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

Consultant physician Dr Mark Vanderpump guides you through this potentially problematic primary care presentation

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

Comments on this article are now closed.

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.

References                                                                                                                    

  1. NICE (2011). Clinical Knowledge Summaries. Hypothyroidism
  2. Association of Clinical Biochemistry, British Thyroid Association and British Thyroid Foundation. (2006) UK guidelines for the use of thyroid function tests
  3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. (2000) The Colorado thyroid disease prevalence study. Archives of Internal Medicine, 160 (4); 526-534.
  4. Wiersinga WM, Duntas L, Fadeyev V, Vanderpump M. (2012) 2012 ETA guidelines: the use of LT4 + L-T3 in the treatment of hypothyroidism. European Thyroid Journal, 1;  55-71
  5. Royal College of Physicians. (2011) The diagnosis and management of primary hypothyroidism

Patient leaflet

Hypothyroidism

Hyperthyroidism

Readers' comments (16)

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  • Of the 1 million people who are prescribed levothyroxine, how high is the patient satisfaction rate?

    Judging by the amount of coverage given to the subject and the amount of patients complaining, it appears that dosing on LT 4 is far from perfect.

    I was one of the patients who remained symptomatic on LT4, I am compliant, have no other auto immune diseases, and I was offered support. - In the form of Liothyronine at 20 mcg per day, in a split dose, later increased to 30 per day , along with the LT 4 which was reduced from 100 to 50.

    I now have no thyroid related symptoms and have signed the register which lists people who have improved on preparations containing t3. http://www.surveymonkey.com/s/BZYHTK3

    The thyroid does not produce t4 only, it produces both t4 and t3.

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  • Why is it so hard for doctors to believe that T4 is not suitable for all hypothyroid patients? Eighteen months of compliance post thyroidectomy for Hurthle cell carcinoma led to me being bed ridden 90% of the time. Ceasing T4 saw withdrawal and disappearance of the illnesses which accumulated during the time I was on T4. Of course, the exquisitely sensitive TSH rose to 107.5 but I still felt better than on T4.

    Self medicating with T3 monotherapy and T3+T4 combination, I am better on the combination. Nevertheless, I have to purchase T3 online as the CCG prohibits prescribing because of RCP guidelines.

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  • Not all meds suit all patients. It really is that simple.

    A rebuttal from Dr. Jonc C. Lowe (deceased) to the BTA re Dessicated Thyroid vs Levothyroxine http://www.thyroidscience.com/Criticism/lowe.3.16.09/bta.rebuttal.htm

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  • As a learned author for a learned journal I believe that Dr Mark Vanderpump will understand that statements such as his assertion that Armour " is potentially harmful" are meaningless. Something either is or isn't harmful. Such statements should not be made unless they can be substantiated with experience and trials. I'm sure Dr Vanderpump is aware that Armour and other forms of natural dessicated thyroid have been in use for over a hundred years. I would be interested to hear his studies and experience showing patients who have been harmed by its use.

    His claim that the move to Armour is "patient-led" is telling. One would presume that patients would be the best guides to the effectiveness of any medicine and I find his use of this phrase more than a little condescending. I would expect the goal of any good doctor would be the reduction of their patients' symptoms and returning their patients to as good a health as possible. If patients find Armour more effective I find it deeply disturning that Dr V prefers to ignore their experience.

    I find his assertion that the goal of treatment is " restore a normal (euthyroid) state"....." so that the serum TSH is reduced to within the laboratory reference range" equally disturbing. My goal for treatment ,as a patient,(who doesn't take porcine products) is the reduction or removal of symptoms.

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  • The RCP position statement that Dr Vanderpump refers to is flawed and is seriously detrimental to those who have the misfortune to be in range on the so-called gold standard TSH assay yet suffer the debilitating symptoms of hypothyroidism. Such sufferers often have no choice but to resort to restoring their own health by sourcing thyroid medication via the internet. That should be a cause for concern for all GPs but I know that for some at least it is most definitely not the case.

    Straightforward primary hypothyroidism is not a problem to diagnose and manage by means of levothyroxine. However, there are plenty of people whose condition is more complex (e.g. TSH in range) but can be successfully treated using thyroid medication. The RCP position statement deters practitioners from attempting to get to the bottom of the more complex cases which can be treated successfully with thyroid medication including or containing T3.

    The RCP has refused to engage with the storm of criticism that descended on the position statement when it was first issued in 2009 and continues to avoid engagement. The RCP proclaims transparency but, in the case of the position statement, that could not be further from the truth.

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  • I feel I have to question this statement:

    "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."

    The glandular secretion has been very well described by looking at serum levels in this paper:

    http://press.endocrine.org/doi/pdf/10.1210/jc.2007-2674

    Serum levels achieved by oral levothyroxine doses are described in this paper:

    http://www.fda.gov/ohrms/dockets/ac/03/briefing/3926B1_02_B-Abbott-Appendix-A.htm

    In my estimation, by simply looking at the T4 levels, there are two very different patterns. Single dosing results in a high but short-lived peak. Glandular secretion results in a complex and much less peaky pattern.

    The idea that taking a single levothyroxine tablet, once a day, results in thyroid hormone levels that remotely resemble glandular secretion appears fanciful.

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