Original Article Annals of Clinical Biochemistry 2015, Vol. 52(4) 497–501 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0004563214568686 acb.sagepub.com Appropriateness of prescribing thyroxine in primary care Rachel Cooper1, Jonathan Pinkney2 and Ruth M Ayling1 Abstract Introduction: A practice hypothyroid register is part of the quality and outcomes framework. In literature, the prevalence of hypothyroidism is stated to be 2% but the prevalence, defined from quality and outcomes framework data, is 3.2% in the UK and 3.6% in Plymouth. We sought to investigate the diagnosis of hypothyroidism and reasons for prescription of thyroxine to patients on the hypothyroid register in Plymouth. Methods: A letter was sent to the 10 practices with the highest prevalence of hypothyroidism requesting a list of patients on their registers. The hospital pathology system was used to identify those with biochemically documented hypothyroidism (defined as thyroid stimulating hormone >10mU/L) For two large practices the clinical records of the remaining patients were reviewed to ascertain the reasons for prescription of thyroxine and whether it led to symptomatic improvement. Results: Seven practices responded with 1246 patients on their registers, of whom 43.6% had documented hypothyroidism. A review of notes of patients on the register, but without documented hypothyroidism, showed <25% to have an improvement in symptoms after prescription of thyroxine. Tiredness was the most common symptom prompting prescription of thyroxine. Conclusion: Of the patients on the register, only 43.6% had documented biochemical evidence of hypothyroidism and, from notes review of those without documented hypothyroidism, at least two-thirds may have been prescribed thyroxine outwith current national guidance. If this is correct, it has significant resource implications, impacts upon the workload of primary care, pharmacy and the laboratory service and may have clinical implications for patients. Keywords Hypothyroidism, thyroxine, prescription Accepted: 24th December 2014 Introduction Symptoms of hypothyroidism are common, yet clinical symptoms and/or signs alone are insufficient to make a diagnosis of hypothyroidism and require biochemical investigation for confirmation. In any one year, it is estimated that one in four of the population has their thyroid function checked.1 However, the results of blood tests for thyroid function testing can be influenced by other factors, e.g. some illnesses which do not permanently damage the thyroid gland. In these circumstances, the tests will return to normal after the illness, and thyroid hormone therapy is not needed (and may be harmful). These illnesses may be associated with transient symptoms which themselves resemble the symptoms of hypothyroidism. 1 Clinical Biochemistry, Derriford Hospital, Plymouth, UK Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, UK 2 Corresponding author: Ruth Ayling, Clinical Biochemistry, Derriford Hospital, Plymouth PL6 8DH, UK. Email: ruthayling@clinicalbiochemistry.org.uk 498 Annals of Clinical Biochemistry 52(4) The prevalence of spontaneous hypothyroidism in the UK has been stated in the literature to be 2% and that of subclinical hypothyroidism to be about 8% in women and 3% in men in the UK,2 although with the increasing age of the population this figure may be an underestimate. The Quality and Outcomes Framework (QOF) is an annual reward and incentive programme for Primary Care in the UK and requires practices to keep a register of patients with hypothyroidism (QOF thyroid 1 is defined as patients taking thyroxine with a recorded diagnosis of hypothyroidism). The prevalence of hypothyroidism, as defined from QOF1 in 2011 was 3.2% in the UK as a whole and 3.4% within the South West. Within Plymouth the prevalence was 3.7%, with 28 of 41 practices having a reported prevalence above the national average. In July 2006, clear national guidance on the use of thyroid function tests was issued.3 After discussion with colleagues in the department of endocrinology and in primary care, the Derriford laboratory has been issuing thyroid function tests with interpretative comments in line with this guidance to assist best practice with respect to thyroxine prescription. We were keen to investigate potential reasons for the apparent high prevalence of hypothyroidism in Plymouth and undertook this study. Methods From the QOF 2011 database the prevalence of hypothyroidism for Plymouth practices was obtained. A letter was sent to the 10 practices with the highest prevalence of hypothyroidism requesting a list of the patients on their hypothyroid register by NHS number. The laboratory information system was used to identify patients on the register who had documented biochemical evidence of primary hypothyroidism (defined for this purpose as a TSH >10 mU/L). For the two largest practices who responded, the primary care records of patients without laboratory evidence of hypothyroidism were reviewed to find the clinical indications for commencement of thyroxine. Any improvement in symptomatology resulting from treatment and the current TSH were also noted. Results The prevalence of hypothyroidism in Plymouth practices is shown in Figure 1. Letters were sent to 10 practices of whom seven responded. From their responses, details were provided of 1246 patients of whom 543 (43.6%) had documented laboratory evidence of hypothyroidism. The two largest practices investigated in more detail had 788 patients on the hypothyroid register, of whom 387 (49%) were documented to be hypothyroid (Figure 2); of these, two patients had hypopituitarism and seven congenital hypothyroidism. Ten had been commenced on thyroxine because of the presence of a goitre and 30 because of a history of specific thyroid disease (thyroidectomy 16, radio-iodine ablation 8, thyroiditis 2, Graves’ disease 1, uncertain 3) In two 6 5 Prevalence 4 3 2 1 0 Practice Figure 1. Prevalence (%) of hypothyroidism in Plymouth practices. 499 Cooper et al. patients with a marginally raised TSH the indication for prescription of thyroxine was stated to be co-existing Down Syndrome and in three patients ongoing treatment with lithium. Of the remaining 356 patients without documented laboratory evidence of hypothyroidism the indications for commencement of thyroxine are shown in Table 1. In the two practices investigated in detail, 196 of the 788 patients on the register were diagnosed with hypothyroidism after the release of laboratory TFT reports allied to the 2006 guidance document of whom 95 (48.5%) were commenced on thyroxine without biochemical evidence of hypothyroidism. Of the 356 patients treated with thyroxine without documented laboratory evidence of hypothyroidism, the most recent TSH was outside the reference range (0.35–4.5 miU/L) in 11% (above the reference range but <10 mU/L in 24 and below in 15 patients). INVITATION 10 Plymouth pracƟces with highest prevalence of hypothyroidism (4.4-5.5%) 2656 paƟents on register Response YES 7 pracƟces 1246 paƟents on register 543 (43.6%) documented hypothyroid NOTES REVIEW 2 pracƟces 788 paƟents on register 387 (49.1%) documented hypothyroidism 196 paƟents diagnosed aŌer release of laboratory TFT results with comments in line with 2006 ACB Thyroid guidance3 101 (51.5%) documented hypothyroid Figure 2. Study flow chart. NO 3 pracƟces 500 Annals of Clinical Biochemistry 52(4) Table 1. Indications for commencement of thyroxine in patients without laboratory documentation of hypothyroidism. Tiredness Not stated or unclear Apparently asymptomatic Other Weight gain Low mood Constipation Oedema Notes unavailable Total Number of patients Positive thyroid peroxidase antibodies Improvement of symptoms with T4 129 101 36 12 59 (46%) 6 (6%) 40 10 28 20 9 6 3 20 356 7 4 4 2 0 – 75 (21%) – 12 (43%) 5 (25%) 2 (22%) 2 (33%) 0 (0%) – Discussion Summary Subclinical hypothyroidism is defined as being present when the TSH concentration is above, but the free thyroxine remains within the reference range. National guidance suggests that subclinical hypothyroidism should be confirmed by repeat thyroid function testing after three to six months to exclude transient causes of elevation which include the effects of non-thyroidal illness and medication, and routine prescription of thyroxine is not recommended.3,4 When TSH <10 mU/L there is no consistent evidence of an association with symptoms, secondary biochemical abnormalities or cardiac events. There is evidence of progression from subclinical to overt hypothyroidism with the passage of time, particularly in patients with positive thyroid peroxidase antibodies; progression to hypothyroidism of 5–8%/year has been suggested. However, normalization of thyroid function is a possibility and many patients do not have systematic deterioration in thyroid function for years.5 There is no conclusive data regarding beneficial effects of thyroxine treatment in patients with subclinical hypothyroidism. American guidance suggests that consideration should be given to treatment of subclinical hypothyroidism based on individual factors, particularly if patients have symptoms suggestive of hypothyroidism, positive thyroid peroxidase antibodies or evidence of atherosclerotic cardiovascular disease, heart failure or associated risk factors for these diseases.6 Current UK guidance suggests that thyroxine treatment is not recommended as a routine therapy but that thyroid function should be monitored (yearly in antibody-positive patients, three yearly in those who are antibody negative) and thyroxine commenced if the TSH rises above 10 mU/L.3,4 A trial of thyroxine may be appropriate in some patients, for example those with goitre, those whose TSH is rising and women who are pregnant or planning to become so.3,4 It is also suggested that consideration may be given to a trial of thyroxine in patients with symptoms compatible with hypothyroidism but that treatment should only be continued if there is clear improvement.4 However, in a random double blind controlled trial in patients with symptoms of hypothyroidism but without documented hypothyroidism, thyroxine had no greater effect than placebo.7 NICE clinical knowledge summary cites those symptoms with greatest discriminatory ability between people with hypothyroidism and those who are euthyroid as constipation, hoarse or deep voice, feeling cold, puffy eyes and weak muscles.4 In our patient group there was documented improvement in symptoms after prescription of thyroxine in 24%. However, if the finding of an elevated TSH had been a temporary finding attributable to the effect of the presence of non-thyroidal illness, it is possible that symptoms may have regressed spontaneously with time without treatment. In a study looking at thyroxine prescription in six GP practices in Germany, the authors found that a GP diagnosis was non-existent in 47.7% of patients.8 They postulated that thyroxine may have been prescribed as an intervention for unexplained medical symptoms. Over-treatment of patients with thyroxine replacement is potentially harmful and may result in cardiac problems9 or bone loss.10 The optimal dose of thyroxine for long-term therapy should be assessed from the results of thyroid function tests together with clinical finding and the biochemical target is a TSH concentration that is within the reference range. Whilst thyroxine is a relatively cheap drug (e.g. 1/ month) the cost of its prescription Devon Wide for 2012–2013 was 1.7 m and the biochemical monitoring of therapy represents a significant resource. Furthermore, the diagnosis of hypothyroidism qualifies patients for medical exemption from prescription charges for thyroxine and any other medication. The study looked at a large number of patients but was confined to seven practices, with medical records being examined in only two. There are obviously many reasons why reported disease prevalence and prescription patterns differ (e.g. patient and demographic factors, partners’ special interests and expertise, etc.). It is appreciated that the findings of this study may not be able to be generalized but it is likely that they may be 501 Cooper et al. relevant at least to other practices with a high reported prevalence of hypothyroidism and it may be helpful to use the data to reflect upon local protocols with respect to the management of subclinical hypothyroidism. reviewed case records in primary care. RMA wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version. References Conclusion From scrutiny of QOF data the prevalence of hypothyroidism is higher in Plymouth than in England and the South West as a whole and is particularly high in certain practices. A number of demographic and clinical factors may underlie these data but this study has suggested that the diagnosis of hypothyroidism and prescription of thyroxine may not always be made in accordance with the current national guidance. If correct, this has significant resource implications, impacts upon the workload of primary care, pharmacy and the laboratory service and may have clinical implications for patients. Declaration of conflicting interests None declared. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethical approval This study was approved as an audit by Plymouth Hospitals NHS Trust. Guarantor RMA. Contributorship All authors contributed to the study design. RMA was involved in liaison with primary care and data analysis. RC 1. Royal College of Physicians. The diagnosis and management of primary hypothyroidism. 2008, www.rcplondon.ac.uk/specialties/Endocrinology-Diabetes/Documents/ Hypothyroidism.pdf. 2. Vanderpump MPJ, Tunbridge WMG, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow up of the Whickam survey. Clin Endocrinol 1995; 43: 55–68. 3. Association for clinical biochemistry, British Thyroid Foundation 2006. UK guidelines for the use of thyroid function tests. http://acb.org.uk/docs/tftguidelinesfinal. pdf. 4. NICE Clinical Knowledge Summary Hypothyroidism. 2011, http://cks.nice.org.uk/hypothyroidism#!evidence. 5. Karmisholt J, Andersen S and Laurberg P. Variation in thyroid function in subclinical hypothyroidism:importance of clinical follow-up and therapy. Eur J Endocrinol 2011; 164: 317–323. 6. Garber JR, Cobin RH, Gharib H, et al. Clinical Practice Guidelines for Hypothyroidism in Adults: cosponsored by the American Association of Clinical Endocrinology and the American Thyroid Association. Endocr Pract 2012; 18: 989–1028. 7. Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ 2001; 323: 891–895. 8. Viniol A, Bosner S, Baum E, et al. Forgotten drugs: longterm prescriptions of thyroid hormones – a cross-sectional study. Int J Gen Med 2013; 6: 329–334. 9. Biondi B, Palmieri EA, Lombadi G, et al. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 2002; 137: 904–914. 10. Uzzan B, Campos J, Cucherat M, et al. Effects on bone mass of long term treatment with thyroid hormone: a meta-analysis. J Clin Endocrinol Metab 1996; 81: 4278–4289.