or activities not just Pulse. There is a lot of information we have that is not being disseminated to GPs. GPs are notious for ignoring what others tell them and the GMC is attempting to redress this in Good Medical Practice and its subordinate specific guidance.

The best way for GPs (or any supervisory body up to the courts) to accept a non Medical College written CPD course or document is to write CPD in accordance with (or as near to) the guidance produced by the Academy of Medical Royal Colleges.- Standards and Criteria for CPD Activities aomrc.org.uk/publications/r.... As this guidance says, "external accreditation of these activities will help doctors to recognise that the activities are likely to be of sufficient quality and free from bias or competing interest The Academy is the National Accreditation Authority recognised by the EU, which sets out standards". These standards mainly apply to training courses and the like but I'm sure we can either adapt literature to meet relevant criteria or find other suitable guidance.

This carrot is crucial because the GMC's revalidation framework. gmc-uk.org/CPD_guidance_Jun... in the preamble expects "patients to give feedback to doctors about areas where CPD may benefit their care". In other words highlight areas where the GP hasn’t kept his/her knowledge and skills up to date so that they can get up to date and improve their care of their patients.

My thought is that the patient gives the GP TUK written CPD documents whe nthe aptient becomes aware that the GP has not kept his/her knowledge and skills up to date. This is because the GMCs CPD guidance states that at paragraph 12 "Not all CPD opportunities will be planned. Opportunities for informal learning and reflection about your (the GPs) performance will arise spontaneously from your (the GPs) day-to-day practice. This can be one of the most fruitful forms of CPD because it links directly to your everyday work". In other words, a discussion about hypothyroid matters with a patient is a spontaneous opportunity for CPD.

This is amplified further in paragraph 13 where the CPD guidance states that "You (the GP) should therefore ask for, and be receptive to, advice from others about your learning and development. This includes seeking feedback from patients, carers and colleagues". Feedback from patients includes a patient giving a GP information about hypothyroidism either verbally or in writing. This feedback is best if it is accompanied by references and accredited. That’s where Thyroid UK come in by helping patients give that feedback and providing CPD for the GP. If the patient records what they have given to the GP, this can then be used as evidence at later date if necessary. (hopefully never)

The GP should then reflect on that CPD as required by the CPD guidance which states that "You (the GP) must reflect on all aspects of your (the GP) professional work. This should be informed by discussion with others and by specific evidence, such as data from audit, complaints and compliments, significant events, information about service improvements, results of workplace-based assessments and feedback from patients and colleagues" In other words the GMC expects GPs to take notice of complaints and respond to them and it will monitor how GPs dealt with those complaints.

The GMC's guidance on CPD goes on to say at paragraph 18 "You (the GP) must also reflect on what you (the GP) have learnt from your CPD activities and record whether your CPD has had any impact (or is expected to have any impact) on your performance and practice. This will help you assess whether your learning is adding value to the care of your patients and improving the services in which you work". In other words, the GP must reflect on what the patient has told him or her about how s/he has not kept up to date and record what s/he is going to do about this feedback.

The point of CPD is to keep a GP's knowledge and skills up to date. We know that GPs are not doing that from al lthe awful reports on the forum. The Government is making the GMC more proactive in pushing GPs to get up to date and is allowing the patient to participate in that process. We must take advantage of this in a positive way by producing some Form of CPD and "training" patients to deliver the CPD. In other words giving feedback and making complaints.

[helvella Administrator in reply to NBob]

I think your research into how the systems have been set up, are supposed to work, and boundless optimism that we can make a difference is admirable.

I'd love to think you are right.

Will certainly be thinking about the issues...

Feel free to PM me if you wish.

[Hidden in reply to helvella]

agree

[helvella Administrator in reply to NBob]

And this blog where the paper says that individual TSH variability over a year is only 0.5in healthy folk:

thyroiduk.healthunlocked.co...

[diogenes Remembering in reply to NBob]

Glad to have been of some help (I hope). I'm no doctor, but long retired as a physical chemist, molecular biologist and clinical trials coordinator for blood test development. I invented the one-step FT4/3 tests in Amersham 30 odd years ago. Until 1985 they were used together with TSH, because the TSH test wasn't then sensitive enough. When that test became sensitive, tick box mentality took over, and cheapness overcame diagnostic superiority - ie TSH became the screen and the FT4/3 took a back seat. I always thought this wrong, but it took me until Rudolf Hoermann produced results that I knew wuld change matters. We collaborated and drew in others, with the results you see. I too hope it changes things.

[NBob in reply to diogenes]

Well, diogenes,

What you have just posted is really interesting, particularly the one step FT4/3 tests. I didn't know about that.

What is your view on how to use your recent research?

[diogenes Remembering in reply to NBob]

Hi,

Simple: go back to what was optimal when TSH assays were insensitive and FT4/3 assays had to be used in conjunction. That is, intelligent diagnosis! Fact: all reference ranges for tests are based on 95% inclusion of "correct" samples and 2.5% either side which are "outside" but only by statistical definition (they are still "normal" though). Thus, 5/100 people, though normal, are classified by pure numerological grounds as "abnormal". Add to that the imprecision of any assay (around 3-5%) then by accident, up to 8-10% of people would get "abnormal results" - 5% always outside, perhaps another 3% who were just at the right side of the boundary but, given the unavoidable test imprecision by accident, put them over on the "wrong" side at the occasion of the test. Add to this the fact that in the thyroidological area, the setting point for individuals is far more closely controlled for eg TSH than is indicated by the 95% reference range you get into real trouble about what is "normal" for an individual if you use TSH as the setting screen. My opinion: all tests should be done if a given result by one test doesn't chime in with the patient's subjective feeling. And this MUST be paramount over number-counting! NB: FT4/3 are much less prone to "wandering about" in values day to day, unless critical illness sets in!

[helvella Administrator in reply to diogenes]

diogenes,

Thank you so much for your contribution.

I feel that medics are so busy shouting about the "exquisite sensitivity" of the current generation of TSH tests that they entirely miss the meaning of the word "sensitivity" as opposed to its utility in diagnostic terms.

Why - we even have the bizarre situation in which the word "suppressed" as applied to TSH testing is now used when current tests are sensitive enough to detect and measure some TSH. It might have made some sense when TSH tests had a relatively high lower limit of detection. It is now a misleading,seemingly random, term for low TSH - and one that has no obvious, accepted definition.

Rod

[diogenes Remembering in reply to helvella]

Hello,

Just to say I have an "anecdote" (my wife would kill me if she knew I was calling her that!) to whom I've been married for almost 50 years. That is, 44 or so years ago she contracted Hashimoto's thyroiditis, which rapidly and completely destroyed her thyroid. Since then, she has been on T4, and has never had a detectable TSH in all that time except for one occasion. That was when one of our GP's swallowed the TSH-must-be-normalized line and reduced her T4 from 125/150 to 100. OK TSH was normalized but hypo symptoms (high cholesterol, dry skin, hair etc) came in straight away within a week. Since then, she lives with FT4 high-normal, TSH undetectable, T4 dose 125 but 150 if going hiking, and as far as thyroid is concerned, in good health (arthritis aside). OK an anecdote, but there are lots of them about! One thing that annoys me , thinking about doses - the big steps between doses (50,75,100,125,150). In Germany there are 12.5 steps rather than 25, which leads to better fine tuning.

[NBob]

That's marvellous. I would like to copy and paste that for my Endo if you don't mind.

I was really thinking about promoting your research such as letters to the BMJ and Lancet, the Chief Medical Officer, NHS Medical Director, using it in correspondence to Clinical Commissioning Groups etc. I think that the letters should be on the lines of Good Medical Practice says you should treat patients as individuals, then quote your study to show that each individual has their own set point,then showing that treating a patient as a sample of a population (with reference to you post above) is not treating a patient as an individual. Any thoughts?

[diogenes Remembering in reply to NBob]

Sorry for the written diahorrea but when you see scientific light at the end of a long tunnel, it's quite invigorating. I have (as Martin Luther King once put it) "a dream". That is, what I would consider as the optimal strategy for thyroid function diagnosis. It would be quite different from today. The first requirement would be that all manufacturers of FT4/3 tests standardized their performance so that they all got essentially the same result from a given sample ( they do not nowadays because of sloppy development and weak control of test performance by the regulatory authorities). However, this could readily be rectified by setting standards of performance, which if not met, would result in refusal to allow commercial sale. Given that step, this is how I would see the optimum strategy, regardless of cost.

First: everyone at about the age of 21-22 years would give a blood sample when obviously healthy and not suffering from severe disease, and have their FT4/3 measured. This would be archived in their medical records for future reference. (NB in healthy people FT4/3 doesn't change much from 20-at least 65 years). Also it's unusual to develop thyroid disease as young as 21, though a minority might get it. Second, when someone develops thyroid disease eg becomes hypo in later life, then they would be given a suitable mixture of SLOW-RELEASE T4 and T3 tablets, and their dose would be titrated to mimic what their historical levels were in their medical records. In this way there are two advantages. 1) you are taking into account the individual genetic/physiology state of the patient when restoring the dose of T4/3, 2) you are not (as today) giving people a sudden "bolus" of hormone when it's taken once a day, but spreading it throughout the day, as the normal thyroid does when active. With the present "bolus" once a day dose, the FT4 level loses nearly 10% of its value after 24 hours, to be restored by the next pill. Also, I worry about using thyroid extract, because the T3 content is not constant, and giving T3 as a "bolus" can be dangerous. Whether this over the long term is not advantageous I do not know, but no one else knows either. Notice I say little of TSH. This has its uses in detecting hypothyroidism, but not so much in controlling therapy. That's all. A counsel of perfection, maybe unachievable.

[helvella Administrator in reply to diogenes]

My fanciful thoughts are not a million miles away. I have been thinking about the possibility of avoiding the gut and delivering directly into the bloodstream using some sort of dosing machine - whether implanted or external. We hear of so many gut issues in those on thyroid hormone I do wonder if any are caused by the high concentration of hormones at least in the lumen of the gut.

Plus automated semi-continuous testing. I see that there are such devices in development at least for glucose:

wired.co.uk/news/archive/20...

Much less likely to be achieved than your modest proposal.

[NBob in reply to diogenes]

You point to the lack of HEALTH in the National Health Service.

What you propose is pro-active health promotion and disease prevention. The current NHS is about disease management.

The NHS was set up in the year that the World Health Organisation formulated the definition of health "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." (1948)

Today's GPs aim for "not chronic or dead", it seems to me.

That is laudable aim.

Does the MHRA license tests?

[NBob in reply to NBob]

I'm making too many typos

I mean that diogenes proposal is laudable, not "not chronic or dead".