Management of thyroid disorders in primary care: challenges and controversies

Transcription

1 Correspondene to: Dr C H Todd, Westongrove Partnership, Wendover Health Centre, Aylesbury Road, Wendover, Aylesbury, Buks HP22 6LD, UK; hashtodd@yahoo.o.uk Reeived 2 April 2009 Aepted 5 July 2009 Management of thyroid disorders in primary are: hallenges and ontroversies C H Todd ABSTRACT Thyroid diseases are ommon, and most an be safely and effetively managed in primary are. Two of the most ommon reasons for thyroid funtion testing are fatigue and obesity, but the vast majority of affeted patients do not have hypothyroidism. There is no plausible basis for the assertion that hypothyroidism ommonly ours despite normal thyroid funtion tests. In primary hypothyroidism all patients, exept the elderly and those with ishaemi heart disease, an safely be started on a full replaement dose of thyroxine; the aim is to restore thyroid stimulating hormone (TSH) to normal. Triiodothyronine (T3) has no role in the treatment of primary hypothyroidism. Sublinial thyroid disease should not be treated exept in ertain well defined situations. Its main importane lies in the inreased risk of progression to overt thyroid disease. The development of hyperthyroidism is easily overlooked, and it is important to maintain a high index of suspiion, espeially in the elderly. The most ommon auses are Graves disease and thyroiditis (espeially postpartum), and in the elderly toxi nodular goitre and amiodarone. Patients taking amiodarone should have their thyroid funtion heked every 6 months. Patients with overt hyperthyroidism should be referred for speialist management; b-blokers and sometimes antithyroid drugs may be initiated in primary are. Most thyroid nodules, espeially those deteted inidentally on ultrasound sanning, are benign. Indiations for referral inlude newly ourring nodules.1m in diameter, painful nodules, and nodules that are inreasing in size. Thyroid disorders are ommon; 3% of the population is taking long term thyroid replaement therapy, 1 and every year about 4.1 women and 0.6 men per 1000 of the adult population develop hypothyroidism, and 0.8 women per 1000 develop hyperthyroidism. 2 Patients with these onditions may present to us with a wide range of different symptoms beause of the effets of either over or under prodution of thyroid hormones on the various organs of the body (table 1). The other reason patients with a thyroid disorder may onsult us is in regard to onerns about a swelling in the nek. This artile disusses some of the more hallenging and ontroversial aspets of managing thyroid disorders in primary are. A basi level of knowledge of thyroid disorders is assumed, and an be found in standard textbooks suh as Kumar and Clark 3 and the Oxford textbook of primary medial are. 4 A useful free online resoure with in depth information on all aspets of thyroid disease is the Thyroid Disease Manager ( Review In treating hypo- and hyperthyroidism it is important to remember that these are funtional diagnoses. Understanding the underlying ause of the hormonal disturbane is key in management. In hypothyroidism the most important distintion is between primary thyroid failure (most ommonly due to autoimmune destrution of the thyroid, thyroidetomy and ertain mediines) and pituitary failure. Graves disease, toxi nodular goitre and amiodarone treatment are the main auses of hyperthyroidism; seondary auses are rare. AN EPIDEMIC OF THYROID FUNCTION TESTS Ten million requests for thyroid funtion test are made every year in the UK, at an estimated annual ost of 30 million (J35 million, US$50 million). 5 Thyroid funtion tests are being ordered with low pre-test probability, 6 and thorough linial assessment does not seem to play an important role in the assessment of patients. 7 Symptoms suh as tiredness and lethargy are probably the most ommon indiation given by general pratitioners (GPs) for requesting thyroid funtion tests in patients with no pre-existing thyroid disease. The value of suh testing is debatable in the absene of goitre or other linial features of thyroid dysfuntion. There are a wide range of auses of fatigue and psyhologial fators are frequently important. 8 Reent evidene has shown that hypothyroidism is unommonly diagnosed, and supports a strategy of trying to postpone ordering blood tests, in patients with unexplained fatigue. 9 Spending time talking in some depth with patients who omplain of being tired all the time is muh more likely to provide us with appropriate lues as to the underlying problem rather than ordering blood tests. Thyroid funtion testing is only reommended as a matter of ourse when symptoms of fatigue are prolonged and debilitating. 10 A lower threshold for ordering thyroid funtion tests should also be onsidered in women aged over 55 years with vague symptoms: sublinial thyroid dysfuntion is highly prevalent in this group with its attendant risk of progression to overt thyroid failure. 5 Another ommon indiation given for thyroid funtion testing is obesity, and this is often requested by patients who believe that there must be a glandular ause for their weight gain. Although a reent review reommended thyroid funtion testing in the assessment of obesity, 11 hypothyroidism is a rare ause and thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) are not affeted by obesity. 12 The value of performing thyroid funtion Postgrad Med J: first published as /pgmj on 14 January Downloaded from on 3 Otober 2018 by guest. Proteted by opyright. Postgrad Med J 2009;85: doi: /pgmj

2 Table 1 Common linial features in hypothyroidism and hyperthyroidism Organ Hypothyroidism Hyperthyroidism Skin Cold intolerane, ool dry skin, pallid omplexion, puffy fae, oarse brittle hair, Heat intolerane, warm moist skin, inreased sweating alopeia, diminished sweating Nervous system Paraesthesia, lethargy, deafness, slow speeh, depression, slow reflexes Nervousness, irritability, tremor, eyelid retration Musuloskeletal Weakness, myalgia, musle ramps, easy fatigability Weakness, myopathy Cardia Dereased exerise tolerane, slow pulse, ardiomegaly Shortness of breath, palpitations, arrhythmias, heart failure Gastrointestinal Anorexia, onstipation, weight gain Inreased appetite, frequent bowel movements, weight loss Genitourinary Menorrhagia, redued fertility Santy periods Others Raised holesterol, anaemia Eye and skin hanges of Graves disease tests on obese patients in the absene of any other symptoms suggestive of hypothyroidism is therefore doubtful. There is a dearth of reent work whih an provide data for liniians to guide them on whih symptoms and signs mean that the patient has a signifiantly raised probability of hypo- or hyperthyroidism. The lassi studies quoted in textbooks are of limited relevane beause they were undertaken when thyroid funtion tests were muh less sensitive than those urrently used, and patients generally presented with muh more advaned thyroid dysfuntion than they do now. One reent study has shown that the most disriminating symptoms and signs of hypothyroidism are dry skin, diminished sweating, weight inrease, paraesthesia, delayed ankle reflex, oarse skin, periorbital puffiness and old skin. 13 This study suggests that patients with overt hypothyroidism most ommonly present with skin manifestations of the ondition. The usual first line test of thyroid funtion is serum TSH assay 5 ; it is important to give adequate linial information with the request so the laboratory an judge whether T4 onentrations should also be measured even if TSH is normal. Thyroid peroxidase (formerly mirosomal) antibodies (TPOAb) should only be tested if TSH onentrations are raised or if the result would have lear linial relevane. One in 10 women in the general population are positive for TPOAb, 2 so undue signifiane an easily be plaed on a positive result. HYPOTHYROIDISM WITH NORMAL THYROID FUNCTION TESTS There is a voiferous shool of thought that hypothyroidism frequently ours in the absene of abnormalities in standard funtion tests. One website asserts Many dotors simplistially think that thyroid disease an be diagnosed, and even worse, an govern treatment, by testing only TSH levels ( 14 A heklist suggests that a huge range of symptoms may be due to hypothyroidism, and a utoff of 2 mu/l is proposed for the upper limit of normal for TSH. This is very misleading. In fat TSH assay is extremely sensitive, and in the absene of assoiated systemi disease a normal TSH onentration (0.3 4 mu/l) has over 99% negative preditive value in ruling out primary hypothyroidism and hyperthyroidism. 15 Hypothyroidism may our when TSH is normal or even low in pituitary failure, and it is always important to be open to this possibility, although rare. Other features of hypopituitarism will usually be present. The impliation that hypothyroidism with normal TSH and T4 ommonly ours due to failure of peripheral onversion of T4 to T3 or tissue unresponsiveness 14 is in the absene of systemi disease highly ontentious. The onversion of T4 to T3 and TSH seretion are affeted in unwell, hospitalised patients, but this is not normally an issue when testing ambulant patients in primary are. True resistane to thyroid hormones has been desribed but is very rare. 16 Of more pratial importane is the effet that ertain mediines may have on thyroid funtion, notably gluoortioids and amiodarone. It is important to respond sympathetially to a patient who believes they have hypothyroidism and is persistent in requesting further tests, despite a normal TSH, and it may be appropriate to speifially request a T4 assay if the patient has typial features of hypothyroidism. However, if TSH and T4 values are both normal, an alternative explanation should be sought for their symptoms. The patient may be relutant to aept this; in suh ases referene to the Royal College of Physiians statement on the diagnosis and management of primary hypothyroidism, 17 and to the available evidene, 18 may be helpful. OPTIMAL TREATMENT OF HYPOTHYROIDISM: IS THERE A ROLE FOR T3 IN TREATMENT? All patients with lear-ut hypothyroidism (TSH.10 mu/l, FT4,10 pmol/l) should be treated: this will almost ertainly be lifelong. It is wasteful and unneessary to titrate up the dose of thyroxine in most ases; rather patients should be started on a full replaement dose of around 1.6 mg/kg daily. 1 For a 60 kg woman this is 100 mg, and 125 mg for a 75 kg man. Those over 60 years and patients with ishaemi heart disease should be started on 25 mg per day and the dose titrated gradually upwards: in severe ishaemi heart disease or older patients with very high initial TSH onentrations, start at 12.5 mg/day. Thyroid funtion tests should be heked after at least 8 weeks; testing too soon does not give the pituitary gland suffiient time to adjust. The aim in treatment is to restore the patient s TSH value to normal; fine tuning of the dose may be needed and some patients may only feel better one their TSH is in the lower half of the referene range ( mu/l). 1 Overtreatment should be avoided, although in younger patients it may be aeptable for TSH onentrations to be below the referene range if a higher dose of levothyroxine is required to fully ontrol symptoms. 1 Maintaining TSH onentrations below 0.1 mu/l is poor pratie due to the inreased risk of osteoporosis and atrial fibrillation. The exeption to this is after thyroidetomy for thyroid aner, when TSH values may need to be suppressed to and maintained at a onentration,0.1 mu/l. 5 A soure of onfusion is that sometimes patients are reommended treatment with a ombination of T4 and T3 (as liothyronine), although there is no good evidene to bak up the use of this ombination. A meta-analysis of randomised, ontrolled studies of T4 T3 ombination therapy found no advantage when ompared with standard T4 monotherapy, 19 and the reent College of Physiians statement does not reommend additional T3 in any form, inluding Armour Thyroid (porine thyroid extrat). 17 Addition of T3 also poses a risk of overtreatment unless doses are arefully ontrolled, as T3 is five times more ative than T4. Postgrad Med J: first published as /pgmj on 14 January Downloaded from on 3 Otober 2018 by guest. Proteted by opyright. 656 Postgrad Med J 2009;85: doi: /pgmj

3 SUBCLINICAL THYROID DISEASE: SHOULD IT BE TREATED? Sublinial thyroid dysfuntion ours when TSH values are outside the normal range (0.3 4 mu/l) while FT4 and FT3 (where relevant) are normal. Sublinial hypothyroidism is very ommon, espeially in older people, with up to 20% of women over 60 years of age affeted. Sublinial hyperthyroidism, exept when due to overtreatment of hypothyroidism, is muh less ommon. When first identified it is important to exlude known thyroid disease or drugs suh as amiodarone whih may interfere with thyroid funtion (see below). Testing should be repeated after 2 3 months and a deision then made on further management. The main importane of sublinial thyroid disease is that affeted patients are at inreased risk of progression to overt disease. Whether sublinial thyroid disease itself should be treated is ontroversial; however, there is little robust evidene that treatment is benefiial and it is not reommended exept in ertain defined situations. 20 In sublinial hypothyroidism treatment should be onsidered in those whose TSH onentrations are.10 mu/l, espeially if positive for TPOAb, as they are at higher risk of progressing to overt disease. Treatment should also be offered to women with sublinial hypothyroidism who are pregnant or trying to oneive, and a trial of treatment should be onsidered in patients who have typial symptoms of hypothyroidism. In sublinial hyperthyroidism where TSH values are,0.1 mu/l there is an inreased risk of atrial fibrillation and osteoporosis. 20 However, the evidene that treatment is benefiial even when TSH is at very low onentrations is thin. Treatment might be justified if TSH values remain,0.1 mu/l and there are other features of onern suh as typial symptoms or the subjet develops atrial fibrillation. In suh ases the opinion of an endorinologist should be sought. If treatment is onsidered to be warranted, management is broadly along the same lines as overt hyperthyroidism. In subjets with sublinial hypothyroidism, approximately 2 5% per year will progress to overt hypothyroidism. 20 Those with higher TSH values and those positive for TPOAb are more likely to progress. In sublinial hyperthyroidism 1 2% per year of those with TSH values,0.1 miu/l develop overt hyperthyroidism. 20 Those with higher TSH values are at muh lower risk of progression. Patients onsidered at a high risk of progression should be offered annual follow up thyroid funtion tests, and those at lower risk should be tested every 3 years. MANAGEMENT OF HYPERTHYROIDISM IN PRIMARY CARE The development of thyrotoxiosis is easily overlooked. Initial symptoms suh as fatigue, palpitations and anxiety may easily be attributed to stress. It is important to maintain a high index of suspiion look arefully for goitre and eye signs, hek for tremor, and feel the hands. In primary anxiety they are old and dry, whereas in thyrotoxiosis they are typially warm and moist. Thyroid funtion tests will show a suppressed TSH and raised T4 or T3, or both. Hyperthyroidism is a ondition and not itself a diagnosis, whih depends on the underlying ause. Further investigation will be needed to establish this with ertainty, but linial lues may often give a guide as to what it may be. In younger subjets the most ommon auses are Graves disease and thyroiditis (espeially postpartum). In the elderly the majority of ases are due to toxi nodular goitre and/ or our in those being treated with amiodarone. Thyrotoxiosis is partiularly easily missed in older subjets. Lethargy or fatigue and tremor are ommon presenting omplaints in this age group. Typial eye signs will often be absent as most ases are not due to Graves disease. Comorbidities mean that symptoms may be asribed to other onditions or drug side effets, and drugs espeially b- blokers may mask some of the symptoms. Critial lues ome from taking into aount possible ausative fators suh as treatment with amiodarone and previous thyroid surgery. Patients found to have overt hyperthyroidism should be referred to an appropriate speialist for further management unless the GP has relevant training and experiene. Those affeted may be treated with antithyroid drugs suh as arbimazole and propylthiourail, surgery or radioiodine. Reommendations on treatment in a partiular patient are based on a number of fators inluding underlying ause, the subjet s age, severity of the ondition, and the presene of omorbidities. Pending referral, a b-bloker may be presribed to ontrol symptoms if not ontraindiated for example, propranolol 40 mg three times daily. If a long wait is likely before the patient is seen by a speialist it may be appropriate for the GP to initiate treatment with anti-thyroid drugs in onsultation with the endorinologist onerned. In the UK the most ommonly used anti-thyroid drug is arbimazole, and the typial starting dose in adults is mg daily. This is then redued to a maintenane dose of 5 15 mg daily after 6 8 weeks aording to response. When monitoring thyroid funtion, T4 values should usually be the marker of hoie to guide treatment 5 ; TSH onentrations may take several months to return to normal. The main hazard of arbimazole treatment is bone marrow suppression. If the subjet develops symptoms or signs of infetion, espeially a sore throat, a full blood ount (FBC) should be heked without delay. If neutropenia is onfirmed, arbimazole should be stopped immediately. It is good pratie to ensure that an FBC is heked at the same time as eah follow up thyroid funtion test is performed. Treatment with anti-thyroid drugs alone is a realisti option in unompliated Graves disease on the basis that, after months of treatment, 40 60% of patients will enter permanent remission. 21 Remission is unlikely in severe disease and in those with a large goitre, and it is very unlikely in toxi nodular goitre inluding toxi adenoma; in suh ases it is sensible to opt promptly for definitive treatment, either radioiodine or surgery. The latter is partiularly suitable in older subjets with omorbidities. For a more detailed disussion readers are referred to a reent review. 21 AMIODARONE AND THYROID DISEASE Amiodarone is widely used for the treatment and prevention of arrhythmias suh as atrial fibrillation and ventriular tahyardia; 100 mg of amiodarone ontains 37 mg of iodine, and treatment results in severe iodine overload. Thyroid funtion abnormalities are ommon in patients taking amiodarone, and both frank hypothyroidism and thyrotoxiosis may our. 22 Hypothyroidism assoiated with amiodarone treatment may only be temporary; if sustained it should be treated with thyroxine with the aim of keeping FT4 at the upper end of the normal range. Amiodarone indued thyrotoxiosis is serious, espeially beause of the potential for life threatening ardia effets in patients who already have heart disease. Assessment is ompliated by the fat that TSH onentrations are often suppressed and T4 (and FT4) values may inrease above the normal range in up to 40% of patients taking amiodarone, although they are euthyroid. Diagnosis rests on the presene of typial linial features and the finding of elevated T3 values. Two types of amiodarone indued thyrotoxiosis are reognised, depending on whether there is a predisposing thyroid abnormality or not. 23 However, it is not always easy to ategorise Postgrad Med J: first published as /pgmj on 14 January Downloaded from on 3 Otober 2018 by guest. Proteted by opyright. Postgrad Med J 2009;85: doi: /pgmj

4 patients as having one or other type, and in pratie the key distintion is whether they respond well to standard antithyroid drugs, possibly with the addition of potassium perhlorate, or whether high doses of steroids are needed. The other important question is whether amiodarone treatment an safely be stopped or not; even if it an, it may take several months for its effets to wane beause of its very long half-life (up to 55 days). The key role of the GP is to ensure that all patients taking amiodarone have their thyroid funtion measured at least every 6 months, 24 and to be espeially vigilant if they report new symptoms at any time. Thyrotoxiosis is more likely after treatment has been established for 2 3 years, and may our quite suddenly. 23 Hypothyroidism an be managed within primary are, but those with thyrotoxiosis should always be referred to an endorinologist as treatment is hallenging. If the patient is obviously unwell the GP should refer urgently; hospitalisation may be neessary in the most severe ases. The GP should also liaise with the ardiologist who initiated amiodarone to disuss whether it an be stopped and, if so, what antiarrhythmi drug should be used instead. MANAGING THYROID NODULES Many people have thyroid nodules that are visible and/or palpable, and on high definition ultrasound up to 50 70% of adults are found to have thyroid nodules. 25 The vast majority of thyroid nodules are benign, espeially those found inidentally. The optimal management of inidentally found non-palpable thyroid nodules is ontroversial 26 ; a few will be histologially malignant, but the value of deteting all of these at an early stage is debatable and may ause undue anxiety to the patient Key learning points Most thyroid disorders an be safely and effetively managed in primary are. The vast majority of patients with fatigue and obesity do not have thyroid disease. Skin manifestations are the most ommonly presenting feature in overt hypothyroidism. There is no plausible basis for the assertion that hypothyroidism ommonly ours despite normal thyroid funtion tests. In primary hypothyroidism the aim of treatment is to restore TSH to normal. Most patients an safely be started on a full replaement dose of thyroxine. T3 has no role in the treatment of primary hypothyroidism. Sublinial thyroid disease should not be treated exept in ertain well defined situations. Its main importane lies in the inreased risk of progression to overt thyroid disease. The development of hyperthyroidism is easily overlooked espeially in the elderly. Patients taking amiodarone should have their thyroid funtion heked every 6 months. Patients with overt hyperthyroidism should be referred for speialist management. While the vast majority of thyroid nodules are benign and do not require investigating, patients with newly ourring thyroid nodules.1 m diameter or ones that are inreasing in size should be referred urgently if any additional suspiious features are present. and may have other unpleasant onsequenes suh as loading of life insurane. Current guidelines reommend that those patients with a thyroid nodule whih has not hanged for years, and those who have asymptomati non-palpable thyroid nodules found inidentally whih are,1 m in diameter with no suspiious features, an be managed in primary are. 27 The following groups should be referred non-urgently aording to loal referral pathways: patients with nodules who have abnormal thyroid funtion tests; patients with a history of sudden onset of pain in a thyroid lump (who are likely to have bled into a benign thyroid yst); and patients with a thyroid lump whih is newly presenting or inreasing in size over months. 27 The key investigations are thyroid imaging and fine needle aspiration ytology. Certain linial features are partiularly suggestive of malignany: notably large size (.4 m), rapid growth, pain, hard onsisteny, fixation to adjaent strutures, loal lymphadenopathy, stridor (refer same day), and hoarseness. 27 All patients with any of these features should be urgently referred to a thyroid surgeon under the 2 week wait rule. A family history of thyroid aner and a history of irradiation of the nek also put the patient at inreased risk and are indiations for urgent referral, as are thyroid nodules ourring in hildren. IS THE POPULATION OF THE UK AFFECTED BY IODINE DEFICIENCY? Lak of iodine during pregnany and early hildhood affets the development of the nervous system resulting in neuroognitive defets of varying degree; subtle effets our even when the defiieny is mild and the visible manifestations of iodine defiieny, espeially endemi goitre, are absent. For a long time it has been assumed that the diet in the UK and Ireland is iodine replete, but this does not appear to be the ase 28 possibly plaing the ognitive abilities of future generations at risk. An up-to-date piture of iodine nutrition in the UK is needed, and the British Thyroid Assoiation is embarking on a nationwide survey to assess urrent iodine status. (For more information on iodine defiieny, see Competing interests: The author is a member and former board member of the International Counil for Control of Iodine Defiieny Diseases. Key referenes Vaidya B, Peare SHS. Management of hypothyroidism in adults. BMJ 2008;337:a801. Assoiation of Clinial Biohemistry, British Thyroid Assoiation, British Thyroid Foundation. UK guidelines for the use of thyroid funtion tests TFT_guideline_final_version_July_2006.pdf Royal College of Physiians. The diagnosis and management of primary hypothyroidism speialties/endorinology- Diabetes/Douments/ Hypothyroidism.pdf Sukks MS, Ortiz E, Daniels GH, et al. Sublinial thyroid disease: sientifi review and guidelines for diagnosis and management. JAMA 2004;291: Peare EN. Diagnosis and management of thyrotoxiosis. BMJ 2006;332: Postgrad Med J: first published as /pgmj on 14 January Downloaded from on 3 Otober 2018 by guest. Proteted by opyright. 658 Postgrad Med J 2009;85: doi: /pgmj

5 REFERENCES 1. Vaidya B, Peare SHS. Management of hypothyroidism in adults. BMJ 2008;337:a Vanderpump MP, Tunbridge WM, et al. The inidene of thyroid disorders in the ommunity: a twenty-year follow up of the Wikham survey. Clin Endorinol (Oxf) 1995;43: Drury IL, Howlett TA. Endorine Disease. In: Kumar P, Clark M, eds. Clinial mediine, 5th ed. Edinburgh: WB Saunders, 2002: Pop VJ. Thyroid disorders. In: Jones R, Britten N, Culpepper L, et al, eds. Oxford textbook of primary medial are, volume 2, linial management. Oxford: OUP, 2005: Assoiation of Clinial Biohemistry, British Thyroid Assoiation, British Thyroid Foundation. UK guidelines for the use of thyroid funtion tests TFT_guideline_final_version_July_2006.pdf 6. Stokigt J. Assessment of thyroid funtion: towards an integrated laboratory-linial approah. Clin Biohem Rev 2003;24: O Reilly D StJ. Thyroid funtion tests time for a reassessment. BMJ 2000;320: Sharpe M, Wilks D. ABC of psyhologial mediine: fatigue. BMJ 2002;325: Koh H, van Bokhoven MA, et al. Ordering blood tests with unexplained fatigue: what does it yield? Results of the VAMPIRE trial. Br J Gen Prat 2009;59: National Institute for Health and Clinial Exellene. Chroni fatigue syndrome/ myalgi enephalomyelitis (or enephalopathy): diagnosis and management of CFS/ ME in adults and hildren. London: NICE, Labib M. The investigation and management of obesity. J Clin Pathol 2003;56: Sikaris KA. The linial biohemistry of obesity. Clin Biohem Rev 2004;25: Zulewski H, Müller B, Exer P, et al. Estimation of tissue hypothyroidism by a new linial sore: evaluation of patients with various grades of hypothyroidism and ontrols. J Clin Endorinol Metab 1997;82: Thyroid UK Stokigt JR. Thyroid funtion tests and the effets of drugs. In: Wass JA, Shalet SM, eds. Oxford textbook of endorinology and diabetes. Oxford: OUP, 2002: Chatterjee VK, Gurnell M. Thyroid hormone resistane syndrome. In: Wass JA, Shalet SM, eds. Oxford textbook of endorinology and diabetes. Oxford: OUP, 2002: Royal College of Physiians. The diagnosis and management of primary hypothyroidism Diabetes/Douments/Hypothyroidism.pdf 18. Pollok MA, Sturrok A, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid funtion tests within the referene range: randomised double blind plaebo ontrolled rossover trial. BMJ 2001;323: Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al. Thyroxine-triiodothyronine ombination therapy versus thyroxine monotherapy for linial hypothyroidism: metaanalysis of randomized ontrolled trials. J Clin Endorinol Metab 2006;91: Sukks MS, Ortiz E, Daniels GH, et al. Sublinial thyroid disease: sientifi review and guidelines for diagnosis and management. JAMA 2004;291: Peare EN. Diagnosis and management of thyrotoxiosis. BMJ 2006;332: Harjai KJ, Liata AA. Effets of Amiodarone on Thyroid Funtion. Ann Intern Med 1997;126: Wiersinga WM. Management of thyrotoxiosis without hyperthyroidism. In: Wass JA, Shalet SM, eds. Oxford textbook of endorinology and diabetes. Oxford: OUP, 2002: British National Formulary. BNF 57. London: BMJ Group and RPS Publishing, Marh 2009: Mehanna HM, Jain A, Morton RP, et al. Investigating the thyroid nodule. BMJ 2009;338:b Patel CN, Gerrard G, Sarsbrook AF. Inidental thyroid nodule. BMJ 2009;338:b British Thyroid Assoiation, Royal College of Physiians. Guidelines for the management of thyroid aner, 2nd ed org/news/dos/thyroid_aner_guidelines_2007.pdf 28. Lazarus JH, Smyth PPA. Iodine defiieny in the UK and Ireland. Lanet 2008;372:888. Postgrad Med J: first published as /pgmj on 14 January Downloaded from on 3 Otober 2018 by guest. Proteted by opyright. Postgrad Med J 2009;85: doi: /pgmj