Family Practice Advance Access published March 17, 2015

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1 Fmily Prctice Advnce Access published Mrch 17, 2015 Fmily Prctice, 2015, 1 5 doi: /fmpr/cmv010 Thyroid function testing in primry cre: overused nd under-evidenced? A study exmining which clinicl fetures correspond to n bnorml thyroid function result Alexnder Werhun nd Willim Hmilton b Primry Cre Dignostics, Exeter University nd b Peninsul College of Medicine nd Dentistry, Exeter, UK. *Correspondence to Alexnder Werhun, c/o Willie Hmilton, Office 1.18 College House, University of Exeter Medicl School, St. Luke s Cmpus, Exeter, Devon EX1 2LU, UK; E-mil: [email protected] Abstrct Bckground nd im. Dignostic testing is incresing in primry cre, including for thyroid disese. This study exmined which clinicl fetures were ssocited with n bnorml thyroid stimulting hormone (TSH) result. Design nd setting. This ws cross-sectionl study in one generl prctice of ptients in Exeter, Devon, UK. Methods. We exmined the primry cre records relting to every TSH test tken in the yer from August 2012, nd extrcted symptoms nd/or the indiction for testing. Associtions with n bnorml result were tested using multivrible logistic regression. A cohort study ws then performed of 100 ptients newly recorded with ech of the six fetures ssocited with n bnorml test result in the cross-sectionl study, nd the proportions tested for TSH nd the results of tht testing identified. Results. Two thousnd thirty-five ptients (12% of the prctice popultion) hd TSH testing in the yer. Of these 35 (1.7%) hd TSH >4.5 miu/l, suggesting hypothyroidism, nd 7 (0.3%) hd TSH <0.01 miu/l suggesting hyperthyroidism. Fetures ssocited with n bnorml TSH were: pregnncy, odds rtio 41 (95% confidence intervl ), constiption 9.7 (2.1 45), plpittions 23 ( ), hir loss, 21 ( ), weight gin, 18 ( ) nd dirrhoe, 13 ( ); in seprte nlyses only pregnncy nd constiption were ssocited with rised TSH, nd the remining four fetures with low TSH. Conclusion. The dignostic yield of thyroid disese in this study ws 2.1% suggests testing could be better trgeted without missing dignoses. The symptoms ssocited with thyroid disese differ from those generlly reported. This my represent fewer ptients presenting with dvnced disese. Keywords. Dignostic tests, endocrinology disorders (thyroid), fmily helth, screening, thyroid disorders. Introduction Over-testing is becoming more nd more commonplce in modern medicine. It occurs when tests re ordered indiscrimintely without full considertion of the resons for testing nd possible use of results. The problems this cretes re multifceted, from the finncil burden of testing to the inpproprite lbelling of ptients nd subsequent tretment for symptomtic conditions (1). Testing nd treting for thyroid disese is good exmple. Thyroid disese is common in the UK. The incidence of hypothyroidism in dults is round 4.1/1000/yer [95% confidence intervl (CI) ] for women nd in men 0.6/1000/yer (CI ) (2). The hyperthyroidism incidence is 0.77/1000/yer for women nd 0.14/1000/yer for men (3) equting to pproximtely The Author Published by Oxford University Press. All rights reserved. For permissions, plese e-mil: [email protected]. 1

2 2 Fmily Prctice, 2015, Vol. 00, No. 00 new UK dignoses of one of these diseses nnully. In n verge prctice of ptients we would therefore expect 20 women nd 3 men to be dignosed over yer for hypothyroidism. Agin in prctice of we would therefore expect 4 cses/yer for women nd t most 1 cse/yer for men for hyperthyroidism. The stndrd testing for either condition is serum thyroid stimulting hormone (TSH); TSH origintes from the pituitry glnd fter stimultion by thyrotrophin relesing hormone. This comes from the hypothlmus in response to negtive feedbck from the mount of thyroxine (T4) nd triiodothyronine (T3) circulting in blood vessels. TSH is mesured in preference to mesuring the ctive unbound compound of T3 becuse doing so sidesteps protein binding of thyroid hormones (which my vry) nd the different biologicl ction of T3 nd T4. One rre condition cn led to low TSH in hypothyroidism: hypopituitrism. Good tretments exist for both hypo- nd hyperthyroidism mking timely dignosis vluble. The only ntionl guidnce on testing for thyroid disese comes from the British Thyroid Assocition (4): this sttes tht tht when testing for hypothyroidism, clinicl judgment is needed s such ptients often do not hve typicl fetures. This relince upon clinicin s judgment, coupled with the heterogeneous mnner tht thyroid disese my present mkes vrition in testing between clinicins likely (5). The locl lbortory cost for single test is pproximtely 1.67, to which must be dded costs of smple tking nd trnsport, plus ptient costs. In 2006, the overll estimted NHS cost of thyroid function tests ws 30 million. Over 10 million TSH ssys re performed per yer in the UK (4). A prevlence of 2% hypo- nd 0.5% hyperthyroidism mens 2.5% of the popultion would be expected to hve nnul testing to monitor their condition which equtes to round 1.5 million tests. This implies there re pproximtely 8.5 million tests performed for potentil new dignoses, to identify the pproximte new thyroid disese dignoses, test positivity rte of 2%. The rtionle for this study ws to study if test positivity rtes were indeed s low, nd to identify which clinicl fetures were ssocited with positive test result. Methods This ws cross-sectionl study to identify the prevlence of thyroid testing, nd ssocitions with positive test result, followed by cohort study, studying the outcomes of ptients with fetures found to be ssocited with positive result in the first phse. Both phses were performed in generl prctice in Exeter, Devon, UK, with prctice popultion of ptients. Prticipnts in cross-sectionl study All ptients with TSH test between 1 August 2012 nd 31 July 2013 were identified by AW, clinicin in the prctice. No ge limits were pplied. Ptients with prior dignosis of hypo- or hyperthyroidism (either defined biochemiclly or on tretment) were excluded. Ptients with norml testing of thyroid function t ny erlier dte previously were included. Repet tests within the yer of study were not counted. New dignoses of thyroid disese were identified in two wys: firstly, the TSH results were ctegorized into hypothyroid (TSH > 4.5 miu/l the locl lbortory upper limit of norml ), hyperthyroid (TSH < 0.01 miu/l), nd euthyroid. The second method involved serching for relevnt Red codes for hypothyroidism nd hyperthyroidism dignoses, to identify ny thyroid disese dignosed outside the prctice, lthough it trnspired no ptients hd lbel of thyroid disese without ccompnying TSH bnormlities. Identifiction of fetures prompting testing The index consulttion prompting testing ws identified. All clinicl fetures from tht consulttion were extrcted by direct exmintion of the records. Some TSH testing ws protocol-driven (nd without pprent symptoms): the rtionle for such investigtion ws lso extrcted from the records. The cohort study This study sought to quntify the risk of thyroid disese in ptients with ny of the fetures identified in the cross-sectionl study. We identified ptients of ny ge with Red code for ny of these fetures in inclusive. A rndom smple (using the NHS number) of 100 ptients ws obtined for ech feture in order to record (i) whether TSH test hd been undertken nd (ii) ny positive thyroid disese dignoses. Anlysis Simple descriptive sttistics were used in both studies. In the crosssectionl study, ssocitions between clinicl fetures/protocol testing nd bnorml TSH results (either hypothyroid or hyperthyroid) used logistic regression. Initilly univrible nlysis ws performed, nd vribles with P vlue 0.1 retined for multivrible nlysis. The multivrible nlysis used P < 0.05 for vrible retention, nd included ge nd gender. Secondry nlyses exmined hypothyroidism nd hyperthyroidism seprtely, nd for the screening group seprtely. Finlly, ll discrded vribles were checked ginst the finl model. Results Descriptive chrcteristics of ptients tht hd TSH testing The totl prctice popultion ws ptients. In the yer of the study 2589 ptients hd thyroid testing; 554 hd previous thyroid disese, nd were excluded, leving 2035 ptients (12% of the prctice). Of these ptients 35 (1.7%) hd lbortory result >4.5 miu/l, suggesting hypothyroidism, of whom 16 (0.8%) hd vlue 10 miu/l, indictive of hypothyroidism. Seven (0.3%) hd suppressed TSH suggestive of hyperthyroidism, giving n overll dignostic yield for thyroid disese of 2.1%. The prctice is one of the lowest prctices for requesting TSH tests in Exeter nd Cornwll (14th lowest out of 108 prctices (personl communiction, Dr O. Okoumunne). Of the 35 ptients with TSH >4.5 miu/l, 26 were given Red code for hypothyroidism (X40HE, X40IQ, XE108, X3ed) nd commenced tretment. The remining nine were given Red code for subclinicl hypothyroidism (XJ9F), though one hd TSH >10 miu/l; seven of these ltter ptients were strted on T4, hence out of the 35 ptients dignosed with hypothyroidism 33 received tretment. All seven hyperthyroidism ptients received the pproprite Red code nd were commenced on pproprite tretment. There were more women tested thn men (P < 0.001, χ 2 test) nd more femles hd positive results; 33 (2.5%) positive tests, from 1305 smples, compred with 9 (1.2%) positive tests in mles from 730 smples: P = 0.049, χ 2 test. Testing ws performed more frequently in older ptients; 733 (22%) of 3333 ptients over 60 yers were tested nd 1302 (10%) of ptients 60 yers old nd under (P < 0.001).

3 Thyroid function testing in primry cre 3 Fetures prompting TSH testing One thousnd thirty-one ptients (75% of the entire smple) were tested for clinicl fetures deemed suspicious of possible thyroid disese, with test results positive in 32 (2.1%). Five hundred nd four ptients were tested s prt of protocol-driven or screening procedure, with 10 (2.0%) being positive tests. The min symptoms nd diseses prompting testing re shown in Tble 1. Fifteen of the ptients were on lithium nd three on miodrone: one on miodrone hd positive result on TSH testing. Fetures ssocited with thyroid disese There were 15 seprte fetures with frequency of bove 2.5% in either the norml result group, or the bnorml result group. Fetures ssocited with n bnorml thyroid test re shown in Tble 2, long with seprte nlyses for hypothyroidism nd hyperthyroidism. Numbers were too smll for relible nlysis of the screening group. The strongest ssocition with hypothyroidism ws pregnncy two of these ptients hd testing longside routine obstetric blood tests (one subsequently hving positive dignosis), four hd co-existing lethrgy (one lso hving subsequent positive dignosis) nd one more hd gesttionl dibetes. The cohort study For the six fetures present in Tble 2, 100 ptients could be identified with the feture, other thn for weight gin s this ws Red coded for only six ptients over the pst 5 yers so this feture could not be nlysed further. The remining five fetures were ssocited with high levels of TSH testing nd reltively high yield of bnorml results (Tble 3). Discussion In this study in single prctice of ptients, 2035 ptients (12%) hd thyroid function testing, pprently for dignostic purposes, in single yer. Of these ptients, only 42 (2.1%) yielded positive results, most hving high TSH suggestive of hypothyroidism. Six fetures were ssocited with positive result: pregnncy nd constiption were ssocited with high TSH vlues, nd hir Tble 1. Common resons for performing thyroid function testing in ptients t GP prctice in Devon over yer period Reson Symptoms (n = 1531) Lethrgy 308 (20) Abdominl pin 108 (7.0) Joint pins 102 (6.7) Weight loss 81 (5.3) Presthesi 76 (5.0) Plpittions 73 (4.8) Dizziness 68 (4.4) Loose stool 63 (4.1) Protocol-driven/screening (n = 504) Dibetes review 268 (53) Hypertension review 94 (19) Number of ptients with this feture (% of subgroup) Symptoms group hd fetures recorded in notes prompting testing. Screening group hd vrious co-morbidities with no recorded fetures prompting testing. Forty-five other clinicl fetures nd 14 other screening modlities were reported. Ptients with multiple symptoms re reported for ech symptom. loss, plpittions, weight gin nd dirrhoe with suppressed TSH. When seprte cohort of ptients with these symptoms ws studied, modertely high levels of TSH testing nd high percentges of positive tests were found. Strengths nd limittions The popultion being studied ws from single prctice, lbeit lrge one, so the numbers of tested ptients ws lso lrge, even though overll the prctice ws reltively low in prevlence of testing compred with others in Devon. A smller proportion of Devon ptients re from ethnic minorities when compred with the UK, reducing generlisbility somewht, though hypothyroidism is more common in the white popultion (6). Our methods of identifying resons behind testing were thorough, including hving clinicin exmine the medicl records individully. The min limittion ws relince on existing clinicl records to identify the feture(s) prompting TSH testing. Some symptoms my be unrecorded; plus our interprettion could hve been erroneous t times. This ws prticulrly the cse for the pprent screening tests, especilly s no protocol specificlly recommended TSH testing in the groups we encountered. In mny cses, it ppered s if the TSH testing ws dded to other blood tests without specific rtionle being considered (or t lest one tht ws documented). Relying on Red coded entries for the cohort study is nother limittion s this my introduce selection bis, if only the ptients with the more severe symptom were Red-coded for tht symptom. Another potentil source of bis is regrding the pprent screening group of ptients. Some of these ptients my hve hd TSH tested for clinicl fetures, though these were unrecorded, lthough most hd TSH testing in chronic disese clinics s prt of generl nnul blood tests. Potentil bis my lso be found in the scertinment of Red coded fetures in ptients dignosed with thyroid disese. Would this dignosis cuse the clinicin to revisit the consulttion nd retrospectively code fetures tht now seem more relevnt in the light of the new dignosis? It is difficult to scertin the extent this my hve occurred by doing retrospective study but performing prospective study nd exmining ctul consulttions would help to remove this potentil bis. The notes re entirely computerized, so legibility ws not n issue. Comprison with previous literture The prevlence of thyroid disese in the UK popultion is 2.4% (2% hypothyroid, 0.4% hyperthyroid). The men nnul incidence of spontneous hypothyroidism during the 20-yer follow-up period of the Wickhm survey in North-Est Englnd ws 3.5 per 1000 nd 0.6 per 1000 in surviving women nd men, respectively (2). The men nnul incidence of spontneous hyperthyroidism ws 0.8 per 1000 women in the sme survey (no men were found to hve hyperthyroidism). Extrpolting these figures to prctice of implies tht the prctice should hve 35 new ptients with hypothyroidism nd seven with hyperthyroidism, exctly the number identified in this study. However, definitions differed: the Wickhm study defined hypothyroidism s rised TSH (not cler on the vlues used) nd/or rised nti-thyroid ntibodies so my be slightly more restrictive definitions thn we used. The dignostic yield of thyroid disese in this study ws 2.1%, in previously undignosed ptients. A tril of unexplined ftigue in 173 ptients from the Netherlnds yielded one ptient with hypothyroidism (7), this symptom ws not shown to be ssocited with n bnorml TSH in our study. Thyroid disese is more common in femles, nd hypothyroidism is more common with incresing ge (8), so our incresed testing nd yield ws to be expected.

4 4 Fmily Prctice, 2015, Vol. 00, No. 00 Tble 2. Symptoms ssocited with bnorml TSH test results in ptients t GP prctice in Devon over yer period nd their corresponding odds rtios nd P vlues Feture Any bnorml TSH TSH bove 4.5 miu/l TSH below 0.01 miu/l Odds rtio (CI) P vlue Odds rtio (CI) P vlue Odds rtio (CI) P vlue Pregnncy 36 ( ) < ( ) <0.001 Omitted Constiption 8.7 (1.9 40) (2.1 45) Omitted Hir loss 4.9 (1.1 21) ( ) ( ) Plpittions 3.5 (1.2 10) ( ) ( ) Weight gin 3.9 ( ) ( ) ( ) Dirrhoe 1.9 ( ) ( ) ( ) Bold indictes the vlues tht re significnt. Omitted observtions by model s predicts filure perfectly. Tble 3. Prevlence of TSH testing in cohort of 100 symptomtic ptients over 5-yer time period t GP prctice in Devon, nd the results of the test with the ssocited positive predictive vlue for ech feture Feture No TSH testing Norml TSH Abnorml TSH PPV for n bnorml TSH in tested ptients % (95% CI) Hir loss (12 33) Pregnncy (6.3 38) Plpittions ( ) Constiption (3 16.4) Dirrhoe ( ) Twelve of these positive results relted to hypothyroidism. One surprise ws the similr proportion of test positives in both the symptomtic nd the screening group. Argubly, testing bsed on soft clinicl fetures is no more ccurte thn indiscriminte screening. No rndomized trils of TSH screening of dults hve been performed in primry cre (9), nd no recommendtions for such screening re ctive. Trgeted screening hs been recommended, for instnce in Down s syndrome ptients or with lithium or miodrone tretment, the ltter two recommended for routine TSH testing by the British Endocrine society, or if worsening crdic function nd/or weight loss is present, irrespective of mediction. Thus, it ws unexpected to identify pprent screening in this study (with very few of our ptients being in these groups) nd with similr yield. The strongest ssocition with n bnorml TSH ws with pregnncy, though numbers were smll nd most hd co-existing lethrgy % of women become hypothyroid during pregnncy (10). This follows the increse in serum T4-binding globulin levels, nd consequent decrese in free hormone, precipitting n increse in TSH between the first trimester nd term. Fewer women (n estimted 1%) become overtly hypothyroid. Severl clssicl fetures of thyroid disese were identified both in the resons for testing nd in the ptients with bnorml results. Plpittions nd loose stools re usully ssocited with hyperthyroidism (11,12), which we found. Hir loss is usully considered to be feture of hypothyroidism (13), though in this study it ws ssocited only with hyperthyroidism. Weight gin ws lso unexpectedly ssocited with hyperthyroidism, though it is normlly reported with hypothyroidism (11,12). Constiption ws ssocited with hypothyroidism, s expected (14,15). Overll, the symptoms used for testing re well-known mrkers of thyroid disese. Three indices hve been published for identifying thyroid disese: Wyne s index describes 19 fetures of hyperthyroidism; nd Billewicz dignostic index nd Zulewski s clinicl score (14,15), describe 13 nd 12 fetures of hypothyroidism, respectively. Bsed on our results in this study popultion nd subsequent nlysis there is much reduced number of significnt fetures correlting with bnorml thyroid function which llows us to cutiously postulte tht by putting more emphsis on testing for these significnt fetures would give higher dignostic yields for thyroid disese nd hence be more effective test. However, the screening group in this study were not wholly untrgeted s they hd co-morbidities tht could hve prompted the TSH request, such s type 2 dibetes mellitus (16,17), or hypertension (18,19), ech with higher prevlence of hypothyroidism. We cnnot know if this ws the rtionle for testing, even though such screening is not recommended. Use of the results It could be rgued tht this level of testing is pproprite, in tht the expected number of ptients with thyroid disese were identified, without hving screened the entire popultion. However, test-positivity rte of 2.1% still leves room for improvement. Using these six significnt fetures found in this study would be good step towrds mking testing more discriminte. There will lso be the rre clssicl cse of hypothyroidism, though even some of these ptients prove to be euthyroid on testing. It my be tht clssic signs nd symptoms re of limited relevnce becuse they were undertken when thyroid function tests were much less sensitive thn those currently used (20), nd ptients generlly presented with much more dvnced thyroid dysfunction thn they do now. The threshold for tretment is flling (21); whether this is cuse or consequence of incresed testing could not be nswered by our study, but we suspect the ltter. It lso reduces the incidence of dvnced hypothyroidism t first dignosis. If we re to reduce testing, our results suggest tht ftigue is cler cndidte for omitting testing, or perhps testing deferred until it is clerly prolonged (22).Apprent screening for thyroid disorders should be restricted to protocol-bsed indictions. It would be helpful to test such policy of more restrictive testing in

5 Thyroid function testing in primry cre 5 tril; without such study, we expect further increse in TSH testing, much of it unnecessry. Declrtion Funding: funded by deprtmentl resources. Ethicl pprovl: none. Conflict of interest: Prof Hmilton is n ssocite editor of this journl. References 1. Moynihn R, Doust J, Henry D. Preventing overdignosis: how to stop hrming the helthy. BMJ 2012; 344: e Vnderpump M, Tunbridge W, French J et l. The incidence of thyroid disorders in the community: twenty-yer follow-up of the Whickhm Survey. Clin Endocrinol 1995; 43: Flynn R, McDonld T, Morris A, Jung R, Leese G. The thyroid epidemiology, udit, nd reserch study: thyroid dysfunction in the generl popultion. J Clin Endocrinol Metb 2004; 89: Assocition of Clinicl Biochemistry, British Thyroid Assocition, British Thyroid Foundtion. UK Guidelines for the Use of Thyroid Function Tests finl_version_july_2006.pdf. 5. Wng C, Crpo LM. The epidemiology of thyroid disese nd implictions for screening. Endocrinol Metb Clin North Am 1997; 26: Sichieri R, Bim J, Mrnte T, De Vsconcellos MTL, Mour AS, Vismn M. Low prevlence of hypothyroidism mong blck nd Multto people in popultion-bsed study of Brzilin women. Clin Endocrinol 2007; 66: Koch H, len, vn Bokhoven MA, ter Riet G et l. Ordering blood tests for ptients with unexplined ftigue in generl prctice: wht does it yield? Results of the VAMPIRE tril. Br J Gen Prct 2009; 59: e Prle J, Frnklyn J, Cross K, Jones S, Shepprd M. Prevlence nd followup of bnorml thyrotrophin (TSH) concentrtions in the elderly in the United Kingdom. Clin Endocrinol 1991; 34: U.S. Preventive Services Tsk Force. Screening for thyroid disese: recommendtion sttement. Ann Internl Medicine 2004; 140: Lzrus JH. Thyroid disorders ssocited with pregnncy: etiology, dignosis, nd mngement. Tret Endocrinol 2005; 4: Crooks J, Murry IP, Wyne EJ. Sttisticl methods pplied to the clinicl dignosis of thyrotoxicosis. Q J Med 1959; 28: Melish J. Thyroid Disese. Boston, MA: Butterworths, Bkry OA, Bsh MA, El Shfiee MK, Sheht WA. Thyroid disorders ssocited with lopeci ret in egyptin ptients. Indin J Dermtol 2014; 59: Zulewski H. Hypothyroidism [in Germn]. Ther Umsch 2011; 68: Werner SC. The eye chnges of Grves' disese: overview. Myo Clin Proc 1972; 47: Perros P, McCrimmon R, Shw G, Frier B. Frequency of thyroid dysfunction in dibetic ptients: vlue of nnul screening. Dibet Med 1995; 12: Akbr D, Ahmed M, Al-Mughles J. Thyroid dysfunction nd thyroid utoimmunity in Sudi type 2 dibetics. Act Dibetol 2006; 43: Kotsis V, Alevizki M, Stbouli S et l. Hypertension nd hypothyroidism: results from n mbultory blood pressure monitoring study. J Hypertens 2007; 25: Sito I, Ito K, Srut T. Hypothyroidism s cuse of hypertension. Hypertension 1983; 5: Vnderpump M, Ahlquist J, Frnklyn J, Clyton R. Consensus sttement for good prctice nd udit mesures in the mngement of hypothyroidism nd hyperthyroidism. BMJ 1996;313: Tylor P, Iqbl A, Minssin C et l. Flling threshold for tretment of borderline elevted thyrotropin levels-blncing benefits nd risks: evidence from lrge community-bsed study. JAMA Intern Med. 2014; 174: Hmilton W, Wtson J, Round A. Investigting ftigue in primry cre. BMJ 2010; 341: c4259.