What are some of the current issues or controversies in thyroid hormone replacement?

Several interesting controversies are being quite widely discussed at present. For example, should mild thyroid failure, the earliest stage of hypothyroidism, be treated, or not? Which groups in the population should be tested for possible thyroid deficiency? Does thyroxine alone always provide satisfactory treatment?

What is meant by the term mild thyroid failure?

This term is used to describe situations where people show the first feature of hypothyroidism, that is, a rise in the serum level of thyroid stimulating hormone (TSH) while the level of thyroxine (T₄) remain within the population normal range. This entity is also known as subclinical hypothyroidism or diminished thyroid reserve.

The reason for recent preference for the term mild thyroid failure is that the early stages of primary hypothyroidism really do seem to have some important consequences - we should not just regard the elevation of TSH as a finding that is predictive of hypothyroidism in the future.

What is the prevalence of mild thyroid failure in the Australian community?

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Why is the term mild thyroid failure preferable to subclinical hypothyroidism or diminished thyroid reserve?

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What is the evidence that mild thyroid failure has clinical consequences?

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In mild thyroid failure, why does TSH increase before T₄ becomes abnormal?

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In mild or early thyroid failure, the first change that we observe is an elevation in TSH, while the T₄ remains within the reference range - but eventually the T₄ also becomes low, associated with progressively increasing levels of TSH. The level of TSH can be elevated several hundred fold in severe primary hypothyroidism.

How has the normal reference range for serum TSH been established?

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If we simply aim for TSH values in the middle of the range, some individuals will remain under-treated.

What is the rate of progression from mild thyroid failure to overt hypothyroidism with both high TSH and low T₄?

The generally quoted figure is about 5% per year,¹ but that can vary widely. The rate of progression is greater if the TSH is higher or if there are positive anti-thyroid antibodies. The rate of progression may also be greater in people who had previous treatment with radioiodine or surgery.

Is there a role for thyroid antibody measurement in deciding whether to treat mild thyroid failure?

The peroxidase or microsomal antibody is certainly important in identifying autoimmune thyroid disease, and the presence of this antibody indicates an increased likelihood of progression. However, I wouldn’t let the presence of the antibody dominate the decision whether to treat or not, and certainly the antibody level itself does not require any treatment. I think the TSH and symptoms should be the dominant decision-making factors.

Which patient groups are at higher than normal risk of thyroid failure?

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Are there any special issues during pregnancy or in the post partum period in treating mild thyroid failure?

From recent literature there is now good evidence that even mild thyroid failure with isolated maternal TSH elevation in the first trimester, can have a slight but significant adverse effect on later intellect.²

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Should any patient groups be routinely tested to detect thyroid failure, particularly mild thyroid failure?

The American College of Physicians recent recommendation suggests that women over 50 should be checked for thyroid failure when they present for medical care.

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What are the potential benefits of treating mild thyroid failure?

There are three possible benefits.

1. Symptomatic improvement - this has been demonstrated in mild thyroid failure in some double-blind crossover studies.^3,4
2. Cardiovascular benefits are perhaps more controversial but they relate to effects in improving the plasma lipid profile as well as beneficial effects on the compliance or elasticity of blood vessels.
3. Avoidance of later severe hypothyroidism, which particularly in the elderly, can be a devastating disorder with a poor prognosis, is probably the most important benefit.

Are there any adverse effects from treating mild thyroid failure?

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How do you personally assess a patient with isolated TSH excess?

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I think one needs to be a little conservative in suggesting that someone should take tablets for the rest of their lives, especially in young people.

Does mild thyroid failure require full dosage of thyroxine, or is low dosage preferable?

At first you might think that treatment of a mild deficiency requires a lower dosage of replacement medication. However, if you think of the feedback relationship, a low dose T₄ really may just turn the TSH down a bit, and you may gain very little. It is a personal view that mild thyroid failure requires full dose replacement with the aim of bringing the TSH to a target value of about 1 mU/ L before you can really say that a full therapeutic trial has been given.

In Australia we have thyroxine in only three tablet sizes, 50, 100 and 200 microgram (0.05, 0.1 and 0.2 mg). How do we achieve subtle dose adjustments to get the TSH on target?

It is important to appreciate that thyroxine is slowly metabolized in the body - it has a plasma half-life of about a week and is slow in its action. For this reason, we can use alternate daily dosage to achieve any overall weekly dosage that we want. In this way, we can achieve subtle dose adjustment without the 10 or so different tablet sizes that are marketed in North America and most of Europe.

How does the use of thyroxine differ between replacement for hypothyroidism and follow up treatment of differentiated thyroid cancer?

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Which medications interfere with thyroxine absorption or action?

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Are there any situations where you would give thyroxine even if TSH was completely normal?

This line of treatment particularly applies in some younger people with goitre, where suppressive dosages of thyroxine aiming at a subnormal TSH, can lead to a dramatic regression of goitre size - this may avoid the subsequent development of a multi-nodular goitre which may need surgery later in life. This treatment is effective particularly if it is given early before nodularity of the gland has developed.

Is there a place for using T₃ in addition to T₄ in the treatment of hypothyroidism?

This is certainly a controversial area, and there is really only one study, which shows objectively, some psychological benefit in hypothyroid patients who were treated with T₃ along with thyroxine.⁵

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It is a personal view that we should avoid T₃ supplements for standard replacement until more information is available.

When should patients with thyroid deficiency be referred to an endocrinologist?

In any situation of diagnostic doubt, an endocrine opinion is worthwhile before people are put on a medication effectively for life.

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Particularly where primary hypothyroidism is very severe, referral to a specialist with access to hospital facilities is a wise precaution because of the severe consequences that can arise during the early phases of treatment of this disorder.

References

1. Vanderpump M.P.J. et al. The incidence of thyroid disorders in the community: a twenty year follow-up of the Whickham Survey. Clin Endocrinol 1995; 43: 55-68. [Abstract]
2. Haddow J et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549-555. [Abstract]
3. Cooper DS et al. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med 1984;101:18-24. [Abstract]
4. Nystrom E et al. A double-blind cross-over 12-month study of L-thyroxine treatment of women with “subclinical” hypothyroidism. Clin Endocrinol (Oxf) 1988;29:63-76. [Abstract]
5. Bunevicius R et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism, N Engl J Med 1999; 340: 424-429. [Abstract]

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