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Thyroid Disorders—An Update

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Thyroid Disorders—An Update Postgrad Med J 2000;76:529–536 529 Postgrad Med J: first published as 10.1136/pmj.76.899.529 on 1 September 2000. Downloaded from 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. www.postgradmedj.com 530 Lazarus, Obuobie Postgrad Med J: first published as 10.1136/pmj.76.899.529 on 1 September 2000. Downloaded from 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
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