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                                       The thyroid gland             ...
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        The thyroid gland

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       The thyroid gland

     through the tongue and usually dege...
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        The thyroid gland

     • Coupling.
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        The thyroid gland

     Fig. 3.9 Symptoms and sig...
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        The thyroid gland

     Fig. 3.10 Symptoms and signs of
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         The thyroid gland

         Causes of solitary thyroid ...
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The thyroid gland

  1. 1. Ch03-M3427.qxd 3/5/07 12:02 AM Page 31 The thyroid gland 3 Objectives By the end of this chapter you should be able to: • Describe the anatomical shape and location of the thyroid and parathyroid glands, and explain why the thyroid gland moves during swallowing. • Describe the blood supply to the thyroid gland, and describe the nerves that are related to these vessels. • Describe how the cells of the thyroid gland are arranged, and how this relates to hormone synthesis. • Envisage how the thyroid and parathyroid glands develop in the embryo. • List the hormones secreted by the thyroid gland, and describe their actions. • Describe thyroid hormone synthesis. • Explain the endocrine control of the thyroid gland. • State the main causes, symptoms and signs of thyrotoxicosis. • State the main causes, symptoms and signs of hypothyroidism. • Describe the treatment of hyperthyroidism and hypothyroidism. Hormones convey information that maintains • T4—a prohormone that acts as a plasma reservoir. homeostasis. Levels of thyroid hormone do not • T3—the active hormone. fluctuate greatly under normal physiological con- Disease of the thyroid gland is the second most com- ditions, and the hormone therefore acts more like mon endocrine disorder, after diabetes. Thyroid dis- a substrate that maintains cellular processes than a ease ranges from the production of too much or too hormone that regulates cellular processes. Nonetheless, little of the thyroid hormones, to the development of pathological fluctuations in thyroid hormone neoplasia. Excessive release of thyroid hormones in levels cause significant problems, which makes this the presence of normally functioning downstream system an important area of study. pathways is referred to as hyperthyroidism. These The thyroid, from the Greek ‘thyreoeides’, mean- patients tend to be hyperactive, heat sensitive and to ing shield shaped, is made up of two lobes and a lose weight. Insufficient thyroid hormone is called bridging ‘isthmus’. The gland consists of spherical hypothyroidism, and is associated with a slow metab- ‘follicles’, which are composed of an outer base- olism, making patients feel lethargic and gain weight. ment membrane, a peripheral layer of follicular cells and a core of proteinaceous colloid. The thy- roid hormones are synthesized and stored in these follicles and are dependent on an adequate iodine ANATOMY supply. The thyroid gland acts as a store of iodine and, in evolutionary terms, has allowed animals to Overview migrate away from the ocean, the primary source of The thyroid gland is palpable in about 50% of women iodine. Thyroid hormone levels are regulated by a and 25% of men. It is located in the neck, inferior to the multiplex negative feedback loop with control from larynx and cricoid cartilage. It has two lobes, each about the hypothalamic–pituitary axis and autoregulation 5 cm long and joined by a narrow isthmus. The lobes lie within the thyroid itself. The end product of this either side of the trachea and oesophagus, and the isth- process is the production of the two thyroid hor- mus crosses the trachea anteriorly, usually over the mones (Fig. 3.1): second and third tracheal cartilages (Fig. 3.2). 31
  2. 2. Ch03-M3427.qxd 3/5/07 12:02 AM Page 32 The thyroid gland external thyroid cold stress laryngeal cartilage nerve + – hypothalamus superior superior TRH thyroid thyroid artery vein + middle anterior isthmus thyroid pituitary of thyroid vein gland TSH + oestrogen – + + inferior inferior thyroid thyroid artery vein feedback recurrent trachea thyroid gland loop T4 T3 laryngeal nerve 80% 20% Fig. 3.2 Anterior view of the neck, showing the location and blood supply of the thyroid gland. T3 heat development production of CNS and skeleton The inferior thyroid artery is a branch of the thyro- cervical trunk that arises from the subclavian arteries. increased increased use It ascends behind the carotid sheath to enter the thy- rate of and availability roid posteriorly. The right recurrent laryngeal nerve is metabolism of metabolites intimately related to this artery near the inferior pole of the thyroid gland. Surgery to the thyroid gland can Fig. 3.1 Hormonal regulation of the thyroid hormones. (T3, tri- damage this nerve, causing temporary difficulty with iodothyronine; T4, thyroxine; TRH, thyrotrophin-releasing hormone; speaking. To minimize the risk to this nerve, the artery TSH, thyroid-stimulating hormone.) is ligated far away from the thyroid gland during thy- roidectomy. The superior thyroid artery is usually the first branch of the external carotid artery. The external The thyroid gland is surrounded by a fibrous cap- laryngeal nerve is related to this artery, but it is at less sule derived from the pretracheal layer of the deep cer- risk than the recurrent laryngeal during thyroid vical fascia (Fig. 3.3). Extensions of this capsule into surgery. The superior thyroid artery is ligated close to the body of the thyroid create septae, which divide the the thyroid gland to reduce this risk (Fig. 3.2). gland into lobules. This connective tissue firmly con- A third artery, called the thyroid ima artery, is present nects the thyroid to the larynx and explains why the in 10% of people. It supplies the isthmus and it arises thyroid moves on swallowing. near the aortic arch, although the exact origin varies. The thyroid gland is drained by three veins: Blood supply, nerves, and lymphatics • Superior thyroid vein. • Middle thyroid vein. The thyroid is highly vascular, and a bruit (the sound • Inferior thyroid vein. of turbulent blood flow) is sometimes heard in over- active glands. It is supplied by two arteries that anas- The first two veins drain into the internal jugular, tomose (join) within the gland: the inferior and whereas the inferior vein drains into the brachio- superior thyroid arteries. cephalic veins. 32
  3. 3. Ch03-M3427.qxd 3/5/07 12:02 AM Page 33 Development 3 Fig. 3.3 Horizontal section of the anterior isthmus neck at the level of the sixth cervical tracheal cartilage vertebra, showing the location of the skin anterior thyroid and parathyroid glands and their surrounding structures. trachea thyroid gland parathyroid gland muscles fibrous capsule posterior carotid sheath contains recurrent laryngeal oesophagus internal jugular vein nerve carotid artery vagus nerve Thyroid lymphatics drain into four groups of DEVELOPMENT nodes: • Prelaryngeal lymph nodes. The thyroid gland develops from an endodermal • Pretracheal lymph nodes. extension in the floor of the pharynx known as the • Paratracheal lymph nodes. thyroglossal duct. The thyroglossal duct descends • Deep cervical lymph nodes. MICROSTRUCTURE sympathetic and lumen containing large network of parasympathetic thyroglobin colloid fenestrated capillaries nerves supply gland supply the gland The thyroid is composed of about one million spher- ical follicles or acini. Each follicle is lined by a single layer of secretory epithelial cells (follicular cells) around a colloid-filled space. These cells secrete thy- microvilli roglobulin into the lumen of the follicle, and thyroid hormones are synthesized from thyroglobulin at the cell–colloid boundary. When the thyroid gland is not actively secreting hormones, the size of the colloid store and the follicle itself increase in diameter. When the follicular cells enter an active secretory phase, microvilli form on their inner surface and thy- roglobulin is absorbed. The colloid store shrinks as a lymphatics result. The absorbed thyroglobulin is broken down to cuboidal/columnar parafollicular cells thyroid follicle release thyroid hormone. The histology of the thyroid follicle cells surround (C cells) are outside gland is shown in Fig. 3.4. each follicle follicles but within basement membrane Another type of secretory cell is found between the surrounding follicle follicles. These parafollicular cells (C cells) synthesize and secrete calcitonin. Fig. 3.4 Histology of the thyroid gland. 33
  4. 4. Ch03-M3427.qxd 3/5/07 12:02 AM Page 34 The thyroid gland through the tongue and usually degenerates when the Thyroxine (T4) thyroid develops. The vestigial marking of the thy- I I roglossal duct is the foramen cecum of the tongue. NH2 Remnants of thyroglossal duct anywhere else in its track HO O CH2 CH can develop into a thyroglossal cyst. These present as neck lumps that rise when the tongue is protruded. In COOH 50% of people a remnant of this duct forms a small I I pyramidal lobe extending superiorly from the isthmus. The parafollicular (C) cells are derived from the neural Tri-iodothyronine (T3) crest. I I NH2 HO O CH2 CH HORMONES COOH I The thyroid gland synthesizes and secretes three hor- Fig. 3.5 Structures of T3 and T4. mones: • Thyroxine (T4). • Tri-iodothyronine (T3). against a steep concentration gradient by the Na/I • Calcitonin. symporter (NIS). This is a rate-limiting step. – Calcitonin is involved with calcium homeostasis (dis- Iodide oxidation I is rapidly oxidized into iodine (I2) cussed in Chapter 8). by thyroid peroxidase (TPO) anchored on the luminal surface of the follicular cell membrane. Synthesis The two components are then combined in the col- T4 and the less abundant but more potent T3 are syn- loidal lumen: thesized in a step-by-step process that takes place in Iodination of thyroglobulin Reactive iodine rapidly both the colloid and the follicular cells. Thyroid hor- attaches to the tyrosine molecules within the mones are lipophilic, and therefore must be bound extracellular thyroglobulin in a process that is up as residues of the thyroglobulin molecule during catalysed by TPO. Monoiodotyrosine (MIT or T1) synthesis in order to restrict their movements. and diiodotyrosine (DIT or T2) are formed. Thyroglobulin in the colloid acts as a precursor and Coupling Tyrosine molecules within thyroglobulin storage form of thyroid hormones. T3 and T4 are syn- are then coupled together. Combinations of T1 and thesized by three or four iodination reactions, respec- T2 can form thyroid hormones: tively, of tyrosyl residues in thyroglobulin. Their structures are shown in Fig. 3.5. • T3 is made from T1 + T2. Thyroid hormones are formed in the lumen of fol- • T4 is made from T2 + T2. licles, not in the cells. The process of T3 and T4 syn- Only a small proportion of coupling reactions form thesis involves the processing of tyrosine and iodine T3 and T4. followed by a reaction to bind them together. These The thyroid hormones can now be released on steps are also shown in Fig. 3.6. demand: Tyrosine processing is relatively simple, since tyro- Secretion Under the direction of thyroid- sine molecules are already within the cell: stimulating hormone (TSH or thyrotrophin), Thyroglobulin synthesis Tyrosine is converted into iodinated thyroglobulin is taken into the follicular the glycoprotein thyroglobulin, which contains cells by pinocytosis and degraded by lysosomal approximately 110 tyrosine residues. enzymes. Coupled tyrosine molecules are released, including some T3 and T4. Some T4 is converted to T3 The processing of iodine involves two stages as in the follicular cell cytoplasm by the enzyme type plasma iodine concentrations are very low: 1,5’deiodinase. Whilst the secreted ratio of T4:T3 is Iodine trapping Plasma iodide ions (I–) are actively usually 20:1 conversion to T3 is promoted by TSH transported from the plasma into the follicular cells stimulation and can result in the so-called T3 34
  5. 5. Ch03-M3427.qxd 3/5/07 12:02 AM Page 35 Running head Hormones 3 Fig. 3.6 Steps in the synthesis and secretion I− of T3 and T4. (T3, tri-iodothyronine; T4, iodine thyroxine.) ATPase trapping iodine − oxidation I peroxidase I2 secretion coupling T2 T3 T1 iodin T3 + T 4 T2 T1,T4 T4 T2 T2 T4 ation T thyroglobulin T1 + T 2 T1 T4 T2 T1 synthesis T3 T4 T I− T4 T T thyroglobulin T T colloid T T T tyrosine follicular cells thyrotoxicosis. MIT and DIT are also released, but they are deiodinated by iodotyrosine deholgenase to Thiacarbimide drugs, such as carbimazole, used in the recycle iodine. treatment of hyperthyroidism, inhibit thyroid peroxidase. This inhibition results in decreased oxidation of iodide, decreased iodination of iodides and ultimately reduced thyroid hormone production. The majority of plasma T3 is formed by the deiodination of T4, and not from the thyroid gland. This is important in the treatment of hypothyroidism, since only T4 is given Regulation Hypothalamic thyrotrophin-releasing hormone (TRH) stimulates the release of thyroid-stimulating hormone (TSH) from thyrotrophs in the anterior pituitary gland and also causes upregulation of TSH gene transcrip- Iodine metabolism tion. TSH acts on extracellular receptors (TSH-R) on Iodine is acquired from the diet mainly from iodized the surface of thyroid follicle cells, activating the G- salt, meat and vegetables. About 150 mg of iodine is protein–adenyl-cyclase–cAMP and phophatidylinosi- needed per day, though only a fraction of this is tol (PIP2) pathways. Ultimately, TSH stimulates the absorbed. The thyroid gland cells are the only cells that following processes in the thyroid gland: can actively absorb and utilize plasma iodine; a con- siderable quantity of iodine is stored in the thyroid as • Iodine uptake. preformed thyroid hormones. Iodine is returned to the • Transcription of thyroglobulin and thyroid plasma by the breakdown of these thyroid hormones. peroxidase. Iodine is excreted mainly via the kidneys. • Iodination. 35
  6. 6. Ch03-M3427.qxd 3/5/07 12:02 AM Page 36 The thyroid gland • Coupling. Fig. 3.7 Comparison of T3 and T4 • Type 1 5’deiodinase conversion of T4 to T3. • Pinocytosis and secretion of thyroid hormones. T3 T4 As a result, T3 and T4 are synthesized and secreted Proportion of secreted thyroid hormone 10% 90% more rapidly (see Fig. 3.1). TSH also has long-term Percentage free in plasma 1% 0.1% actions on the thyroid gland by increasing its size and Relative activity 10 1 vascularity to improve hormone synthesis. Half-life (days) 1 7 A number of factors affect thyroid hormone release. Three main factors stimulate secretion: • Long-term exposure to cold temperatures acting on the anterior pituitary. • Oestrogens acting on the anterior pituitary. • Type 1—mostly in liver and kidney but also in other tissues. It supplies plasma with T3 and is • Adrenaline acting directly on the thyroid gland. inhibited by the propylthiouracil that is used to TSH forms part of a negative feedback loop, as its release treat hyperthyroidism. is inhibited by increased serum T3 and T4 and also by • Type 2—intracellular enzymes that maintain somatostatin, glucocorticoids and chronic illness. constant T3 in the central nervous system (CNS) and pituitary gland in the face of rising plasma T4. Transport of thyroid hormones A further deiodinase enzyme can remove a different The thyroid hormones circulate bound to plasma pro- iodine molecule from T4 to form reverse T3 (rT3). This teins produced in the liver, which protect the hor- is an inactive molecule that is rapidly cleared from the mones from enzymic attack: circulation by the kidney and liver. Production of rT3 • 70% are bound to thyroid-binding globulin is favoured by low energy stores and illness when (TBG). energy stores need to be conserved. • 30% are bound to albumin. Free plasma T3 enters cells and binds to intracellu- lar T3 receptors, which are capable of binding specific Only 0.1% of T4 and 1% of T3 are carried unbound— sequences (or thyroid response elements) of DNA. it is this free (unbound) fraction that is responsible Accordingly, after a lag of several hours, the expression for their hormonal activities. of various thyroid response genes is up- or downreg- Both T3 and T4 can cross cell membranes, though a ulated. The intracellular actions are described in carrier transport may be involved. Fig. 3.8 and related to physiological effects. The concentration of circulating T4 is much higher In general, T3 promotes energy production in every than that of T3 (50:1). There are two reasons for this: cell in the body. This causes heat production and • The thyroid secretes more T4 than T3. maintains metabolism. • T4 has a longer half-life (7 days vs 1 day). Actions Fig. 3.7 describes some of the differences between T4 The thyroid gland is the only endocrine and T3. T4 is a relatively inactive, stable molecule that gland to store its hormone in an can be thought of as a prohormone. T3 is the active extracellular compartment. 2–3 months’ hormone, since it is readily available and it has more supply of thyroid hormone are stored within the effect on receptors. The benefit of producing both follicles, and this delays the onset of symptoms in hormones is that T4 can maintain a background level deficiency diseases. of activity, whilst T3 levels can adapt rapidly to chang- ing environments. Peripheral tissues can regulate local T3 levels by increasing or decreasing T3 synthesis. T4 is converted Feedback to T3 by deiodination, i.e. removal of one iodine atom T3 receptors are also found in the pituitary gland and catalysed by deiodinase enzymes. Two main forms of the hypothalamus, where they inhibit transcription this enzyme have been found: of the gene for TRH prohormone and the release of 36
  7. 7. Ch03-M3427.qxd 3/5/07 12:02 AM Page 37 Disorders of the thyroid gland 3 Fig. 3.8 Intracellular and physiological actions of T3 Site of action Intracellular effects Physiological results Cell membrane Stimulates the Na+/K+ATPase Increased demand for pump metabolites, e.g. glucose Mitochondria Stimulates growth, replication Increased heat production, and activity; basal metabolic oxygen demand, heart rate rate is raised and stroke volume Nucleus Increases expression of Lipolysis, glycolysis and enzymes necessary for energy gluconeogenesis increased to production raise blood metabolite levels and cellular metabolite use Neonatal cells Essential for cell division and Essential for normal maturation development of CNS and skeleton TSH, respectively. Excess T3 inhibits TSH release while (thyrotoxicosis factitia) or ectopic hormone produc- a deficiency of T3 stimulates TSH release. This feed- tion (ovarian struma or metastatic thyroid cancer) It back mechanism helps to maintain T3 levels, and is a common disorder affecting 1/50 females and therefore stabilizes metabolic rate. 1/250 males. The symptoms and signs of thyrotoxi- cosis are illustrated in Fig. 3.9. Presentation is usually slow with a history lasting DISORDERS OF THE THYROID over 6 months. An acute exacerbation of symptoms is called a thy- GLAND rotoxic crisis; it is usually brought on by infection in pre- viously undiagnosed patients. Surgery or radioactive The thyroid gland is prone to a number of diseases that ablation of the thyroid gland can also be responsible as can alter its function and structure. These diseases fre- the damaged thyroid follicles release their contents. quently have wide-ranging systemic effects because thy- The main causes of hyperthyroidism are: roid hormones regulate the metabolism of almost every cell in the body. The main categories of disease are: • Diffuse toxic goitre: Graves’ disease—an autoimmune disease involving autoantibody • Hyperthyroidism—excess of thyroid hormone stimulation of TSH receptors. production. • Toxic multinodular goitre—nodular enlargement • Hypothyroidism—deficiency of thyroid of the thyroid in the elderly. hormone production. • Toxic nodule—autonomously functioning • Goitre formation. thyroid nodule; most are adenomas (benign • Adenoma (benign growths) of the thyroid. thyroid hormone producing tumours). • Carcinoma of the thyroid. • Lymphocytic thyroiditis—inflammation causes release of stored hormones (followed by Hyperthyroidism hypothyroid phase). Hyperthyroidism is defined as an overactive thyroid • Subacute thyroiditis—thyroiditis associated with gland, leading to excess thyroid hormones (T4 and a painful goitre. T3). When this becomes symptomatic it is called thy- rotoxicosis. Thyrotoxicosis can occur in the absence Diagnosis of true hyperthyroidism. This phenomenon is seen Thyroid function tests are the main component of during inflammation of the thyroid (thyroiditis), diagnosis. Serum TSH, free T3, and free T4 are mea- which stimulates the release of stored hormone or can sured by radioimmunoassay (RIA). Raised T3 and T4 be the result of excess exogenous thyroid hormone indicate that hyperthyroidism is present. Raised TSH 37
  8. 8. Ch03-M3427.qxd 3/5/07 12:02 AM Page 38 The thyroid gland Fig. 3.9 Symptoms and signs of thyrotoxicosis (hyperthyroidism). The brain hair features in italic are only found in Graves’ - emotional lability - loss disease. - fatigue eyes - anxiety - exophthalmos (protruding eyes) - restlessness - lid retraction - lid lag neck - predisposes to keratitis - goitre heart muscles - palpitations - proximal myopathy - tachycardia (rapid pulse) (in upper arms and legs) - atrial fibrillation bowel - diarrhoea - increased appetite uterus hands - menorrhagia - tremor - infertility - warmth - reduced libido - sweating reflexes - increased bones - osteoporosis skin and adipose tissue - increased sweating - heat intolerance - weight loss - pretibial myxoedema suggests the fault lies in or above the pituitary gland, the patient becomes euthyroid. The alternative is whereas low TSH points to a thyroid organ lesion. the ‘block and replace’, which involves full-dose Other tests include: carbimazole and thyroxine replacement. • Radioactive iodine therapy—131I is only taken up • Autoantibody detection, e.g. Graves’ disease. by thyroid tissue; it kills the cells leading to • Radioisotope scanning to show the size of the reduced T3 and T4 synthesis. The response is slow thyroid gland and any abnormal ‘hot’ areas such and carbimazole may be required. The benefits as a toxic adenoma. include a reduced chance of relapse and taking • ECG for sinus tachycardia or atrial fibrillation. away the need to take carbimazole, which carries Treatment risk of agranulocytosis, in the long term. • Partial thyroidectomy—the thyroid gland is There are three methods of treatment: surgically removed leaving some tissue and the • Carbimazole—this drug inhibits the peroxidase parathyroid glands. Used in patients with reactions of T3 and T4 synthesis. It takes 3–4 weeks relapsing disease or allergy to medical treatment. to have an effect. Two principal regimes exist for Carries risk of recurrent laryngeal nerve palsy and antithyroid therapy. The titration regime involves hypocalcaemia due to the removal of parathyroid giving increasing doses of anti-thyroid drug until glands. 38
  9. 9. Ch03-M3427.qxd 3/5/07 12:02 AM Page 39 Disorders of the thyroid gland 3 Both radioactive iodine and partial thyroidectomy Thyroid hormone resistance carry a high risk of long-term hypothyroidism. The syndrome remaining thyroid tissue may be insufficient to meet the body’s needs, especially as the patient ages. Their This is a rare condition that occurs due to a mutation treatment is described under hypothyroidism. in one of the thyroid receptor genes. In most cases the raised levels of T3 and T4 compensate for the resis- Graves’ disease tance, but ‘generalized resistance’ can present with congenital hypothyroidism. Graves’ disease, the most common form of thyrotox- icosis, is an autoimmune disease in which autoanti- Hypothyroidism bodies against the TSH receptors stimulate the receptors so that thyroid hormones are produced in Hypothyroidism is defined as an underactive thyroid excess. Graves’ disease is the most common cause of gland leading to deficient thyroid hormones (T4 and hyperthyroidism; it is especially common in middle- T3). When this becomes symptomatic, it is called aged women (B:D, 8:1) and it has a genetic com- myxoedema. It is slightly less common than hyper- ponent with some human leucocyte antigen (HLA) thyroidism, affecting 1/100 females and 1/500 males. association. The symptoms and signs of myxoedema are illustrat- The disease follows either a relapsing-remitting ed in Fig. 3.10. Presentation is even more gradual than course or one with fluctuating severity. Rarely in hyperthyroidism, with many symptoms frequent- Graves’ disease can progress to hypothyroidism with ly being ignored. time. Thyroid hormones are essential between birth and Graves’ disease can cause the classical picture of puberty for the normal development of the CNS. hyperthyroidism with bulging eyes (exophthalmos), Deficiency can cause irreversible mental retardation goitre (with bruit) and swollen legs (pretibial called cretinism. TSH levels are checked in all new- myxedema). It is diagnosed by detection of autoan- borns for this relatively common abnormality; the tibodies along with low TSH and raised T3. The thy- levels will be raised if the thyroid gland is not func- roid autoantibodies, thyroglobulin antibody (Tg Ab) tioning correctly. and thyroid peroxidase (TPO) antibody, are present in both Graves’ disease and Hashimoto’s thyroiditis. Diagnosis However, stimulating thyroid-stimulating hormone Hypothyroidism is not investigated as thoroughly as receptor (TSH-R) antibodies are specific to Graves’ hyperthyroidism, since treatment does not vary. Free disease. The treatment is consistent with other caus- T3 and T4 levels are low, whereas TSH levels are usual- es of hyperthyroidism, but radioactive iodine and ly raised. If TSH is low then a lesion of the hypothal- surgery are especially likely to cause hypothy- amus or pituitary is likely. Autoantibodies can be roidism. detected in Hashimoto’s thyroiditis. Eye disease is an important symptom of Graves’ dis- ease as it can lead to compromised vision due to optic Treatment nerve compression and corneal ulcers. Inflammation All hypothyroidism is treated with thyroxine (T4) of the orbit causes the eye to protrude, which can lead administered as an oral tablet in varying doses. The to discomfort and double vision. This symptom may dose is increased over several months, with regular occur before thyroid hormone levels rise. monitoring of TSH levels until they are within the normal boundaries. This process is slow, since it takes 4 weeks for TSH levels to reflect an increased dose due to the long half-life of thyroxine. Thyroxine therapy is usually maintained for life. The major symptoms of hyperthyroidism can be remembered as: ‘Don’t Evade Overtreatment of hyperthyroidism Feeling Hot And Sweaty Patients’ i.e. Radioactive ablation and surgical removal of the thy- Diarrhoea, Emotional lability, Fatigued, Heat roid gland initially cure hyperthyroidism, but with intolerance, increased Appetite, Sweating, and time, the remaining thyroid tissue is often insufficient. Palpitations. Hypothyroidism can develop and life-long thyroxine treatment is required. 39
  10. 10. Ch03-M3427.qxd 3/5/07 12:02 AM Page 40 The thyroid gland Fig. 3.10 Symptoms and signs of myxoedema (hypothyroidism). The main hair brain features are shown in bold. - coarse and thin hair - mental slowing - loss of outer third of eyebrows - apathy - tiredness face - psychosis - myxoedemic features, i.e. hoarse voice pale puffy face, coarse features neck - deafness - goitre heart - bradycardia muscles (slow pulse) - slowing of activity - muscle weakness in upper arms and legs (proximal myopathy) bowel - constipation uterus - amenorrhoea hands - cold hands - carpal tunnel syndrome reflexes - slow relaxing skin and adipose tissue - weight gain/obesity - intolerance to cold - decreased sweating - chronic oedema (caused by increased capillary escape of albumin) - cold, dry skin Many drugs can also cause reversible hypothy- The initial destruction of the thyroid gland can roidism including lithium amiodarone and excess release the thyroglobulin colloid causing temporary iodine. hyperthyroidism. The patients usually progress to a euthyroid (normal) state and finally develop pro- Hashimoto’s thyroiditis gressive hypothyroidism. When the thyroid gland is inflamed, the disease is called thyroiditis. This can be caused by autoimmune Subacute (de Quervain’s) thyroiditis or viral processes. Hashimoto’s thyroiditis is a destruc- De Quervain’s thyroiditis is inflammation of the thy- tive autoimmune disease that is especially common roid gland caused by a virus. It is common in young in middle-aged women. It is mediated by autoanti- or middle-aged women, in whom it causes a tender bodies against rough endoplasmic reticulum (micro- swollen gland along with a febrile illness. The inflam- somal antibodies) or thyroglobulin. The presence of mation causes an initial increase in thyroid hormone these antibodies can be tested to confirm the diagno- release followed by destroying the follicles, which sis. The thyroid gland is infiltrated by lymphocytes causes hypothyroidism and leakage of the thyroglob- that cause the gland to enlarge, forming a goitre. ulin colloid. An immune reaction against this colloid 40
  11. 11. Ch03-M3427.qxd 3/5/07 12:02 AM Page 41 Thyroid gland neoplasia 3 causes the formation of granulomas, so this disease is becomes very vascular, to the extent that a bruit can be also called granulomatous thyroiditis. heard using a stethoscope. Primary atrophic hypothyroidism Spontaneous or primary atrophic hypothyroidism is Graves’ ophthalmopathy is caused by lymphocytic a disease resulting in hypothyroidism in the elderly. infiltration of the periorbital tissues and activation of The biochemical profile may include the presence of fibroblasts to secrete osmotically active hyaluronic TSH-R blocking autoantibodies, but in this condition acid. This increases the pressure and pushes the eye the thyroid fibroses and shrinks so that there is no forward, resulting in proptosis. This pressure change goitre. It is suspected that this disease is the end-stage also causes muscle fibrosis and diplopia due to of many thyroid diseases, including Hashimoto’s and weakening of the extraocular muscles. The eye de Quervain’s thyroiditis. disease may precede the onset of thyroid dysfunction, and does not respond to correction of thyroid status. Dyshormonogenesis Treatment involves radiotherapy and surgery. This is an inherited defect in the synthesis of thyroid hormones, and can present with hypothyroidism and goitre. Puberty and pregnancy Iodine deficiency Higher levels of thyroid hormones are required in Iodine deficiency was once a common cause of goitre puberty and pregnancy so the thyroid gland often in regions where the soil lacked iodine (e.g. Derby, enlarges to meet the increased demand. This enlarge- England), but nowadays iodine is added to salt to ment is a physiological response, not a pathological prevent this. Deficient iodine means that thyroid hor- process. The goitre regresses once the demand lessens. mones cannot be synthesized with a resultant rise in TSH levels. TSH causes thyroid enlargement by stim- Multinodular goitre ulating follicle growth and the development of new Many elderly people have an enlarged thyroid that con- blood vessels, so the thyroid gland enlarges. tains many nodules of varying sizes. These nodules are formed from hyperplasia (increased number) of thy- Goitres roid cells. The excess cells sometimes cause excess A goitre is a swelling in the neck caused by an thyroid hormone production, i.e. hyperthyroidism. The enlarged thyroid gland. It is a common finding, and disease is then called toxic multinodular goitre. it is usually asymptomatic; however, large goitres can compress the oesophagus and trachea. If a goitre is Thyroiditis associated with hyperthyroidism it is described as Inflammation of the thyroid gland can cause swelling, ‘toxic’. Non-toxic goitres secrete normal or reduced and infiltration by lymphocytes can also cause enlarge- levels of thyroid hormones. Non-toxic goitres are usu- ment. The goitre formed is usually slightly nodular, but ally the result of excessive TSH stimulation in the it may be tender if the inflammation is acute. presence of hypothyroidism. Goitres are treated by correcting the underlying pathology or by surgical removal for cosmetic reasons or to prevent compres- sion of surrounding structures. Thyroid gland neoplasia Thyroid lumps are common and usually benign; Iodine deficiency however, they must be investigated. Solitary thyroid The goitre formed by this process is diffusely enlarged lumps are found in 5% of women and it is very diffi- and smooth. It is sometimes called an endemic goitre cult to distinguish between benign (80%) and malig- because it occurred in certain regions. nant (20%) on clinical grounds. A fine-needle aspiration should be performed along with thyroid Graves’ disease function tests. Aspiration alone will not distinguish a The constant stimulation of TSH receptors in Graves’ follicular adenoma from a follicular carcinoma but disease causes a goitre in a similar manner to iodine low TSH suggests the former as malignant nodules are deficiency with similar characteristics. The gland not usually hyperfunctioning. 41
  12. 12. Ch03-M3427.qxd 3/5/07 12:02 AM Page 42 The thyroid gland Causes of solitary thyroid lumps include: an abnormal ‘fusion protein’ (PAX-8/PPARγ), which is the result of two gene fragments coming together by • Thyroid cysts. translocation and producing a single gene product. • Nodule of multinodular goitre. Medullary thyroid cancer often occurs as part of the • Follicular adenoma. multiple endocrine neoplasia syndrome and as such • Malignancy. is often associated with RET mutations. The more Five separate forms of cancer can arise in the thyroid aggressive form, anaplastic thyroid cancer, is often gland, but three of these are derived from the follicle associated with a p53 mutation. This new knowledge cells. These tumours are summarized in Fig. 3.11. of the events driving thyroid neoplastic transforma- Medullary carcinomas of the parafollicular cells tion has opened up novel avenues for therapy. often secrete ectopic hormones, including: • Calcitonin—usually asymptomatic. • Adrenocorticotrophic hormone (ACTH)— Cushing’s syndrome. • 5-hydroxytryptamine (5-HT; serotonin)— Occasionally thyroid disorders can present as carcinoid syndrome. emergencies. A thyrotoxic crisis (thyroid storm) is an acute episode of hyperthyroidism with pyrexia, and The molecular biology of thyroid can cause life-threatening arrhythmias. Thyroid storms cancer can be precipitated by radioactive iodine treatment, A great deal has been learnt about the molecular biol- thyroid surgery or by severe illness. Treatment is ogy of thyroid cancer. 50% of papillary thyroid cancers aimed at preventing cardiovascular complications, and have a translocation that causes constitutive activation the mainstays are antithyroid therapy and beta- of the RET proto-oncogene. RET is a transmembrane blockers. Undertreated hypothyroidism can progress receptor with tyrosine kinase activity, which when to a life-threatening myxoedema coma. This rare active can drive oncogenesis (the development of neo- condition is characterized by bradycardia and plasia). In follicular thyroid cancer (FTC), 40% of hypotension. Plasma levels of glucose and sodium can cases have an activating point mutation of the RAS also drop, and type II respiratory failure may develop. proto-oncogene. 60% of FTCs were shown to produce Fig. 3.11 Characteristics of the five primary thyroid gland malignancies Type Cell type Age group Route of metastasis Prognosis Papillary Follicle cells All Cervical lymphatics Excellent Follicular Follicle cells Middle-aged Blood to bone, Good lung and brain Medullary Parafollicular Middle-aged Cervical lymphatics Variable but cells and elderly usually good Malignant Lymphatics Elderly Local invasion Poor lymphoma Anaplastic Follicle cells Elderly Local invasion Very poor 42