(BQ) Part 2 book Clinical Biochemistry presents the following contents: Thyroid disease, diabetes mellitus and hypoglycaemia, adrenal disease, reproductive endocrinology, biochemical nutrition, gastrointestinal disorders and malabsorption, specific protein markers,... and other contents.
12 Thyroid disease Garry McDowell Learning objectives After studying this chapter you should be able to: ■ Describe the structure and function of the thyroid gland ■ Explain the function of thyroid hormones ■ Outline the action of thyroid hormones and control of their secretion from the thyroid gland ■ Describe the conditions which lead to abnormal thyroid hormone production ■ Discuss the investigation of suspected thyroid dysfunction Introduction The thyroid gland secretes thyroid hormones that are required for normal metabolism of body cells Disorders of thyroid function can result in either inadequate or excess production of thyroid hormones causing altered cellular metabolism and development of associated clinical features This chapter will describe the nature and role of thyroid hormones, their regulation in the blood and the consequences of changes in their secretion The value of laboratory investigations in diagnosis and monitoring of treatment will be discussed 12.1 Structure of the thyroid gland The thyroid gland is found below the larynx and is a butterfly shaped gland composed of a right and left lobe on either side of the trachea Both lobes are joined by an isthmus in front of the trachea The normal thyroid gland weighs approximately 30 g and is highly vascularized, receiving 80–120 mL of blood per minute, as shown in Figure 12.1 12.1 STRUCTURE OF THE THYROID GL AND 321 Hyoid bone Common carotid artery Thyroid cartilage of larynx Internal jugular vein Right lateral lobe of thyroid gland Isthmus of thyroid gland Left lateral lobe of thyroid gland Trachea Clavicle Sternum FIGURE 12.1 Anatomical location of the thyroid gland in the neck Microscopic examination of thyroid tissues shows small spherical sacs called thyroid follicles that make up most of the thyroid gland The wall of each follicle is composed mainly of follicular cells, most of which extend to the lumen of the follicle Figure 12.2 shows the structure of thyroid follicles Follicular cell FIGURE 12.2 Follicle containing thyroglobulin Histological structure of the thyroid gland showing the follicles in which thyroid hormones are made Courtesy of Dr A L Bell, University of New England College of Osteopathic Medicine, USA 322 12 THYROID DISEASE A basement membrane surrounds each follicle Follicular cells produce two hormones: thyroxine (T4), which contains four iodine atoms and tri-iodothyronine (T3), which contains three iodine atoms Together T4 and T3 are known as thyroid hormones The parafollicular cells or C-cells lie in between the follicles and produce a hormone called calcitonin, which regulates calcium homeostasis SELF-CHECK 12.1 What are the two cell types in the thyroid gland and what hormones they secrete? 12.2 Thyroid hormones The thyroid hormones T4 and T3 are produced by the incorporation of iodine into tyrosyl residues in thyroglobulin in a series of steps which are described as: • • • • • • • • iodide trapping synthesis of thyroglobulin oxidation of iodide iodination of tyrosine coupling pinocytosis of colloid secretion of thyroid hormones transport of thyroid hormones in the blood We will now consider each step in a little more detail Figure 12.3 shows the steps involved in the synthesis of thyroid hormones Follicular cells in the thyroid gland trap iodide ions by active transport from the blood into the cytosol The synthesis of thyroglobulin also occurs in the follicular cells Thyroglobulin is a large glycoprotein that is produced in the rough endoplasmic reticulum, modified by the attachment of a carbohydrate molecule in the Golgi apparatus and packaged into secretory vesicles The vesicles then release thyroglobulin in a process known as exocytosis into the follicle Thyroglobulin contains a large number of tyrosine residues that will ultimately become iodinated In the diet, iodine is present in the form of iodide and this must be oxidized to iodine which can be used for iodination of tyrosine residues of thyroglobulin As iodide becomes oxidized to iodine it passes across the cell membrane into the lumen of the follicle As iodine molecules form they are incorporated into tyrosine residues of thyroglobulin The binding of one atom of iodine to the tyrosine residues results in the formation of monoiodothyronine (T1), whilst the binding of two iodine atoms results in the formation of di-iodothyronine (T2) During the coupling step, two molecules of T2 join to form thyroxine (T4), while a coupling of T1 and T2 results in tri-iodothyronine (T3) Iodinated thyroglobulin incorporating T4 and T3 is stored in the colloid Oxidation of iodide, iodination of tyrosine residues, and coupling reactions are all catalysed by the enzyme thyroid peroxidase Then, under the control of thyroid stimulating hormone (TSH) which is produced by the anterior pituitary, droplets of colloid re-enter the follicular cells by a process known as pinocytosis and merge with lysosomes The enzymes present in lysosomes catalyse the proteolytic digestion of thyroglobulin releasing T4 and T3, whose structures are shown in Figure 12.4 12.2 THYROID HORMONES Colloid Tyrosine I2 I2 T3 I2 I2 I2 I I2 T4 I– Iodide I2 Iodine I2 TBG I2 T2 T4 T3 I2 Thyroxine-binding globulin I2 T3 T3 T1 I2 I2 Thyroglobulin I2 Oxidation of iodide T3 Follicular cells I– T4 Secretory vesicles I– T4 Golgi complex I– I– Rough endoplasmin reticulum Active transport of iodide I– I– I– I– Lysosome T3 I– Synthesis of thyroglobulin Breakdown of thyroglobulin T3 T4 T3 T3 TBG T4 I– Blood FIGURE 12.3 Synthesis of thyroid hormones T4 and T3 Since T4 and T3 are lipid-soluble, they diffuse across the plasma membrane and enter the circulation Due to their lipophilic nature, more than 99% of T4 and T3 are bound to the transport protein thyroxine binding globulin (TBG) Thyroxine is released from the thyroid gland in greater amounts than T3, although T3 is the more biologically active hormone Thyroxine enters cells and is deiodinated (removal of one I atom) to form T3 T4 TBG 323 324 12 THYROID DISEASE I HO I O CH2CH COOH NH2 I I Thyroxine (T4) I HO I O CH2CH COOH NH2 I FIGURE 12.4 Chemical structures of T4 and T3 Tri-iodothyronine (T3) The majority of thyroid hormones in plasma are bound to specific proteins in order to render them water-soluble, reduce renal loss, and to provide a large pool of hormones, whilst protecting the cells from the physiological effect of the hormone The plasma binding proteins are TBG and to a lesser extent albumin and pre-albumin The plasma concentrations and proportions of thyroid hormones which are bound are shown below: TBG Pre-albumin Albumin Concentration T4 (%) T3 (%) 20 mg/L 0.3 g/L 40 g/L 70–75 15–20 10–15 75–80 Trace 10–15 The unbound or free T4 and T3 are considered to be the biologically active fraction that can enter cells, bind to specific receptors, and initiate the physiological response and cause the negative feedback regulation of thyroid hormone secretion The approximate reference ranges for serum concentrations of total and free thyroid hormones are: T4 T3 Total Free 60–160 nmol/L 1.2–2.3 nmol/L 10–25 pmol/L 4.0–6.5 pmol/L Thyroxine is the major hormone secreted by the thyroid gland, which is converted by specific de-iodinase enzymes, particularly in the liver and kidney, to form T3, the biologically active hormone The peripheral deiodination of T4 provides approximately 80% of plasma T3, the remainder being derived from thyroid gland secretion SELF-CHECK 12.2 What are the steps involved in the synthesis of thyroid hormones? 12.4 CONTROL OF THYROID HORMONE SECRETION 325 TABLE 12.1 Effects of thyroid hormones on metabolic indices Increased by a rise in [thyroid hormone] Increased by a decline in [thyroid hormone] Basal metabolic rate Plasma cholesterol Plasma calcium Creatine kinase Sex hormone binding globulin Creatinine Angiotensin converting enzyme Thyroxine binding globulin Liver enzymes (gamma-glutamyl transferase) Function of thyroid hormones 12.3 Table 12.1 shows the effect of thyroid hormones on metabolism They increase intracellular transcription and translation, bringing about changes in cell size, number, and differentiation They also promote cellular differentiation and growth SELF-CHECK 12.3 What are the effects of thyroid hormones on metabolism? Control of thyroid hormone secretion 12.4 Hypothalamus – – TRH + Thyroid hormone production is under both positive and negative feedback control as shown in Figure 12.5 Thyrotrophin releasing hormone (TRH) from the hypothalamus acts on the anterior pituitary causing release of TSH, which in turn acts on the thyroid gland and stimulates the synthesis and release of thyroid hormones Briefly, a low blood concentration of free T4 or T3 stimulates the hypothalamus to secrete TRH, which enters the hypothalamic portal veins and flows to the anterior pituitary where it stimulates thyrotrophs to secrete TSH The TSH then acts on the follicular cells to stimulate T4 and T3 production and their subsequent release A rise in the concentration of unbound T4 and T3 in the blood inhibits further release of TRH and TSH from the hypothalamus and anterior pituitary respectively, via a negative feedback effect – Anterior pituitary TSH + Thyroid gland T4 T3 SELF-CHECK 12.4 What is the name given to the control mechanism where thyroxine controls its own release? FIGURE 12.5 Regulation of thyroid hormone secretion – 326 12 THYROID DISEASE 12.5 Disorders of thyroid function From a clinical perspective disorders of thyroid function can be classified into two broad categories: hyperfunction states where thyroid hormones are produced in excess, referred to as hyperthyroidism, and hypofunction states where there is a deficiency of thyroid hormones, referred to as hypothyroidism 12.6 Hyperthyroidism Hyperthyroidism has a significant short- and long-term morbidity and mortality The prevalence of hyperthyroidism in women is ten times more common than in men The annual incidence of hyperthyroidism is quoted as 0.8/1,000 women Causes of hyperthyroidism The most common causes of hyperthyroidism are Graves’ disease and toxic multi-nodular goitre Less commonly, hyperthyroidism may occur in patients on thyroxine therapy or due to excess thyroid hormones being produced by ectopic thyroid tissue Very rarely, hyperthyroidism may be a consequence of TSH secreting tumours Graves’ disease is an autoimmune condition characterized by the presence of diffuse thyroid enlargement, eye abnormalities and thyroid dysfunction The disease predominantly affects females, with a peak incidence in the third and fourth decades of life Hyperthyroidism can often arise in patients with a multi-nodular goitre and occurs in an older population than affected by Graves’ disease The age of onset is typically over 50 years, with females being affected more than males Drugs such as amiodarone can have a significant effect on thyroid function Amiodarone is used in the treatment of cardiac arrhythmias, has a structure similar to that of thyroid hormones, and interferes with the peripheral conversion of T4 to T3 Consequently the concentrations of T4 may be increased while T3 is low In practice, it is advisable to check thyroid function by assay of TSH and free T4 before commencing amiodarone treatment Interpretation of thyroid function test results can be problematic during treatment and assessment of thyroid status during this time is best undertaken by careful clinical assessment Clinical features of hyperthyroidism The clinical condition is often referred to as thyrotoxicosis and affected individuals present with characteristic features The common symptoms and signs of hyperthyroidism are shown in Table 12.2 On clinical examination of patients with Graves’ disease, a large and diffuse goitre is usually present which is soft to the touch A bruit is frequently heard over the thyroid and its blood vessels due to increased blood flow through the hyperactive gland Patients with Graves’ disease have characteristic eye signs, with a staring expression due to lid retraction, the white of the eye or the sclera being visible above and below the iris In addition there is a tendency for 12.6 HYPERTHYROIDISM TABLE 12.2 Symptoms and signs of hyperthyroidism Symptoms Signs Increased irritability Tachycardia Increased sweating Goitre Heat intolerance Warm extremities Palpitations Tremor Lethargy Arrhythmias Loss of weight Eye signs Breathlessness Proximal myopathy Increased bowel frequency Muscle weakness the movement of the lid to lag behind that of the globe as the patient looks downwards from a position of maximum upward gaze, referred to as ‘lid-lag’ In patients with a toxic multi-nodular goitre, the cardiovascular features tend to predominate in this often older population The goitre is classically nodular and may be large Investigation and diagnosis of hyperthyroidism Measurement of TSH will in most cases of hyperthyroidism show suppression of TSH to a concentration below the lower limit of the reference range and in many cases to less than the limit of detection for the assay The exception to this is a TSH secreting pituitary tumour in which case the concentration of TSH may be normal or at the top of the laboratory reference range Thyroid stimulating hormone secreting pituitary tumours, however, are extremely rare The concentration of free T4 is increased, often in association with a significant increase in free T3 concentration In some cases free T3 alone may be increased, with a normal T4 and low or undetectable levels of TSH, and this is referred to as T3-toxicosis The diagnosis of Graves’ disease is made by the finding of hyperthyroidism on biochemical testing, the presence of goitre, and extra-thyroidal signs such as eye signs In other cases the presence of a thyroid stimulating antibody (TSH receptor antibody) and diffuse increased iodine uptake on thyroid scanning confirms the diagnosis The biochemical diagnosis of hyperthyroidism due to a toxic multi-nodular goitre is fairly straightforward with suppression of TSH concentration Free T4 and T3 concentrations are increased although they may not be grossly abnormal, with values at or just above the reference range Thyroid scintillation scanning shows patchy uptake of isotope with multiple hot and cold areas being seen throughout the gland A TSH secreting pituitary adenoma is a rare cause of hyperthyroidism In these cases TSH is usually within the reference range, or inappropriately normal, or only slightly raised above it, often around mU/L, with an increased free T4 and T3 In such cases imaging will often identify a pituitary lesion SELF-CHECK 12.5 What are the common clinical features of hyperthyroidism? 327 328 12 THYROID DISEASE Management of hyperthyroidism The treatment of hyperthyroidism including Graves’ disease falls into three broad categories These are anti-thyroid drugs, radioactive iodine, or subtotal thyroidectomy Some of the symptoms such as tachycardia and tremor can be controlled with β-blocking drugs for the first few weeks of therapy Radioactive iodine (131I) can be used to treat hyperthyroidism and works by initially interfering with organification of iodine and then induces radiation damage to the thyroid The major side effect of radioiodine treatment is that approximately 80% of subjects will develop hypothyroidism as a result There is no evidence of an increase in the risk of malignancy following radioiodine therapy Subtotal thyroidectomy is highly effective although surgical complications can occur in some patients In elderly patients with a multi-nodular goitre, radioiodine is the treatment of choice, although anti-thyroid drugs can be used until radioiodine treatment becomes effective Surgery may be required in patients who present with symptoms of hyperthyroidism and an enlarged thyroid gland compressing structures in the neck SELF-CHECK 12.6 What are the three broad categories of treatment for a patient with hyperthyroidism? CASE STUDY 12.1 A 30-year-old housewife presented with weight loss, irritability, and had been feeling uncomfortable whilst on holiday in Spain She was taking oral contraceptive pills and was not pregnant On examination, her palms were sweaty, she had a fine tremor, and there was no enlargement of the thyroid gland The following results were obtained for thyroid function tests (reference ranges are given in brackets): TSH