Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of UK endocrinologists

Abstract Objective Management of hypothyroidism is controversial because of medication cost pressures and scientific uncertainty on how to address treatment dissatisfaction experienced by some patients. The objective was to investigate the experience and preferences of UK endocrinologists in use of thyroid hormones. Design Web‐based survey. Patients UK endocrinologists were invited to participate. Measurements Responses to questionnaire. Results The response rate was 21% (272/1295). While levothyroxine monotherapy is regarded as the treatment of choice for hypothyroidism, 51% of respondents stated that combined treatment with levothyroxine and liothyronine could be considered for levothyroxine‐treated patients whose symptoms persist despite normalisation of serum thyroid stimulating hormone (TSH) concentration. However, only 40% are currently prescribing such treatment, and just 23% would consider taking it themselves. A small minority prescribe desiccated thyroid extract, and those most likely to do so are aged over 60 years. Most respondents stated that they have no influence over brand or formulation of levothyroxine dispensed to their patients and expect no major differences in efficacy between different formulations. A total of 9% would prescribe levothyroxine for euthyroid enlarging goitre, and 29% for euthyroid female infertility with high titre thyroid peroxidase antibodies, despite recent trials finding no benefit. Conclusions UK endocrine practice in management of hypothyroidism is broadly in line with international guidance. However, a minority of respondents would consider thyroid hormone supplementation in euthyroid individuals for female infertility, enlarging goitre, and other indications in which evidence of efficacy is lacking. Willingness to consider prescribing combined levothyroxine and liothyronine, for hypothyroid symptoms which persist despite normalised TSH, has increased in comparison to previous international surveys, despite inconsistent evidence of benefit.


| INTRODUCTION
The UK prevalence of hypothyroidism was estimated recently at 3.6% overall, increasing from around 1 in 1000 children aged up to 10 years, to approximately 1 in 10 adults aged over 70 years. 1 This disease burden occurs within a population that had in recent decades been regarded as iodine replete, however, concern about gradually falling iodine intake, particularly in women of child-bearing age, 2 is borne out by the latest results of the UK National Diet and Nutrition Survey, confirming that this cohort (females aged 16-49 years) now meets World Health Organisation criteria for iodine deficiency. 3 Primary hypothyroidism in the United Kingdom is usually diagnosed and managed by general practitioners, within the National Health Service (NHS), which provides tax-funded healthcare. General practitioners tend to refer to NHS endocrinologists only if difficulties arise in diagnosis or management. The latest UK National Institute for Health and Care Excellence (NICE) guidance recommends levothyroxine (LT4) as first-line treatment. Prescribers are directed to achieve thyroid stimulating hormone (TSH) concentrations within the reference interval, measuring TSH every 3 months until stable, and annually thereafter. 4 NICE guidance does not address switching between LT4 tablet brands or formulations, despite several other European countries experiencing widespread difficulties after enforced switches. 5 However, the UK Medicines and Healthcare products Regulatory Agency (MHRA) advises that, while generic prescribing is routinely appropriate, a specific, tolerated product can be prescribed for patients reporting persistent symptoms when switching between different LT4 tablets, and liquid LT4 can be considered if symptoms or poor control of thyroid function persist despite adherence to a specific product. 6 LT3 is not recommended for routine use but NICE guidelines nevertheless direct readers toward NHS England Specialist Pharmacy Services (SPS) guidance, which, in limited circumstances, provides for long-term NHS-funded LT4 + LT3 combination therapy, after a trial of at least 3 months' duration under supervision of an endocrinology consultant.
LT4 tablets are among the most prescribed medications in the United Kingdom. Liquid and soft-gel capsule preparations are available, though their current cost in the United Kingdom is several times greater than tablets. The bioavailability of LT4 in liquid and soft-gel capsules is reported to be greater than for tablets, but their cost-effectiveness in adult hypothyroidism remains uncertain, even when absorption is impaired by comorbidities, concomitant medications, or behavioural factors. 7 Table 1. A total of 264/272 (97%) participants reported treating thyroid patients on a daily or weekly basis.

| Persistent symptoms of hypothyroidism
Participants were asked to outline their experience of managing patients whose hypothyroid symptoms persist despite LT4 treatment returning serum TSH concentration to the reference interval ( Figure 2A). Most (175/239; 73%) respondents stated that such patients represent 10% or less of their caseload, but 50% (119/238) reported that the prevalence has increased over the past 5 years. Opinions were elicited on eight hypothetical explanations for the persistence of hypothyroid symptoms despite normalised serum TSH.
Participants were asked to indicate their level of agreement with each statement (choosing "Strongly agree," "Agree," "Neutral," "Disagree," or "Strongly disagree") and to rank them in terms of perceived aetiological importance. A comparison of the sum of T A B L E 1 Demographic characteristics of respondents | 241 counts of "Strongly agree" and "Agree" with the sum of counts of the top three ranks revealed similar results. "Psychological factors," "Comorbidities" and "Unrealistic patient expectations" were regarded as the most likely explanations for persistent symptoms, while "The inability of LT4 to restore normal physiology," "The presence of underlying inflammation due to autoimmunity," and "The burden of having to take medication" were regarded as least likely (Table 3).

| Prescribing thyroid hormones for euthyroid patients
When asked for their views on thyroid hormone therapy in biochemically euthyroid patients, most respondents (163/259; 63%) answered that treatment is never indicated, but a substantial minority Which of the following preparations of LT4 would you prescribe for a patient with poor biochemical control who is unable (due to busy lifestyle) to take LT4 fasted and separate from food/drink?  29 and is in keeping with BTA Executive Committee guidance. 28 This differs from practice in Greece, 19 Poland, 15 and Romania, 13 where supplements are prescribed more commonly in autoimmune hypothyroidism. It has been speculated that this may be because nutritional deficiencies are more common in those populations. 15 Current practice with respect to monitoring of TSH after starting LT4 treatment, and after a change of brand or formulation, is in line with current NICE and BTA guidance, 4,28 and in keeping with other THESIS collaboration publications to date. Romania, 13 and Belarus 20 indicate lower prevalence.

| Persistent symptoms of hypothyroidism
While the combined caseload of all UK endocrinologists represents only a small minority of patients with hypothyroidism in the United Kingdom, the findings are consistent with the presence of significant morbidity within the specific patient group. A potential limitation is that some responses might have been based on conjecture, rather than on systematic, detailed assessment of caseload, introducing the risk of bias if patients experiencing persistent symptoms are reviewed more frequently and thus come more swiftly than others to mind.
Accepting that the survey underscores the need to ameliorate persistent hypothyroid symptoms, it is noteworthy that few respondents agreed that "in most patients treated with levothyroxine who achieve normal serum TSH, persistent symptoms are due to inability of levothyroxine to restore normal physiology." It can be inferred that a majority do not believe that more complex thyroid hormone preparations than LT4 monotherapy are likely to be helpful. Similarly, the relative lack of priority given to the "presence of underlying inflammation due to autoimmunity," suggests that few, if any, would consider pursuing an immunotherapeutic approach to autoimmune thyroiditis. Instead, respondents tended to regard nonthyroid factors as most important, a finding consistent with almost every THESIS collaboration national publication to date [9][10][11][13][14][15][17][18][19][20][21][22][23] and with the conclusions of a recent narrative review. 33  to be an indication, 9 whereas the proportions are greater elsewhere than in the United Kingdom, particularly Denmark (42%), Sweden (47%), Spain (49%), Hungary (59%), Poland and Germany (63%), and the Czech Republic (78%). [14][15][16][17][21][22][23] With respect to thyroid hormone treatment for euthyroid goitre, the absence of long-term efficacy after treatment withdrawal, 40 coupled with evidence that protracted TSH reduction below the reference interval causes loss of bone mineral density in postmenopausal women, adverse cardiac effects in the elderly, and increased mortality, 41 has led to such treatment being discouraged in recent guidelines. 42 Reports from the THESIS collaboration have again revealed substantial variation between countries, but without close correlation to willingness to prescribe for euthyroid female infertility with positive antibodies. A majority of Czech, German and Bulgarian endocrinologists reported willingness to prescribe for euthyroid goitre, 9,22,23 whereas corresponding figures for Hungary, 21 France, 11 Finland, 10 Poland, 15 and Belgium 18 were between onethird and one-half of participants, and, for Belarus, 20 Greece, 19 Spain, 16 Italy, 12 Sweden, 17 and Denmark, 14 between 12% and 25%.

| Therapy with combined LT4 and LT3 or with DTE
Longstanding differences between European countries in prevalence and, hence, specialists' clinical experience, of endemic goitre might influence this area of practice. At 9.3%, the proportion of UK respondents advocating thyroid hormone treatment for euthyroid goitre is low, and the lack of association with demographic characteristics suggests that the rationale against this practice is widely accepted among UK endocrinologists.
Evidence is weak or nonexistent that any hypothetical benefits of thyroid hormone treatment might outweigh adverse effects in euthyroid patients with the other surveyed conditions. It is therefore reassuring that respondents in the current study overwhelmingly regard such treatment as inappropriate.