helvella - Estimation of Levothyroxine Dosing in Adults

A discussion about the use of formulas to estimate levothyroxine dosing.

Introduction

Years ago, I addressed the question of using a formula to determine levothyroxine dosing. Having observed that, over many years, thyroid specialists have both promoted dosing by weight and dismissed it as a poor approach, why is there a continuing split?

As a part of my investigation, several formulas were implemented as a spreadsheet – currently seven different approaches.

You will realise the very fact that there are several formulas, not just one, undermines the argument that a formula can work! Choose a different formula and you will likely see a different dose, sometimes very different.

My view is that calculating a dose has two specific uses: 

v When someone suddenly loses their thyroid, such as having a total thyroidectomy. In this case, an estimate of how much might be required can be helpful. 

v When you wish to check whether someone’s dose is particularly high or low. Use a formula and, if the dose is much higher or lower, look further.

It is also important to appreciate that there are NO formulas which handle combinations such as levothyroxine and liothyronine, desiccated thyroid, or anything like these. Also, all published formulas assume that the levothyroxine is in tablet form. If it is taken as an oral solution, or a gel cap, or any other form with different absorption, the formulas would need to be reviewed. The differences could be very significant.

NICE

NICE has brought dose by weight right back into focus as they specifically promote its use.

The NICE Guidelines on treating hypothyroidism suggest (they use the word “consider”) starting treatment with levothyroxine at a dose of 1.6 micrograms per kilogram. With the express statement that this needs to be rounded to nearest 25 micrograms.

Consider starting levothyroxine at a dosage of 1.6 micrograms per kilogram of body weight per day (rounded to the nearest 25 micrograms) for adults under 65 with primary hypothyroidism and no history of cardiovascular disease.

https://www.nice.org.uk/guidance/ng145/chapter/Recommendations#follow-up-and-monitoring-of-primary-hypothyroidism 

Consider starting levothyroxine at a dosage of 25 to 50 micrograms per day with titration for adults aged 65 and over and adults with a history of cardiovascular disease.

Ibid.

Levothyroxine starting dose

Some evidence showed that a high starting dose of levothyroxine produced more rapid improvements in quality of life than a lower starting dose followed by titration. The committee agreed that this was also their experience and therefore recommended a high starting dose (1.6 micrograms per kilogram body weight per day) in adults unless contraindicated (adults over 65 or with a history of cardiovascular disease). Although evidence about dosing was very limited, the committee agreed that adults over 65 years are more likely to have cardiovascular comorbidities. Most studies of hypothyroidism and subclinical hypothyroidism use 65 as a cut-off when defining older adults. The committee agreed to recommend a lower starting dose with titration for people over 65.

https://www.nice.org.uk/guidance/ng145/chapter/Recommendations#follow-up-and-monitoring-of-primary-hypothyroidism

Discussion

Going no further than the arithmetic, we see that someone of 70 kilograms would be prescribed 100 micrograms of levothyroxine. But if the patient weighed just one kilogram more, they would get 125 micrograms. A 25% higher dose for a less than one per cent increase in weight.

Weight	Dose by formula (micrograms)
39	50
40 to 54	75
55 to 70	100
71 to 85	125
86 to 101	150
102 to 175	175

This effect is most pronounced at lower weights. As weight rises, the jumps are smaller when expressed as a percentage.

This table shows the cut-off weights between 39 and 175 kilograms. This results in heavy-handed selection of dose.

Further, the moment we hit 65 years of age, the dose to consider is reduced to 25 or 50 micrograms a day. By way of illustration:

	Patient Case Details	Calculated dose expressed in micrograms per kilogram
Case 1:	Person of 71 kilograms in weight and aged 64 – dose to consider = 125 micrograms.	1.76 micrograms per kilogram.
Case 2:	Person of 70 kilograms in weight and aged 64 – dose to consider = 100 micrograms.	1.42 micrograms per kilogram.
Case 3:	Person of 70 kilograms in weight and aged 65 – dose to consider = 25 micrograms.	0.36 micrograms per kilogram.
Case 4:	Person of 140 kilograms in weight and aged 65 – dose to consider = 25 micrograms.	0.18 micrograms per kilogram.

Simply being weighed on different scales, and/or living an extra day, our dose could change by a ratio of five to one! And if the older person is also heavier, the ratio could be nearer ten to one.

There are many unacknowledged assumptions built-in to this recommendation:

v All patients commencing treatment have no thyroid function.

If this is not the case, for example, the patient has a thyroid which has been substantially destroyed by autoimmune processes but still retains, say, 25 or 50% of their capacity to manufacture thyroid hormone, why would the dose not take that into account?

v All patients will absorb the same amount of levothyroxine.

This is typically quoted as 50 to 80% of the dose. The patient for whom 125 micrograms should be considered might absorb anything from 62.5 to 100 micrograms (or 0.80 to 1.41 micrograms per kilogram if they are 125 kilograms). In extreme cases, absorption can be even lower than 50%.

	Weight	Age	Dose	Per kilogram	Absorption 80%	Absorption 50%
Case 1	71	64	125	1.76	1.41	0.88
Case 2	70	64	100	1.42	1.14	0.71
Case 3	70	65	25	0.36	0.29	0.18
Case 4	140	65	25	0.18	0.14	0.09

The table above shows the same example cases as earlier – but with the addition of absorption percentages of 80 and 50%. The numbers in the columns headed Absorption 80% and Absorption 50% show calculated amounts of levothyroxine absorbed in terms of micrograms per kilogram.

 

Other considerations

v Our bodies have variable composition. Some are lean and have very little fat. Others have a lot of fat. And, in hypothyroidism, the retention of water due to mucinous deposits is a cardinal symptom.

Quite clearly, retained water, fat and lean tissues have different requirements for thyroid hormones. Even were 'prescribe by weight' advised, simple weight as measured on a scale is a questionable basis. Occasionally we see reference to using “lean body mass” (rather than total weight) but with little further detail. Or some use of a lean body mass formula such as the Devine formula.

 

v Activity levels vary considerably. It is often reported that those on liothyronine (T3) feel the need for more when they are participating in heavy exercise. It seems likely that activity levels could also influence the need for levothyroxine.

v Levothyroxine must be converted to T3 in order to be active. The rates of conversion will vary among us. Several factors have been suggested to influence conversion: selenium, iron (e.g. ferritin), genes. 

 
v The effects of other medicines, supplements, food and water on absorption and utilisation of thyroid hormone can be significant. 

 
v Bed-time dosing has been reported to marginally increase absorption. However, in some, the effect could be somewhat greater than in others. 

 
v Different formulations of levothyroxine can impact absorption. Specifically, in those who are intolerant of lactose, the presence of lactose in tablets reduces absorption. And, generally, levothyroxine oral solutions (liquid levothyroxine) are regarded as being better absorbed. There have also been issues of tablets which simply do not fully disintegrate.

 
v A number of people find they need to adjust their dose by season. Typically lowering by 12.5 or 25 micrograms a day in summer/raising similarly in winter. 

 
v Suffering other diseases affects the need for thyroid hormone.

Conclusion

I hold to the view that prescribing by formula is poor practice.

Formulas have the two uses indicated at the beginning – estimating full replacement, and as a “sanity check” on existing doses.

Even were it possible to predict the required long-term dose, would it be appropriate to start on that dose? Take the 86 kilogram patient, under 65, who needs full replacement. NICE would recommend 150 micrograms a day.

If, however, 150 proved too much the patient would have been catapulted from hypothyroidism into over-medicated in one go. Which is almost certainly an unpleasant experience.

A more cautious approach might be to start at 100 micrograms and see how that goes. Incrementing to 125, then 150 fairly rapidly if well tolerated. By which I mean, after a thyroid test at six to eight weeks from starting and after every change. Or, even more cautiously, incrementing by 12.5 micrograms at each step. Maybe 100, 125, 137.5 then 150?

Dose by formula seems to endorse a prescribe-and-forget approach. If someone is prescribed their ultimate dose from the start, it is all too easy to assume all is well and not do any follow-up.

At the other end of the scale, prescribing 25 or 50 micrograms and leaving for six to eight weeks seems similarly poor practice. As soon as a hypothyroid person starts to receive that dose of levothyroxine, their bodies will start to re-adjust. But with such small doses, the entire dose is likely to be used up within hours, and the impact on TSH might actually reduce what little thyroid hormone they themselves can produce. Careful, considered titration with very frequent reassessments seems vital for those who have to start on very low doses. As soon as the person needs, they should receive a dose increment.

Finally, we should not be using doses as targets in any way. We should be using wellness and, as a guide, Free T4 and Free T3 levels. For that reason, if someone knew their thyroid hormone levels before they became ill, those might work as practical targets – so long as awareness remains that they are laboratory measurements with all the failings that attach to such.

The conclusion of a recent (2021) paper seems to endorse the view that prediction can only ever be a guide:

Despite a remarkable commitment by researchers to find a
therapeutic scheme able to predict the exact dose of LT4 to be
given to patients after a total thyroidectomy, the attempt to reach
the precise dosage failed to reach the target in the totality of the
cases. It is reasonable to conclude that because most of the
schemes show a considerable complexity but do not offer
significant advantages in the percentage of patients reaching
the expected results, the search for a fully predictive model seems
to be an exercise of futility. Nonetheless, these schemes are of
great utility to start the replacement therapy approaching the
best dosage, but keeping in mind that changes during follow-up
can be necessary according to the TSH values that are to be
reached in every case.

https://www.frontiersin.org/articles/10.3389/fendo.2020.626268/full

A spreadsheet with several active formulas which work out possible levothyroxine requirements including NICE NG145 guidelines. These formulas are referred to in the document above.

This is an Excel spreadsheet but is likely to work in other spreadsheet software. 

From Dropbox:

https://www.dropbox.com/s/aciho6m7x6f1eea/helvella%20-%20Estimation%20of%20Levothyroxine%20Requirement%20in%20Adults.xlsx?dl=1

 

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[i][b] helvella - Estimation of Levothyroxine Dosing in Adults[/b]

A discussion about the use of formulas to estimate levothyroxine dosing. Includes link to a downloadable spreadsheet which calculates several of these.[/i]

https://helvella.blogspot.com/p/helvella-estimation-of-levothyroxine.html

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