Thyroxine and treatment of hypothyroidism: seven decades of experience

[helvella]

Why do we have such difficulty in finding endocrinologists who seem to understand? The abstract below seems to explain that wonderfully well.

Because there are so many comments to be made, I shall depart from my usual approach and will use footnotes.

I couldn't help but hear words such as "smug", "self-satisfied", "complacent", "ignorant" (of more recent research) whooshing through my brain as I read this abstract.

Endocrine. 2019 Jul 18. doi: 10.1007/s12020-019-02006-8. [Epub ahead of print]

Thyroxine and treatment of hypothyroidism: seven decades of experience.

Mateo RCI1, Hennessey JV2.

Author information

1 Division of Endocrinology, Department of Medicine, Rush Medical College, Rush University Medical Center, Jelke Building 6th Floor, 1750 Harrison Street, Chicago, IL, 60612, USA. [e-mail].

2 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Gryzmish 6, Boston, MA, 02215, USA.

Abstract

Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. [1] There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. [2] In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh sheep thyroid glands was noted to be effective. [3] Within a few years, the danger of over-dosage with extracts was recognized and dosing guidance indicated a low dose start and gradual increase as required based on symptoms. [4] Orally ingested extracts became widespread and by 1914 thyroxine had been crystallized. In 1927, thyroxine, was synthesized as an acid, limiting oral absorption. Finally a sodium salt of thyroxine was introduced in 1949. These synthetic preparations were then made available for clinical use. Prior to 1970, extracts and combination therapy with synthetic LT4 and LT3 were standard replacement until the peripheral deiodinase-mediated T4 to T3 conversion documented the endogenous generation of T3 from LT4 in athyreotic subjects. This resulted in advocacy for patients previously treated with combinations and desiccated thyroid be transitioned to L-thyroxine monotherapy. [5] The determination of the optimal dose has evolved such that now a general recommendation for replacement dosage of LT4 is 1.6-1.7 mcg/kg/day. [6] Thyroid hormone extracts were established prior to the FDA's establishment in 1906, and when the Food, Drug, and Cosmetic act of 1938 enhanced the FDA's regulatory authority. In 1997, FDA declared LT4 products to be new drugs subject to regulation and quickly a pharmacokinetic process to determine interchangeability among approved LT4 products ensued. [7] Differences in bioavailability of 12.5% or more may be considered therapeutically equivalent and therefore such products interchangeable. [8] To assure refill to refill consistency, all levothyroxine sodium products now meet a 95-105% potency specification throughout their labeled shelf-lives. [9]Seventy years after Kendall's great achievement in isolating thyroxine, we have thyroxine products with precise amounts of synthetic hormone that meet demanding regulations to assure high product quality, predictable bioavailability given its narrow therapeutic range, and now are left with potential variance in the therapeutic efficacy among different preparations. [10]

PMID: 31321670

DOI: 10.1007/s12020-019-02006-8

ncbi.nlm.nih.gov/pubmed/313...

[1] Yes, hypothyroidism is common. But there is a profound difference between hypothyroidism caused by iodine-deficiency (which appears to be the most common cause in much of the world) and that caused by autoimmune thyroiditis, or any cause other than iodine-deficiency.

[2] A single out-of-context statement. If they did this in the sixth century, why not in the seventh and every subsequent century? Was it ineffective for some reason?

[3] Just a note of its effectiveness? Didn't Murray publish and give lectures? Didn't a doctor in Londonderry start a local patient because of Murray's paper/lecture? Indicating excitement and desire to propagate the potential therapy.

[4] Yes, of course, straight into the problem of over-dosage. Not consistency. Not under-dosage.

[5] Because deiodination (conversion) of T4 to T3 has been documented, don't offer T3. What sort of logic is that? No notice whatsoever of whether the patients do as well, or not, on levothyroxine monotherapy.

[6] This isn't a case of dosing having evolved but of extreme over-simplification. Degeneration rather than evolution. No consideration whatsoever of variable absorption - which is very well documented in many papers.

[7] It would be far more honest to have explained, or even just stated, that the FDA took that action due to continuing and repeated failures of the pharmaceutical industry to deliver products which conform to even basic standards of potency despite numerous warnings from the FDA over the years.

[8] A testament to inadequate proof reading. What nonsense as published - "12.5% or more".

[9] Simply, not true. All USA levothyroxine products are required to meet a 95-105% potency over their shelf lives. There are over 200 other countries and many do not impose this requirement. And having a requirement does not mean that the products actually meet that requirement.

[10] But you have just told us that the products are interchangeable…

[jimh111]

Thanks, I'll read it sometime!

Very unusual for a SpringerLink article but you can get the full paper for free. Go to researchgate.net/publicatio... and click on the 'Download full-text PDF' button.

[helvella Administrator in reply to jimh111]

Thanks Jim, I'd missed that.

Possible some of my comments are addressed in the full paper but the abstract is, I feel, dire.

[Greekchick]

helvella,

Am I wrong in thinking that we have moved backwards in the treatment of thyroid disease after reading this or is it my imagination, or the late hour here across the pond? Hmmm.... utterly depressing. 😬

[humanbean in reply to Greekchick]

I would agree - thyroid treatment is going backwards. It is getting simplified, less effective, and more sadistic all the time.

[Greekchick in reply to humanbean]

Hillwoman

Fruitandnutcase

I agree with all of you. In another thread, Marz replied to me that it seemed like a conspiracy - and sometimes, it really seems that way. We are going that direction in Canada with refusals to allow GPs to test for T4 and T3, so who knows where that will go? I have often wondered what is really needed to move things forward and get patients the care they need? If it is a matter of price - governments and competitive forces have managed that before, so there has to be something else. And, T4, T3 and NDT are all manufactured by Big Pharma, so it's not just that either. I shall think on this - because there is clearly an agenda, but whose and why is the real question.

[vocalEK in reply to Greekchick]

I have been reading through clinicaltrials.gov and I am struck by how many of the projects are using a specified dose of product, rather than determining how much a given participant/patient actually needs to start, and then titrating dosage to meet a specific measurable goal (e.g., FT3 level within range). Probably because the researchers have no idea how to do that.

[Hillwoman in reply to Greekchick]

Recently, on his Facebook thyroid group, Paul Robinson was so despondent about the way things are going in the UK and certain parts of Europe that I grew quite worried for him. He is correct though, and so is Helvella, that the situation for thyroid patients is regressing from very bad to even worse.

[Fruitandnutcase in reply to Greekchick]

Don’t think you’re wrong at all - unfortunately. Utterly depressing barely touches it - ‘abandon all hope’ is the phrase that springs to mind☹️

[humanbean in reply to Greekchick]

I could be wrong about this, but it seems to me the rot started in the UK with the reduction in prescription of T3. It has just spread around the world as a money saving device and a profit generating exercise, the attitude being that if the UK can get away with it then so can everyone else.

I'm particularly cynical about the NHS because I think it is within a whisker of getting privatised. I also think that is why Boris has promised money this week for maintenance of the infrastructure. The NHS will be so much more desirable if the infrastructure and its most urgent maintenance requirements have already been paid for by taxpayers before it is sold to investors. A hospital with leaking roofs and sewage leaking into wards is going to be a less desirable investment than one which has been tarted up and has no leaks.

In terms of actual treatment, we, the NHS patients, are being softened up to have lower expectations. Anything we do want we have to be taught to pay for and accept that this is the current norm.

[Greekchick in reply to humanbean]

I agree with you. I have been following the developments of NICE and the NHS for some time, because things travel across the pond over here in Canada. Where I live in Canada we already have some physicians who are private and many services now are available privately. Our province’s goal, I believe, is to go completely private and they are watching others like the UK to see what they will do and are also looking south of the border as well.

I think the softening up process has begun everywhere and it will continue as the population ages and financial pressures continue on our systems. Well said, humanbean.

[crimple]

Thanks for posting, interesting and thought provoking, also exasperating!

[SilverAvocado]

Helvella, A shame this one is a bit rubbish. We've had other history of treatment articles where the author was obviously quite shocked by how unsupported the contemporary treatments are.

Interesting how this abstract really prioritises synthetics, putting their early date at around 1914! Without even mentioning what treatment people were actually taking for all the time that those synthetics were being developed to the point where they were meaningful treatments.

Somehow they've managed to keep NDT on the margins of the story, with not a mention of how they were developed or any key dates! Just jumping straight from people eating the raw thyroid onto extracts without any attention given. It's an interesting example of how a story can be spun, making it sound like Levothyroxine monotherapy was inevitable and there's a clear unbroken line from the Chinese 6th century treatments to your own GP not having heard of T3

[crabapple]

I've just read the full paper. It should be titled " Treatment of hypothyroidism with synthetic Levothyroxine: seven decades of experience in in the USA".

[Aurealis in reply to crabapple]

I might not bother then, but enjoyed helvella’s comments and the other posts here. What a classic demonstration of lack of sophistication and narrow mindedness... aargh

[Judithdalston]

Looks like someone or two thought they needed their academic papers for the year/ academic assessment exercise bumped up with little actual effort...perhaps the paper proper is better!

[crabapple in reply to Judithdalston]

No other excuse for it.

[Greekchick in reply to Judithdalston]

Doubtful, Judith. I agree with your first assessment!

[iroc1969_aunt]

How ridiculous. Just ask any of us who have had a total thyroidectomy. Dr.'s should be required to bring meds up to the level we were before TT. Dr.s have no clue about the reality of the situation including depression as a result of undermedicated or just not the right combination. I have results of my thyroid prior to surgery. My tsh was .5 and i was well in range for T3 and T4. A normal thyroid has some T2 as well as T3 and T4. They need to work on a combination of T2, T3, and T4 in the same percentage that is normal for humans preferably in a time release capsule that makes us feel good all day instead of spinning their wheels admiring accomplishments that don't really help us. What a shame we have to doctor with a endo with the expense involved for the rest of our lives just to get meds that we cannot live without.

[humanbean in reply to iroc1969_aunt]

In the UK doctors get paid incentives to prescribe anti-depressants. There are no incentives to prescribe thyroid hormones.

There used to be incentives to prescribe for hypothyroidism up until 2014, but even then prescribing anti-depressants was more lucrative.

[diogenes Remembering]

This of course is merely a "puff" history of T4 therapy and carefully avoids any controversy about the limitations of its use and its therapeutic value. It's interesting that the author from Harvard was one of the reviewers of our recent paper "Time for a reassessment of the treatment of hypothyroidism". He said this was both "highly eloquent and highly sophisticated"! Compliments indeed. But the brain seems to have then shut down and ignored the paper content and its implications, extrapolating from the tenor of the above: like the style, ignore the message. There seems to be an unshakeable T4 mindset that simply refuses to stop and reconsider.

[silverfox7]

Sheep comes to mind but then that's an insult to the sheep!

[diogenes Remembering]

For another look at Hennessey's attitude to alternatives to therapy, there is this paper in the International Journal of Clinical Practise:

Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy

James V. Hennessey Ramon Espaillat

First published: 30 January 2018 doi.org/10.1111/ijcp.13062

This is open to view.

[helvella Administrator in reply to diogenes]

Thank you for that, diogenes.

In patients who are biochemically euthyroid with LT4 monotherapy but have persistent symptoms, clinicians should thoroughly investigate alternative causes, such as endocrine and autoimmune disorders, haematological conditions, end‐organ damage, nutritional deficiencies, metabolic syndromes, concomitant drugs, and lifestyle.

The cost of doing that investigation, especially if done thoroughly, would be so much greater than a bit of T3 - even at UK prices.

And the reality is that no matter how many medics say that sort of thing, how many ever do that investigation? How many here feel that they have had their persistent symptoms properly investigated? As much as many can do to get a single B12 test.

It is important not to wear thyroid blinkers but Mr Occam and his razor do have a very obvious part to play. If you already know the person has thyroid issues, isn't that the simplest explanation for many issues?

And when it is not directly thyroid, consider other issues which are known either to be caused by thyroid issues or have known associations. Not so much nutrional deficiencies as nutrient deficiencies caused by thyroid disorders. (Nutritional deficiencies coming back to the old favourite - blame the patient for not eating "properly".)

As published, it looks like a grab bag of possibilities without any intellectual guidance.

[vocalEK]

I take exception to this statement (which I have seen before). "...observed that adequate thyroxine dosing required less per kilogram body weight in the elderly." As measured by what?

As I have grown older, my levothyroxine dose has steadily climbed. TSH has gone up as high as 3.46 uIU/mL (0.300 - 4.200 uIU/mL) in 2012 and my dose was raised from 125 mcg to 150 mcg. My TSH after that ranged from 1.13 uIU/mL to 2.1 uIU/mL in 2017, when my dose was raised from 150 to 175 mcg. In 2012 I weighed 202 lbs (91.6 kg) and only a pound heavier in 2017 (92 kg). This would make my dosage go from 1.6 mcg/kg to 1.9 mcg/kg.

My FT4 was 2.4 pg/mL (0.60 - 1.70 ng/mL) in 2017 when they finally began measuring it. FT3 was very low in range at 2.64 (2.57-4.43 pg/mL).

In October 2017, my FT3 dropped below the new range at 2.3 (2.0 - 4.4 pg/mL] I began taking Cytomel (T3) in December 2018. My FT3 climbed to a high of 4.2 pg/mL in March 2019. My PCP was concerned because my TSH had dropped down to 0.01(0.300 - 4.200 uIU/mL). I dropped my Cytomel dosage by half and FT3 went down to 2.6 pg/mL. FT4 went down to 1.5 (0.60 - 1.70 ng/mL) - still high in range. But TSH only went up by 0.01 to 0.02.

In 2012 I was 66 years old. As I aged, my need for thyroid replacement only went up. I began losing weight in 2017 and am now down to 80 kg. So my current levothyroxine dose works out to 2.1 mcg/kg. I could stand to reduce my levothyroxine by about 25 mcg, but I need more Cytomel to get my FT3 up into the top quadrant of the range.

Yes, I know that I am only one case, but I don't believe it is a general rule that need for thyroid replacement goes down with age. Only that TSH goes higher as our need for thyroid replacement grows as our body ages.

[Judithdalston in reply to vocalEK]

Snap...as i’ve aged and weight gone down ( result of sepsis) on same levo.dose my TSH has raised considerably, and needed T3 to improve hypothyroidism symptoms. So papers’ observation re weight, dosing and aged is rubbish!