Tricky ten minutes - ‘You say my thyroxine dose is correct but I still feel terrible’

It is estimated that one million people within the UK are on levothyroxine (LT4).¹ The most common cause of primary hypothyroidism is deficient production of thyroid hormones (T4) and tri-iodothyronine (T3) by the thyroid gland occurring either spontaneously due to autoimmune thyroiditis (Hashimoto’s thyroiditis) or iatrogenic as a result of surgery or radioiodine therapy.

Why do some patients continue to experience symptoms?

Symptoms at presentation can vary significantly according to the duration and biochemical severity of hypothyroidism.

It is not uncommon for patients on optimal therapy to continue to feel unwell. But we should warn them that it may take between six and 12 months for symptoms to improve even if they are biochemically euthyroid on levothyroxine.

This is especially the case in patients with a history of Graves’ disease who may have been hyperthyroid for many months and who may take considerable time to adjust again back to being “normal” and biochemically euthyroid following radioiodine or surgery.

There are epidemiological data that suggest persistent symptoms associated with hypothyroidism, including lack of well-being and depression, occur in up to 5-10% of LT4 treated hypothyroid patients with normal serum TSH.

Hypothyroid symptoms were reported (despite a normal serum TSH) by 12% of 22,842 healthy participants – of whom 1,525 were taking thyroid medication – in the Colorado Thyroid Disease Prevalence Study.³ Although the magnitude of the problem is therefore limited, the suboptimal outcome of LT4 treatment is recognised as very relevant for certain individual patients.

Suggested explanations for persistent symptoms of hypothyroidism include awareness of having a chronic disease, adjustment to being euthyroid – particularly in those recently treated for hyperthyroidism – and thyroid autoimmunity per se.

There is also the potential for misattribution – attributing these symptoms to the hypothyroid state when in fact they are unrelated. Particularly given the symptoms are non-specific and many – depression, tiredness – are common in patients without any thyroid problem.

What should be the treatment target?

The goal of treatment of hypothyroidism is to restore a normal (euthyroid) state of the tissues with resolution of the symptoms and signs of hypothyroidism.² This is achieved by administering sufficient LT4 so that the serum TSH is reduced to within the laboratory reference range – usually 0.4-4.0mU/l.

Serum TSH assay is an exquisitely sensitive test for identifying any degree of primary hypothyroidism. As thyroid hormone concentrations fall even within the reference range, serum TSH increases by a negative feedback mediated by the hypothalamo-pituitary-thyroid axis.

Compliant LT4 treated hypothyroid patients who remain symptomatic should receive support to deal with the chronic nature of their disease.

Also, as most hypothyroidism is autoimmune in origin, these patients should have other autoimmune diseases – such as rheumatoid arthritis, pernicious anaemia, Addison’s disease, SLE and coeliac disease – ruled out.⁴

Many of these conditions may go unnoticed for a long time in view of the non-specific nature of associated symptoms. Screening for other autoimmune diseases is recommended in subjects with autoimmune thyroid disease presenting with new or non-specific symptoms.

LT4 is the preferred drug because its administration most closely mimics glandular secretion and because its conversion to T3 will be appropriately regulated in the tissues.

LT4 has a long half-life of one week which allows once daily administration. It generates stable T3 levels by conversion of T4 into T3 in peripheral tissues by deiodinase enzymes.

There are no data to support the suggestion that the target TSH range for the treatment of hypothyroidism should differ from the laboratory reference range. However, in practice it is worth trying to achieve a target serum TSH at around 0.5mU/l, as some patients prefer to be at that end of the reference range.

Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and loss of bone density so an undetectable serum TSH should be avoided. In exceptional cases I have left younger patients with an undetectable serum TSH – as long as the free T3 is not raised – whilst warning them of the possible long-term consequences.

Is there any argument for adding T3 to levothyroxine?

The evidence for there being any benefit of adding T3 tablets orally to LT4 to people with hypothyroidism is intriguing, but unconvincing. It is argued that LT4 may not always restore physiological T4 and T3 concentrations in serum and tissues. It is recognised that there is no current formulation of T4/T3 that replicates the natural pattern and relative quantities of these hormones released from the human thyroid, and a slow release preparation might have utility in the future.

However, there is insufficient evidence that LT4 and L-T3 combination therapy is better than LT4 monotherapy, and LT4 monotherapy remains the standard treatment of hypothyroidism. This view was reiterated in the recent statement by the Royal College of Physicians.⁵

T3 preparations are available in the form of liothyronine (L-T3) but the half-life of the currently available T3 preparations is short (about one day) and treatment requires several doses per day. Elevated serum T3 concentrations may occur during L-T3 administration, which can be sometimes associated with symptoms of palpitations and agitation. The monitoring and adjustment of the dose of L-T3 is more difficult.

The movement towards use of desiccated porcine thyroid extract (marketed as Armour ‘Natural’ thyroid) in the UK has been largely patient-led, with the support of a few fringe practitioners. Many patients believe there could be some additional benefit from the use of a ‘natural’ preparation compared to use of synthetic hormones. There have been few randomised trials of LT4 versus porcine thyroid extract and any possible health benefit remains uncertain.

Porcine thyroid is known to synthesise substantially more T3 than human thyroid and is potentially harmful. Due to their relatively high T3 content these animal extracts carry a higher risk of inducing thyroid hormone excess. In addition, porcine thyroid extract is substantially more expensive than LT4 and ineligible for a prescription exemption certificate. Combination LT4 and L-T3 treatment should be reserved for use by specialist endocrinologists, and discontinued if no improvement is experienced after three months.⁵

Dr Mark Vanderpump is a consultant endocrinologist at the Royal Free London NHS Foundation Trust, and an honorary senior lecturer in diabetes and endocrinology

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Pulse’s remit is to provide GPs with clear, accurate and practical clinical advice. All of our articles are written by leading clinicians in their field – of which Dr Mark Vanderpump is one. Dr Vanderpump has used the very latest guidelines and evidence from a variety of sources to support his piece, including NICE, the British Thyroid Association, the European Thyroid Association and the Royal College of Physicians. As such, we are satisfied with the accuracy of the article and are proud that Dr Vanderpump remains a regular contributor to Pulse.

We appreciate that this is a controversial area that will provoke strong views from patients, but our role is to offer GPs expert advice and we do not feel this is best served by engaging in extended discussions with patients which are best conducted elsewhere.

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