Thyroid Disorders—An Update

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REVIEWS

Thyroid disorders—an update

J H Lazarus, K Obuobie

Patients with thyroid disease are seen in many Hypothyroidism is common. The prevalence diVerent general and specialist clinics because in the Whickham survey was 1.5% in women of the many and varied modes of presentation. and less than 1% in men. Recent follow up data This review will highlight recent developments indicate a continuing risk of developing thyroid in aspects of pathophysiology and clinical failure especially if positive thyroid autoanti- management of thyroid disorders but will bodies are present. There is a female/male ratio inevitably not be all inclusive. Recent develop- of about five to one. ments in molecular biology have had important eVects on our understanding of many areas of Hyperthyroidism thyroidology. The causes of hyperthyroidism are shown in table 2. Thyroid hormone action Graves’ disease is the commonest cause of The thyroid produces 100% of circulating thy- hyperthyroidism in the UK and is accompa- roxine but only about 5%–10% of circulating nied by the presence of thyroid stimulating triiodothyronine, the rest being derived from antibodies (TsAb). Recent developments in peripheral monodeiodination of thyroxine in assay methodology have resulted in a near tissues such as heart, liver, kidney, and gut 100% detection rate in Graves’ patients. mucosa by the type I deiodinase. The type II Although the presence of TsAb is not a very deiodinase provides intracellular triiodothyro- satisfactory predictor of relapse after a course nine in specific sites such as central nervous of antithyroid drugs, it is to be hoped that the system and pituitary. newer assays may improve this aspect of treat- Triiodothyronine is the hormone that medi- ment. Graves’ hyperthyroidism has been ates hormone action at the cell level. After treated with thionamide antithyroid drugs for gaining entry to a thyroid responsive cell it binds to a specific nuclear receptor which initi- the past 50 years or so. In addition to blocking ates transcription of messenger RNA leading to thyroid hormone biosynthesis there is persua- new protein production. Three triiodothyro- sive evidence that they have significant immu- nine responsive receptors (TRá1,TRâ1, and nosuppressive eVects thereby aVecting the dis- TRâ2) have been identified and vary in their ease process in Graves’ disease. During this tissue distribution. Mutations in the TRâ gene time it has been realised that (1) the relapse http://pmj.bmj.com/ are seen in patients with the syndrome of rate after a course of six to 12 months’ therapy resistance to thyroid hormone (see below). may be as high as 50% and that this relates to Thyroid hormones also have extranuclear ambient iodine concentration; (2) there is some actions in the cell which will not be further dis- evidence that an 18 month course may lessen cussed. the relapse rate but this is not universally During the last decade advances in thyroid accepted; (3) prediction of relapse in any one patient is not possible, although goitre size,

biology and immunology have resulted in the on September 27, 2021 by guest. Protected copyright. identification of the major thyroid autoanti- HLA haplotype, and pretreatment triiodothy- gens. The genes for these moieties have been ronine levels have been found to predict on a cloned and details of their structure and func- group basis; (4) the report that the addition of tion have been characterised (table 1). thyroxine to the antithyroid drug regimen The prevalence of hyperthyroidism has been would reduce the relapse rate has not been reported to be in the region of 2.5–4.7/1000 confirmed by a recent study. Under conditions females. The prevalence is about 10 times more of iodine deficiency or borderline suYcient common in women than men. The incidence of iodine a supply of 40 mg methimazole daily Department of the disease is about 1/1000 women annually in (approximately 60 mg carbimazole) will render Medicine, University north east England and similar figures are seen more patients with Graves’ disease euthyroid of Wales College of in Scandinavia, Japan, and the USA. within the first six weeks of therapy than 10 mg Medicine, Llandough Hospital, CardiV Table 1 Features of major thyroid autoantigens J H Lazarus K Obuobie TSH receptor Sodium iodide symporter Thyroid peroxidase Thyroglobulin Chromosome 14 19 2 8 Correspondence to: Amino acids 743 643 933 274 Dr John H Lazarus, Reader Protein G protein Transmembrane transporter Haemoprotein enzyme Iodinated glycoprotein in Medicine, Department of MW (kDa) 85 65–77 105–110 660 Medicine, Llandough Glycosylation + + + Hospital, CardiV CF64 2XX, Function Receptor for TSH Iodide uptake Iodination and coupling of Storage of thyroxine + Wales, UK tyrosine triiodothyronine Homologies FSH + LH receptor Na/glucose transporter Myeloperoxidase Anticholinesterase Submitted 30 July 1999 Accepted 20 December 1999 FSH = follicle stimulating hormone; LH = luteinising hormone; MW=molecular weight.

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Table 2 Aetiology of hyperthyroidism and may account for 25% or more, and up to 10% respectively, of a hyperthyroid population Disease Mechanism depending on the geographic location. Graves’ disease Thyroid stimulating IgG antibody In the past patients with familial hyperthy- Congenital (neonatal) hyperthyroidism Transplacental passage IgG antibody roidism and diVuse or nodular goitre have been Non autoimmune hereditary hyperthyroidism Constituitive activation of TSH receptor Toxic multinodular goitre Relative excess iodine exposure in previous goitre described who did not show autoimmune Thyroid stimulating immunoglobulins (?) features. AVected individuals showed thyroid Toxic uninodular goitre (adenoma) Somatic mutation Gsá or TSH receptor autonomy, negative thyroid stimulating hor- Subacute thyroiditis Viral destruction Silent thyroiditis Lymphocytic infiltrate mone (TSH) receptor antibodies and no Postpartum thyroiditis Immune destruction (transient) thyroid eye disease; however they were noted to Iodine induced hyperthyroidism Increased substrate for biosynthesis have recurrent hyperthyroidism. This familial Drug induced hyperthyroidism Iodine Amiodarone non-autoimmune hyperthyroidism is auto- Lithium (?) somal dominantly inherited and is now known Radiocontrast agents Hyperemesis gravidarum Human chorionic gonadotrophin to be due to constituitively activating germline TSH receptor mutation mutations in the TSH receptor gene. The Molar pregnancy Human chorionic gonadotrophin diagnosis can be confirmed by mutation analy- Thyrotoxicosis factitia Exogenous thyroid hormone Hamburger toxicosis Exogenous thyroid hormone sis of genomic DNA obtained from a venous Metastatic diVerentiated thyroid cancer Ectopic thyroid hormone production blood sample. A near total thyroidectomy is Struma ovarii Ectopic thyroid hormone production recommended in order to avoid relapses. Abla- Pituitary resistance to thyroid hormone Mutation thyroid hormone â-receptor Pituitary adenoma Autonomous TSH secretion tive radioiodine may also be given. Genetic counselling is advised. daily but at the expense of an increased rate of adverse reactions. Remission rates are not dose Autoimmune thyroiditis Autoimmune thyroiditis is defined as a state in dependent. The most severe side eVect of the which the thyroid gland is the site of chronic thionamide drugs is agranulocytosis which, in lymphocytic inflammation leading to progres- life threatening states, has been successfully sive destruction and fragmentation of thyroid treated with granulocyte colony stimulating follicular structure. Clinically this condition is factor but does not always respond to this five to six times more common in females, sub- treatment. ject to certain HLA haplotype restriction, and Radioiodine therapy is now widely employed is characterised in many patients by the as a cheap eVective therapy which can be presence of a firm goitre and the presence of administered in the outpatient setting. There is circulating thyroid antibodies.These are the still discussion relating to safety issues of radia- antithyroid peroxidase antibody and antithy- tion exposure to the family of patients receiving roglobulin antibody, the former being thought radioiodine and considerable variation is noted to be more closely involved in the pathogenesis in these regulations in diVerent European of antibody mediated cytotoxicity partly due to countries. Another controversial area is the its expression at the follicular luminal surface. relationship between radioiodine administra- While many patients are euthyroid others tion and development or worsening of ophthal- progress to a hypothyroid state and require http://pmj.bmj.com/ mopathy. Patients who smoke and who have thyroxine treatment. The prevalence of thyroid evidence of significant eye involvement should antibodies in women rises to around 10% with receive prednisone (0.5–1.0 mg/kg) for four to age and the progression to hypothyroidism in eight weeks at the time of treatment to prevent women with positive antibodies is about 5% eye progression. per year. In younger people the presence of The management of thyroid associated oph- thyroid antibodies is usually the only indication thalmopathy is largely symptomatic in the early of potential underlying thyroid autoimmunity

phase. Ophthalmic evaluation of diplopia and as the goitre may not have developed and on September 27, 2021 by guest. Protected copyright. optic nerve dysfunction should be performed if euthyroidism is present. clinically indicated. Attention should be paid to It should be noted that autoimmune thy- the avoidance of smoking, and the use of tinted roiditis may coexist with Graves’ disease, which spectacles. is also an autoimmune disorder. Hyperthy- Elevation of the head end of the bed at night, roidism caused by Graves’ disease will not be diuretic therapy, and frequent bathing will help considered further. to reduce the swelling and periorbital oedema. Many patients with more severe eye changes Hypothyroidism will respond to high dose prednisone (120 The causes of hypothyroidism are shown in mg/day) and some clinicians add azathioprine table 3. Some are dealt with elsewhere in this as a steroid sparing agent during long term review. treatment. After favourable reports of orbital The commonest cause of primary thyroid decompression operations this procedure failure is Hashimoto’s thyroiditis; other fre- should be considered earlier in the disease quent causes of primary hypothyroidism in- process than in the past. A combination of clude post-radioiodine hypothyroidism, post- orbital radiotherapy and steroids is also eVec- thyroidectomy, and drugs. Destruction of tive in reducing proptosis and diplopia in some pituitary thyrotropes by tumour or inﬁltrative patients. When the eyes are quiet, corrective disease results in secondary hypothyroidism muscle surgery may be undertaken for residual and hypothalamic pressure or destruction due diplopia. to tumour causing reduction or loss of Toxic multinodular goitre and toxic ad- thyrotrophin releasing hormone produces ter- enoma are important causes of thyrotoxicosis tiary hypothyroidism.

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Table 3 Causes of hypothyroidism (in decreasing order of SICK EUTHYROID SYNDROME frequency) A range of thyroid function test abnormalities may be observed in non-thyroidal illness. The Adult Hashimoto’s disease abnormalities are more likely with increasing 131I therapy for hyperthyroidism severity of such diseases. The earliest change is Subtotal thyroidectomy for hyperthyroidism or tumour Previous antithyroid drug therapy a decreased concentration of free triiodothyro- Postpartum (60%–70% transient) nine. Drugs (lithium, amiodarone, iodides interferon alfa) This may be followed by low free thyroxine Pituitary hypothyroidism (secondary) Hypothalamic hypothyroidism (tertiary) and TSH concentrations, resulting in transient Subacute thyroiditis, silent thyroiditis central hypothyroidism, which has the benefi- Iodine deficiency cial eVect of preventing excess tissue catabo- Generalised resistance to thyroid hormone lism. High levels of reverse triiodothyronine are Child/neonate Neonatal hypothyroidism also noted. Thyroid agenesis Low free triiodothyronine levels are due to Thyroid ectopia decreased concentrations of 5-monodeiodinase, Thyroid dyshormonogenesis Others the enzyme which catalyses the conversion of Resistance to thyroid hormone thyroxine to triiodothyronine. High concentra- Isolated TSH deficiency tions of cortisol and free fatty acids, present in the sick state, inhibit the activity of this enzyme. Increased activity of the enzyme INVESTIGATION 5-monodeiodinase results in higher levels of A high index of clinical suspicion is important. reverse triiodothyronine, useful in distinguishing Symptoms such as lethargy, mild depression, non-thyroidal illness from true central hypo- variation in menstruation, and weight increase thyroidism. High reverse triiodothyronine levels are common and non-specific but may be a correlate with increased mortality in severe non- pointer to the diagnosis of the hypothyroid thyroidal illness. Management with thyroid hor- state. The plethora of symptomatology means mones is not beneficial since these biochemical that patients may be referred to a variety of changes are transient. clinics—for example, gynaecology, psychiatry, The cause of congenital hypothyroidism should be determined. A thyroid scan using 123I neurology, cardiology, etc. The duration of the 99m history should be ascertained as this often or Tc pertechnetate will indicate the pres- relates to the time taken to achieve full ence or absence of thyroid tissue or any evidence of ectopia. The presence of a rapidly recovery. A family history of autoimmune growing large goitre in an elderly hypothyroid endocrinopathy should be obtained. Recent patient is suggestive of a thyroid lymphoma and pregnancy may suggest postpartum hypo- fine needle biopsy is indicated. As a general thyroidism. rule, fine needle aspiration is not performed in patients with hypothyroidism but if there is a CLINICAL EXAMINATION goitre with a dominant nodule fine needle aspiration will be necessary to exclude malig- The classic features of hypothyroidism should http://pmj.bmj.com/ be assessed. A myotonic ankle jerk is the most nancy. discriminatory clinical feature. The thyroid In primary hypothyroidism cardiac evalua- gland should be palpated. The typical Hashi- tion is important especially in middle aged to moto gland is firm and lobulated. In secondary elderly patients and if angina has been noted or or tertiary hypothyroidism the sallow waxy there is evidence of pre-existing heart disease. appearance of pituitary hypothyroidism may be Usually this will be apparent in the history and apparent. an electrocardiogram will show classic low

voltage changes with bradycardia. Echocardio- on September 27, 2021 by guest. Protected copyright. graphic assessment may be necessary in more LABORATORY TESTS severe cases. A subnormal total or free thyroxine together with a raised TSH conﬁrms the hypothyroid TREATMENT state. The sensitivity of the modern assays has Laevo-thyroxine substitution therapy should made the thyrotrophin releasing hormone test be started once the diagnosis is secure. Laevo- redundant. Thyroid autoantibodies (antithy- thyroxine is preferred to triiodothyronine roid peroxidase antibody) should be deter- because of its longer half life and greater mined routinely by ELISA or radioimmu- chance of compliance with once a day treat- noassay. Investigation of pituitary or ment. hypothalamic hypothyroidism will be In the absence of severe cardiac manifesta- prompted by the initial ﬁnding of a low thyrox- tions 0.1 mg is a reasonable starting dose in an ine and low TSH. Appropriate pituitary adult. The patient should be reviewed in six to function tests and radiology must be arranged eight weeks and the dose increased to 0.15 and the same procedures followed for sus- mg/day. Underlying this straightforward ap- pected tertiary hypothyroidism. Care must be proach are two questions: how much reliance taken not to confuse apparently subnormal can be placed on the patient’s perceived hormone values with a low triiodothyronine or response to thyroxine and what level of thyroid euthyroid sick syndrome (see below). Serum hormones (assuming they are measured) is triiodothyronine concentrations are a poor reasonable while the patient is on therapy? indicator of the hypothyroid state and should It should be noted that there is considerable not be used. variation in patient response to thyroxine

www.postgradmedj.com 532 Lazarus, Obuobie Postgrad Med J: first published as 10.1136/pmj.76.899.529 on 1 September 2000. Downloaded from because of diVerential thyroid hormone recep- economy. There are significant changes in tor isoform tissue concentration. The patient’s iodine metabolism, thyroid hormone transport account of improvement or lack of it with thy- proteins, serum concentration of thyroid hor- roxine therapy should be assessed carefully; mones and, especially in iodine deficient areas, serum triiodothyronine concentration during thyroid gland size. thyroxine therapy must be in the normal range The placenta secretes human chorionic as should that of TSH. Serum thyroxine may gonadotrophin, a glycoprotein hormone which exceed the upper limit of normal on thyroxine shares an á subunit with TSH but has a unique therapy without ill eVect. Often, a high thyrox- â subunit, which confers specificity allowing it ine and normal triiodothyronine is accompa- to act as a TSH agonist. nied by a suppressed TSH (second or third Pregnancy has a profound eVect on the generation assay) but this is not necessarily an immune system in order to maintain the fetal/ indication to reduce the dose of thyroxine if the maternal allograft, which is not rejected despite patient has responded satisfactorily. Clinically, displaying paternal histocompatability anti- such a response implies a normal pulse rate and gens. The presence of thyroid antibodies is complete resolution of presenting symptoms associated with abortion, recurrent abortion, and signs. Occasionally cardiac symptoms such and infertility; fertility is impaired in hypothy- as palpitations will occur with a normal roid women with autoimmune thyroid disease. replacement thyroxine dose; in this case a â-adrenergic blocker drug is indicated. MANAGEMENT OF HYPERTHYROIDISM AND Subclinical hypothyroidism, defined as the HYPOTHYROIDISM DURING PREGNANCY presence of a low normal serum thyroxine The treatment of hyperthyroidism should pref- accompanied by a moderately raised TSH erably be with antithyroid drugs (table 4), (grade 1, 5–10; grade 2, 10.1–20; grade 3, >20) although thyroid surgery can be preformed should nearly always be treated. The patient is safely during the second trimester. Of the questioned carefully about any hypothyroid antithyroid drugs carbimazole may result rarely symptoms and if these are reported, treatment in aplasia cutis and there even have been is started. Even asymptomatic patients may suggestions of a carbimazole/methimazole spe- respond positively to therapy as shown in a cific embryopathy. For these reasons propylth- controlled trial. iouracil is preferred. This drug passes into Apparent lack of response to thyroxine is not breast milk but less so than carbimazole and uncommon and should raise the possibility of breast feeding may be allowed. (1) poor compliance with therapy, (2) presence Patients already receiving thyroxine for of anaemia, particularly pernicious anaemia, hypothyroidism should increase their dose by (3) persisting underlying psychiatric abnormal- at least 50 µg/day after confirmation of ity, (4) other autoimmune disease, for example, pregnancy. Thyroid function should then be Addison’s disease (this should have been tested and further adjustment made as neces- recognised at presentation), (5) other non- sary. thyroid related disease. Hypothyroid myopathy

can take up to a year to resolve completely. Postpartum thyroid disease http://pmj.bmj.com/ As indicated above, the monitoring of In1948HEWRoberton, a general prac- thyroxine treatment should ideally be a combi- titioner in New Zealand, described the occur- nation of patient interview and inspection of rence of lassitude and other symptoms of thyroid hormone concentrations. Where this is hypothyroidism relating to the postpartum not possible or convenient an automated period and treated them successfully with thy- system should be introduced whereby the roid extract. patient is routinely asked to provide a blood Postpartum thyroiditis (PPT) is character-

sample for thyroid hormone measurement. ised by the development of transient hyperthy- on September 27, 2021 by guest. Protected copyright. Computerisation of the recall system will roidism and/or hypothyroidism or both during ensure compliance when dealing with large the ﬁrst six months of the postpartum period. numbers of patients; this is an important aspect The transient hyperthyroidism presents at of the long term management as it is known about 14 weeks postpartum followed by that up to 15% of patients may default on their transient hypothyroidism at a median of 19 therapy. weeks. PPT is usually associated with the presence of antithyroid peroxidase antibodies Thyroid disease and pregnancy detected during pregnancy (in 10% of women It has been known for some time that at 16 weeks’ gestation) and again in the pregnancy has an appreciable eVect on thyroid postpartum period. Hypothyroidism is permanent in up to 25%–30% of women. Table 4 Management of Graves’ hyperthyroidism in pregnancy The disease occurs in 5%–9% of unselected Conﬁrm diagnosis postpartum women. Women with type 1 Start propylthiouracil diabetes have a threefold incidence of PPT Render patient euthyroid—continue with low dose antithyroid drugs up to and during labour compared with non-diabetics. There is an Monitor thyroid function regularly throughout gestation (4–6 weekly) Adjust antithyroid drugs if necessary increase of mild to moderate depression in Check TsAb at 36 weeks’ gestation antithyroid peroxidase positive women irre- Discuss treatment with patient spective of thyroid status compared with EVect on patient EVect on fetus controls. This may be seen as early as 6 weeks Breast feeding postpartum. It is possible that antibodies could Inform obstetrician and paediatrician modulate neurotransmitter function and it is Review postpartum—check for exacerbation known that there are cytokine receptors in the

www.postgradmedj.com Thyroid disorders 533 Postgrad Med J: first published as 10.1136/pmj.76.899.529 on 1 September 2000. Downloaded from brain. The possibility that thyroid antibodies somal dominant and the main clinical features are a marker for a specific genotype related to include goitre, tachycardia, learning disabilit- depression also requires investigation. ies, and deafness. Growth retardation and Follow up of antithyroid peroxidase positive delayed bone age are also seen. The diagnosis is women (at 16 weeks’ gestation) nine years later made by noting high thyroid hormone levels in has shown that the rate of development of the presence of detectable TSH levels after hypothyroidism was significantly greater (48% exclusion of other causes of these laboratory v 8%) in those who had had PPT compared findings. These include abnormal thyroid hor- with those who were euthyroid antibody mone binding proteins, replacement thyroxine positive. There is a 70% chance of developing therapy, neonatal period, systemic illness, and recurrent PPT after a first attack and 25% TSH secreting pituitary adenoma. Treatment chance where the patient is antithyroid peroxi- to lower the TSH level has employed trii- dase positive without thyroid dysfunction. odothyroacetic acid or the D isomer of thyrox- These data suggest that it would be beneficial ine. Symptomatic therapy with â-blockers, to implement a screening programme for antithyroid drugs, and radioiodine can be used. antithyroid peroxidase antibodies at the ante- natal booking clinic. In support of this it has Drug induced thyroid dysfunction also been shown that babies and children born Although several drugs may cause a wide array to women found to have thyroid antibodies of minor alterations in thyroid function, during pregnancy may have reduced psycho- clinically significant abnormalities are caused motor performance compared with control by only a few agents (see table 5). children but more data are required to confirm these findings. AMIODARONE This very eVective antiarrhythmic agent con- Iodine deficiency disorders (IDD) tains approximately 37% iodine by weight. The disorders induced by iodine deficiency are Thus a 200 mg tablet will deliver 6–12 mg of now recognised as part of a spectrum ranging iodine/day, some 40 times the normal recom- from mild psychomotor impairment to severe mended intake of the element. The drug has forms of both neurological and myxoedema- eVects on thyroid hormone synthesis as well as tous cretinism. IDD constitute a major nutri- thyroid hormone metabolism.There is preven- tional world problem in that 1.5 billion people tion of uptake and organification of iodine in 118 countries are at risk. Around 655 million (WolV-ChaikoV eVect) with subsequent re- (about 12% of world population) have goitre. sumption of normal thyroid hormone synthe- IDD are seen as the world’s greatest single sis. The peripheral conversion of thyroxine to cause of preventable brain damage and mental triiodothyronine is reduced due to inhibition of retardation as some 43 million are significantly the 5' monodeiodinase. This results in a fall in mentally handicapped (including 11.2 million serum triiodothyronine and elevation of serum with overt cretinism) due to IDD. Studies dur- thyroxine as well as reverse triiodothyronine. ing the past three decades have emphasised the The serum TSH is often raised in this critical importance of circulating maternal thy- situation. http://pmj.bmj.com/ roxine concentrations during the first trimester to ensure adequate fetal brain development Hyperthyroidism and subsequent maturation. Side eVects of Hyperthyroidism occurs in 2%–12% of pa- iodine supplementation have been reported, tients on chronic therapy. In general thyrotoxi- the most important one being the occurrence cosis occurs in areas of iodine deficiency while of iodine induced hyperthyroidism, especially hypothyroidism is seen more in iodine replete after the sudden and uncontrolled introduction locations. Patients with pre-existing thyroid of excessively iodised salt in severely iodine abnormalities develop iodide induced in- on September 27, 2021 by guest. Protected copyright. deficient populations. Nevertheless it is ac- creased thyroid hormone synthesis (similar to cepted that the benefits of iodine supplementa- jodbasedow) and hyperthyroidism due to tion by far outweigh the risks. Graves’ disease or toxic nodular goitre may occur. This is known as type I hyperthyroidism Thyroid hormone resistance syndrome and is to be distinguished from type II This syndrome, originally described in a family hyperthyroidism in which there is a destructive with deaf mutism, stippled epiphyses and thyroiditis consequent on excess iodide goitre, is characterised by a raised serum TSH in the presence of normal or even high thyroid Table 5 Drugs and thyroid function hormone concentrations. The resistance to the action of thyroid hormone is usually general- Free Free ised, when all tissues are resistant and the Drug thyroxine triiodothyronine TSH patient is euthyroid, or so-called “pituitary Amiodarone ↑/↓↓/→↑/→/↓ resistance” in which the peripheral tissues are Lithium ↓↑ normal thus resulting in an hyperthyroid state. Phenytoin ↓↓ → Phenobarbitone ↓↓/→→ The condition is almost always associated with Phenothiazine, NSAIDS ↓↓ → a mutation in the thyroid hormone â-receptor â-Blockers ↓↓ → Corticosteroids ↓/→↓/→↑ gene. Resistance to thyroid hormone is a rare Heparin ↑↑ ↓ disorder, there being about 450 cases de- Aspirin ↑↑ ↓ scribed, but it is important to recognise so that Radiographic contrast ↑↓ ↑ inappropriate treatment for apparent hyperthy- medium roidism is not given. The condition is an auto- NSAIDS = non-steroidal anti-inflammatory drugs.

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Table 6 Aetiology of congenital hypothyroidism ment of these infants with thyroxine thereby substantially, but not entirely, avoiding subse- Permanent quent neuropsychomotor problems. Interest- Thyroid dysgenesis Thyroid agenesis ingly it has been noted that congenital TSH hypothyroidism is often associated with other Defective synthesis (central hypothyroidism) Hyporesponsiveness congenital malformations raising the possibility Hyper-responsiveness of discrete genetic defects in the aetiology. The Stimulating G protein deficiency discovery of genes relating to development of Iodide transport defect Iodide organification defect the thyroid has resulted in the description of at Thyroglobulin synthesis defect least one specific mutation associated with thy- Iodotyrosine deiodinase deficiency roid agenesis (table 6). Further analysis of Other gene defects: Gene defect Mutation Phenotype cases of congenital hypothyroidism is awaited. Thyroglobulin Homozygous Mouse Various complex Goitrous hypothyroidism Thyroid cancer Thyroid peroxidase Homozygous Heterozygous The classification of thyroid cancer is shown in Iodide symporter Homozygous Goitre table 7. TSH receptor Homozygous Mouse The incidence of thyroid cancer is low in Heterozygous TSH resistance TTF2 Homozygous Athyroid most countries and varies between 1–4/ PAX8 Heterozygous 100 000/year. Although the overall incidence of Transient thyroid cancer does not vary, the ambient Maternal antithyroid drug ingestion iodine concentration influences significantly Excess maternal iodide ingestion (for example, amniofetography) TSH receptor blocking antibodies the distribution of diVerent histological types Extreme prematurity (papillary, follicular, anaplastic). In iodine suf- Transient hyperthyrotrophinaemia ficient areas the most common type is papillary whereas in iodine deficient areas the follicular Table 7 Classification of exposure. Clinical features may be masked by á type exceeds or is as common as papillary. In thyroid cancer and â blocking properties of the drug. iodine suYcient areas papillary accounts for Treatment of type 1 includes withdrawal of the about 65%–80% and follicular around 15%– Follicular cell tumours 30% with anaplastic rarely exceeding 5%. The Papillary carcinoma drug if possible, administration of antithyroid Follicular carcinoma drugs including potassium perchlorate if neces- ratio of papillary to follicular cancer ranges Anaplastic carcinoma from as high as 6.5 in high iodine locations to C cell tumours sary, and the use of prednisone. Type 2 disease Medullary cell carcinoma is managed with steroids similar to that used in as low as 0.19 in iodine deficient regions. Spe- Other other cases of thyroiditis. cial mention should be made of the now well Malignant lymphoma accepted highly significant increase in the inci- Sarcoma Secondary tumours Hypothyroidism dence of thyroid cancer resulting from the Hypothyroidism is usually associated with thy- Chernobyl nuclear power station accident in roid antibodies and is managed with standard 1986. The increase aVected those persons who thyroxine treatment. There is no necessity to were children in 1986 and the tumours, which withdraw amiodarone. are often aggressive in their behaviour, are thought to be related to the huge amounts of http://pmj.bmj.com/ 131 LITHIUM I released at the time of the disaster. This drug is used in the management of bipo- While radiation exposure may be an impor- lar aVective disorders. Thyroidal side eVects tant aetiological factor in thyroid cancer, major have been described during the last 30 years. advances have been made in the past decade or The clinical eVects of the thyroidal actions of so in the understanding of the molecular lithium are goitre and hypothyroidism, occur- mechanisms involved in the initiation and ring in about 15%–20% and 5% of patients progression of thyroid carcinoma. Genes

respectively. thought to be involved in papillary and follicular on September 27, 2021 by guest. Protected copyright. Clinically the goitre is smooth and non- carcinoma include the gsp, ret, trk, ras, met, and tender. It may develop within weeks of starting p53 oncogenes. Activation of the ret proto- lithium therapy but in other cases it may take oncogene located on chromosome 10 is critical months to years of lithium treatment before in the initiation of papillary and medullary can- goitre occurs. Hyperthyroidism caused by cer while the p53 and N-ras may be important lithium has been recorded but is uncommon. for progression of well diVerentiated thyroid Thyroid function should be obtained before carcinomas. starting lithium and thereafter at six monthly Treatment of diVerentiated thyroid cancer intervals. It may be helpful to measure thyroid usually involves surgical resection of the antibodies as well before therapy. If hypo- tumour followed in many cases by radio- thyroidism develops thyroxine in normal thera- therapy. The measurement of serum thy- peutic dose should be given. There is no indi- roglobulin is used routinely as a tumour marker cation for lithium withdrawal in this case. in the follow up of these patients. The thyroglobulin measurement may be subject to Congenital hypothyroidism interference by the presence of thyroglobulin Congenital hypothyroidism is the commonest antibodies thus giving misleading clinical metabolic abnormality in the Western hemi- information (for example, assumption of re- sphere occuring in approximately one in 4000 mission due to false low thyroglobulin levels). live births (see table 6). If serum thyroglobulin is raised thyroxine sup- The advent of neonatal screening by exam- pressive therapy is withdrawn to allow for a ination of heel prick blood spot TSH or, in radioiodine tumour localising scan to be some cases, thyroxine has allowed early treat- performed.The recent advent of recombinant

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Multiple choice questions in thyroid disorders 1.The incidence of congenital hypothyroidism in the Western hemisphere is: (A) 1:500 live births (B) 1:10 000 live births (C) 1:2000 live births (D) 1:1 000 000 live births (E) 1:4000 live births 2. Amiodarone: (A) Amiodarone tablets contain 37% iodine by weight (B) Amiodarone induced thyrotoxicosis is common in iodine replete areas (C) Amiodarone induced hypothyroidism is common in iodine replete areas (D) The destructive thyroiditis caused by amiodarone is usually treated with antithyroid drugs (E) In amiodarone induced hyperthyroidism, clinical features may be masked by the á and â-blocking properties of the drug 3. Thyroid disease and pregnancy: (A) Human chorionic gonadotrophin shows a similar â subunit with TSH (B) Fertility is impaired in women with autoimmune hypothyroidism (C) The drug of choice for treatment of hyperthyroidism in pregnancy is methimazole (D) Propylthiouracil causes aplasia cutis and embryopathy (E) In the management of Graves’ hyperthyroidism in pregnancy, thyroid stimulating antibody (TsAb) levels should be checked at 36 weeks’ gestation 4. Graves’ disease: (A) Is the commonest cause of hyperthyroidism in the UK (B) The presence of TsAb may predict relapse after treatment with antithyroid drugs (C) The remission rate of Graves’ hyperthyroidism is dependent on the dose of antithyroid drugs employed (D) Agranulocytosis complicating thionamide use invariably responds to administration of granulocyte colony stimulating factor (E) The optimum initial dose of carbimazole in Graves’ hyperthyroidism should not exceed 10 mg daily 5. Autoimmune thyroiditis: (A) Histology shows thyroid follicles inﬁltrated by eosinophils (B) 5% of women with positive thyroid antibodies develop hyperthyroidism per year (C) Is clinically more common in males than females (D) Is usually associated with the presence of antithyroid peroxidase and thyroglobulin antibodies (E) May coexist with Graves’ disease 6. Hypothyroidism and pregnancy: (A) Hypothyroid patients who become pregnant may be required to increase their dose of thyroxine by 50 µg daily (B) Postpartum thyroiditis may present as frank hyperthyroidism (C) Depression is not a feature of postpartum thyroiditis (D) Children of poorly controlled hypothyroid mothers may have inferior psychomotor performance (E) The hypothyroidism of postpartum thyroiditis may persist in 20%–30% of cases http://pmj.bmj.com/ 7. Thyroid cancer: (A) The incidence in most countries varies between 1–4/100 000/year (B) Papillary cancers are the commonest variety in iodine deﬁcient areas (C) Follicular cancers are the commonest variety in iodine suYcient areas (D) Radiation exposure may be an important aetiological factor (E) Measurement of serum thyroglobulin is used routinely as a tumour marker

8. Iodine deficiency disorders (IDD): on September 27, 2021 by guest. Protected copyright. (A) IDD are not now a major world nutritional problem (B) IDD are the greatest single cause of preventable brain damage and mental retardation (C) Over a 10th of the world’s population have a goitre (D) Adequate maternal thyroxine levels in the first trimester are required for fetal brain development (E) Iodine deficiency still exists in some parts of Europe

TSH will result in a much shorter period of Reading material hypothyroidism when thyroxine is withdrawn 1 Brent GA. The molecular basis of thyroid hormone action. and thus represents a signiﬁcant advance in N Engl J Med 1994;331:847–53. 2 Chopra IJ. Euthyroid sick syndrome: is it a misnomer? J Clin management. Endocrinol Metab 1997;82:329. While there have been encouraging advances 3 Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99–107. in understanding the aetiology and manage- 4 Delange FM. Endemic cretinism. In: Utiger RD, eds. We r n e r ment of diVerentiated thyroid cancer and some and Ingbar’s the thyroid. 7th Ed. Philadelphia: JB Lippincot, 1996: 756–67. progress in medullary cancer including multi- 5 Harjai KJ. Licata AA. EVects of amiodarone on thyroid ple endocrine neoplasia no similar reports are function. Ann Intern Med 1997;126:63–73. 6 Kendal-Taylor P. Thyrotoxicosis. In: Grossman A, ed. Clini- available for anaplastic cancer. This tumour, cal endocrinology. 2nd Ed. Oxford: Blackwell Science, 1997: although rare, is the most aggressive solid 328–58. 7 Lazarus JH. Hyperthyroidism. Seminar. Lancet 1997;349: tumour known. The spindle and giant cell 339–43. variants are resistant to treatment and trials of 8 Lazarus JH. The eVect of lithium on the thyroid gland. In: multimodal therapy are di cult because of Weetman AP, Grossman A, eds. Pharmacotherapeutics of the Y thyroid gland. Handbook of experimental pharmacology. Vol small numbers of cases. 128. Berlin: Springer-Verlag, 1997: 207–23.

www.postgradmedj.com 536 Lazarus, Obuobie Postgrad Med J: first published as 10.1136/pmj.76.899.529 on 1 September 2000. Downloaded from

9 Lazarus JH. Thyroid disease and pregnancy. In: Grossman 17 Vanderpump MP, Tunbridge WM, French JM, et al. The A, ed. Clinical endocrinology. 2nd Ed. Oxford: Blackwell Sci- incidence of thyroid disorders in the community: a twenty- ence, 1997: 376–82. year follow-up of the Whickham survey. Clin Endocrinol 10 Lazarus JH, Premawardhana LDKE, Parkes AB. Postpar- (Oxf) 1995;43:55–68. tum thyroiditis. In: Weetman AP, ed. Immunology and medi- 18 Weetman AP, McIntosh RS, Watson PF. Autoimmune cine. Endocrine autoimmunity and associated conditions. hypothyroidism. In: Weetman AP, ed. London: Kluwer Academic Publishers, 1998: 83–97. Immunology and medi- 11 Loree TR. Therapeutic implications of prognostic factors in cine. Endocrine autoimmunity and associated conditions. diVerentiated carcinoma of the thyroid gland. Semin Surg London: Kluwer Academic Publishers, 1998: 39–61. Oncol 1995;11:246–55. 12 McIver B, Rae P, Beckett G, et al. Lack of eVect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med 1996;334:220–4. 13 Beck-Peccoz P, Asteria C, Mannavola D. Resistance to thyroid hormone. In: Braverman LE, ed. Diseases of the Answers: true (T)/false(F) thyroid. New Jersey: Humania Press, 1997: 199–239 14 Paschke R, Ludgate M. The thyrotropin receptor in thyroid 1. (A) F, (B) F, (C) F, (D) F, (E) T; 2. (A) T, (B) F, (C) diseases. N Engl J Med 1997;337:1675–81. F, (D) F, (E) T; 3. (A) F, (B) T, (C) F, (D) F, (E) T; 4. 15 Surks MI, Ocampo E. Subclinical thyroid disease. Am J Med (A) T, (B) F, (C) F, (D) F, (E) F; 5. (A) F, (B) T, (C) F, 1996;100:217–23. 16 Utiger RD. Altered thyroid function in nonthyroidal illness (D) T, (E) T; 6. (A) T, (B) T, (C) F, (D) T, (E) T; 7. (A) and surgery–to treat or not to treat? N Engl J Med 1995;333: T, (B) F, (C) F, (D) T, (E) T; 8. (A) F, (B) T, (C) T, (D) 1562. T, (E) T. http://pmj.bmj.com/ on September 27, 2021 by guest. Protected copyright.