The Starting Dose of Levothyroxine in Primary Hypothyroidism Treatment

[helvella]

This paper compared patients started on a calculated full replacement dose of levothyroxine against starting at 25 micrograms and incrementing every four weeks.

Since this paper - and others - the idea of starting on full replacement dose has permeated the guidelines in several countries.

Unfortunately, it appears that cost saving is a significant part of the rationale.

My own belief is that somewhere between the two extremes is probably the best for the patient. But that might also be the most expensive in terms of tests and prescription changes - as well as doctor time.

(I just posted this in a reply on another thread but realised it might be of general interest.)

Original Investigation

August 8/22, 2005

The Starting Dose of Levothyroxine in Primary Hypothyroidism Treatment - A Prospective, Randomized, Double-blind Trial

Annemieke Roos, MD; Suzanne P. Linn-Rasker, MD; Ron T. van Domburg, PhD; et alJan P. Tijssen, PhD; Arie Berghout, MD, PhD, FRCP

Author Affiliations Article Information

Author Affiliations: Department of Internal Medicine, Medical Centre Rijnmond-Zuid, Rotterdam (Drs Roos, Linn-Rasker, and Berghout), Department of Cardiology, Erasmus Medical Centre, Rotterdam (Dr van Domburg), and Department of Cardiology, Academic Medical Centre, Amsterdam (Dr Tijssen), the Netherlands.

Arch Intern Med. 2005;165(15):1714-1720. doi:10.1001/archinte.165.15.1714

Abstract

Background The treatment of hypothyroidism with levothyroxine is effective and simple; however, recommendations for the starting dose vary considerably. To our knowledge, the levothyroxine starting dose has never been studied prospectively.

Methods We conducted a prospective, randomized, double-blind trial that compared a full starting levothyroxine dose of 1.6 μg/kg with a low starting dose of 25 μg (increased every 4 weeks) in patients with newly diagnosed cardiac asymptomatic hypothyroidism. Safety was studied by documenting cardiac symptoms and events, and efficacy was studied by monitoring thyrotropin and free thyroxine levels and by assessing improvement of signs and symptoms and quality of life.

Results Seventy-five consecutive patients were enrolled, of whom 50 underwent randomization. At baseline, the severity of hypothyroidism and age were comparable in the full-dose (n = 25) vs the low-dose group (n = 25): thyrotropin, 61 vs 48 mIU/L; free thyroxine, 0.56 vs 0.64 ng/dL (7.2 vs 8.2 pmol/L); and age, 47 vs 47 years. No cardiac complaints or events were documented during treatment or at bicycle ergometry at baseline, 12 weeks, or 24 weeks. Euthyroidism was reached in the full-dose vs the low-dose group in 13 vs 1 (4 weeks), 19 vs 3 (8 weeks), 19 vs 9 (12 weeks), 20 vs 14 (16 weeks), 20 vs 18 (20 weeks), and 21 vs 20 (24 weeks) patients (P = .005). However, signs and symptoms of hypothyroidism and quality of life improved at a comparable rate.

Conclusion A full starting dose of levothyroxine in cardiac asymptomatic patients with primary hypothyroidism is safe and may be more convenient and cost-effective than a low starting dose regimen.

Primary hypothyroidism is a common disorder, most prevalent in women and most often caused by autoimmune thyroiditis. Overt hypothyroidism can present with classic symptoms of fatigue, weight gain, cold intolerance, and constipation. Fatigue, one of the major complaints, together with depression,1 neuromuscular signs and symptoms,2 and diastolic dysfunction3 can all lead to an impaired quality of life in patients with hypothyroidism. Furthermore, abnormalities of lipid metabolism, hyperhomocysteinemia, and arterial hypertension occur with increased frequency in hypothyroidism4,5 and are associated with an increased risk of premature atherosclerotic vascular disease.6,7

Although the treatment of hypothyroidism with levothyroxine, one of the most commonly prescribed drugs, seems effective and simple, recommendations for the starting dose of levothyroxine vary considerably: from 50 μg to a full replacement dose of 1.6 or 1.7 μg/kg in healthy adult patients younger than 65 years and from 25 to 50 μg/d in older patients and patients with known ischemic heart disease.8-13 The safety and efficacy of different initial doses of levothyroxine have, to our knowledge, never been studied prospectively. Moreover, in daily practice, many physicians still promote the dogma of “start low and go slow” irrespective of age or patient. This dogma is based on the association of hypothyroidism with ischemic heart disease.14,15 Interestingly, and in contradiction to this dogma, high doses of levothyroxine have been given to patients with myxedema coma, a patient group in whom a high prevalence of cardiac ischemia would be expected, without untoward effects.16 However, when levothyroxine was combined with triiodothyronine (T3) in the treatment of such severely ill patients, fatal outcome has been reported.9 Several case series and retrospective studies, dating back 4 to 6 decades, have shown considerable variability in the cardiac responses of patients with hypothyroidism to thyroid hormone therapy, ranging from precipitating acute coronary syndromes in patients without previous cardiac symptoms14,17 to controlling or even abolishing preexisting angina.17,18 These studies can be criticized for being retrospective, cross-sectional, or uncontrolled; for having small numbers of patients; or for using desiccated thyroid preparations that contain differing and therefore unpredictable amounts of both levothyroxine and T3. Levothyroxine is converted into T3 by type 1 deiodinase in the liver.19 The evidence for local deiodination of total thyroxine (T4) in the human heart by type 2 deiodinase20,21 and the increased expression of type 2 deiodinase in the mouse heart during hypothyroidism22 could indicate mechanisms of adaptation in case of low or high serum levels of T4.

Most reviews report a period of 4 to 6 months before normalization of plasma thyrotropin and free thyroxine (FT4) levels is attained.8-12 A more rapid normalization could be of great benefit to patients with hypothyroidism regarding the reduction of cardiac risk factors, improvement of quality of life, and being less cumbersome for regular visits to the clinics. However, the efficacy and safety of different initial doses of levothyroxine have surprisingly never been studied prospectively in patients with primary hypothyroidism. This prompted us to compare a full initiating treatment dose of levothyroxine (1.6 μg/kg)23 with the classic approach of “start low and go slow” in a prospective, randomized, double-blind study. The aim of the study was to prove that restoration of plasma thyrotropin and FT4 levels within the normal reference range can be performed with a straightforward high-dose regimen without any increased risk of major adverse cardiac events.

Full paper accessible here:

jamanetwork.com/journals/ja...

I think we need to realise that the best approach might well be one which tested every single day. (Possibly even more often very early. To catch the situations in which the thyroid hormone seems to run out well before the next dose.) That would allow blood levels and clinical assessment to go together and raise dose fairly fast, but not too fast for the individual. Of course, the cost of so doing is prohibitive.

But that is behind my hope that some technological development would allow indirect assessment of thyroid status - if not actual measurement of thyroid hormones.

[helvella Administrator]

I think total thyroidectomy is a case where full replacement dose will be needed - and quite soon. But there will always be an issue when the person undergoes such a sudden change. And it needs to be a lot more considered than applying a simplistic formula and assuming all will be well.

And I agree that T3 is likely needed in most cases.

[TSH110 in reply to helvella]

And total atrophy of the gland should be included too

[jgelliss]

So well said . Thank you. I'm one with TT that was so mismanaged with high doses of T4 instead of adding some T3 to the T4 mix.

[jgelliss]

Totally agree .

[pennyannie]

And also those of us who have had RAI thyroid ablation for Graves Disease.

[TSH110 in reply to pennyannie]

And those with a gland that completely atrophied due to atropic autoimmune thyroiditis

[jade_s]

Thanks helvella, always interesting info!

Do you happen to know where the 1.6 ug/kg recommendation comes from? Is it based on studies of euthyroid people, or cancer patients on suppressive doses, or ... some very outdated methodology, etc?

I'm just very curious because it's referred to so frequently. Maybe we need to ask diogenes lol.

Apologies if I've missed other discussions on this. Thanks in advance

[helvella Administrator in reply to jade_s]

One of the troubles with it is that you can find references to something like 1.2 to 1.7. They can't all be right!

Also, as diogenes would point out, even if 1.6 were the undisputed number, it would be a population average. And you can't take a population average and apply it to individuals.

For a start, we see many mentions of poor absorption, which would shift the number up. (Whatever the cause - gastroparesis, taking levothyroxine with breakfast, splitting tablets and losing some, missing doses, sub-potent tablets, or anything else.)

Then we see some who seem to need less - and I have no explanation for that if they have no remaining thyroid tissue.

[jade_s in reply to helvella]

All great points. Thank you!

[TSH110]

Is the approach a direct descendant of NDT dosing I wonder?

I was kept on 25mcg for three months, I felt absolutely dire and it was hellish for another six. I wish they had started higher, if my heart withstood a rise of TSH from undetectable to 110 in around a week (and lord knows what vacillations before this) chances are it could have handled a 50 mcg starter dose and a much faster titration up. I had lots of heart pains for three decades (2nd decade I was told it was just a hormonal thing women of my age get by John Ratcliffe Hospital 🤬). They worsened on Levothyroxine and improved greatly on NDT.

I agree a middle ground is probably best, but will be ignored for cost reasons, because we’re not worth it 😠😡🤬.

I wonder if my relatives who made very rapid recovery on Levothyroxine got full replacement doses straight away, both had thyroid cancer. I couldn’t understand why I felt like pants on it even after two years.

[helvella Administrator in reply to TSH110]

I am not aware of any research into day by day, or even hour by hour, changes when starting levothyroxine.

We need that. I suspect that too low a dose causes the compensations the body can make when there is insufficient thyroid hormone to fade before there is enough to cope.

Also, it seems to make sense that levothyroxine by mouth could effectively get used up before the next tablet is due. And with little of the buffer that bound T4 (in the blood) provides, the levels could even worsen.

There is, indeed, evidence for use of substantial injections of T4 and T3 in cases of myxoedema coma. But that says little about the best approach for the rest. And if the decision is to save someone's life by injecting high dose - or not - risk is probably easier to justify.

[TSH110]

They trot out that rot about NDT being unreliable and having any old amount of T4 and T3 you care to guess In every tablet. It really annoys me when such lies are stated as fact.

[helvella Administrator in reply to TSH110]

The one that gets me is when they justify that view because each animal is different.

As if the thyroids from one animal make ten or a hundred, or whatever number makes sense. Then they process the next thyroid.

Even if their quality control is poor, it wouldn't be one by one!

[helvella Administrator]

Until around 1985, assessment of desiccated thyroid in the USA really was stuck in the dark ages. Based on iodine content. Then they changed to what we now have, actual lab measurements of the product.

I get the impression some medics have not caught up. Only the medics approaching retirement would actually have been practising under the old approach.

Even then, Armour had a history of having an animal lab where they tested its potency.

They should really look at the history of levothyroxine in the USA. Around the turn of the century, the FDA forced all manufacturers to apply for full authorisation as a new drug. This came about due to continuing issues of sub-potency and recall after recall.

[helvella Administrator]

There have been quiet a few studies which do blood tests every hour (or whatever).

But I do not remember ever seeing that in someone who has just been diagnosed and has never taken any thyroid hormone tablets.

We especially need that in some people who are severely hypothyroid. But ethics probably preclude it ever being done.

(I think the tests I have read about can see how FT4, FT3 and TSH change after a dose. But they'd have to do much else to demonstrate cellular uptake.)

[helvella Administrator]

Wouldn’t it be sensible to test all hormones at the same time?

I think that there is one reason not to do so:

Resources.

Whether money or laboratory staff or anything else.

And that many doctors would be overwhelmed by a multiplicity of results.

[BB001]

Interesting, thank you. What about those people with longstanding hypothyroidism whose adrenal function has been affected? The research fails to mention how long after the onset of symptoms the levothyroxine is prescribed.

As usual everyone is dumped together with no consideration of individual requirements that would necessitate a different approach.

[annabianca]

All the subjects in the study had overt hypothyroidism since their FT4 levels were under the reference range. Their TSH was high.

TSH median (range) group 1 61(14-79) group 2 48(11-262)

FT4 (reference range 0.78-1.79) group 1 mean 0.56 (±0.25) group 2 mean 0.64(±0.19)

Probably people with quite severe hypothyroidism haven't much thyroid functionality left and are similar to people without a thyroid in their levothyroxine requirements.

In theory a full replacement dose shouldn't make anyone overmedicated, even people without hypothyroidism. But I read somewhere that, even with a TSH of zero, a working thyroid will produce some hormones. Therefore there is the risk that some people may end up overmedicated if they take a full replacement dose.

Also the levothyroxine dose of 1.6-1.8 mcg/kg body weight is approximate and the dose is more related to the lean mass (2.2-2.4 mcg/kg). Therefore for overweight people the full replacement dose could be too much.

The medicine leaflet for Eutirox (by Merck), which is the most used levothyroxine in Italy, says that the average maintenance dose is 2-2.5 mcg/kg. I have no idea where that is coming from. Similar levothyroxine products by Merck in other countries have different indications. In France the replacement dose is 1.7 mcg/kg, while the suppression dose is 2.1-2.5 mcg/kg. In the US the replacement dose is 1.6 mcg/kg.

If overmedication is to be avoided at all costs, a full replacement dose, for people with subclinical or mild hypothyroidism, doesn't seem the best approach.