14 Endocrine system
Hormones are chemical messengers (peptides, amino acids, steroids, catecholamines) produced by endocrine glands that may act locally on adjacent cells (paracrine action), on target cells at a distance (endocrine action) or, on the secretory cell itself (autocrine action). Hormones act by binding to specific target cell receptor proteins on the cell membrane (insulin, adrenaline) or cytoplasmic/nuclear receptors within the cell (thyroxine, steroid hormones). As a result of receptor activation and signalling, cellular growth/metabolism is modified.
High levels of circulating cortisol are inhibitory to secretion of corticotrophin releasing hormone (CRH) secretion from the hypothalamus and adrenocortical trophic hormone (ACTH) by the anterior pituitary. Cortisol output from the adrenal gland falls, circulating cortisol levels are reduced.
Insulin production and release depends on blood glucose concentration. As blood glucose levels rise, so does insulin production: as blood glucose is cleared to normal levels the output of insulin falls.
The thyroid is a bilobed structure lying anteriorly in the base of the neck, the lobes joined by an isthmus of varying size that lies across the trachea usually just below the cricoid cartilage. A pyramidal lobe is evident in 80% of individuals: this is a remnant of the thyroglossal tract and may be seen as a midline upward extension from the isthmus of the thyroid gland extending for a variable distance over the thyroid cartilage. The lobes are variable in size, up to 5–6 cm in length, 2–3 cm in width and about 2 cm thick. The total weight of the normal adult gland will be about 20–40 g. The thyroid is attached to and wrapped around the front and sides of the larynx and trachea, bound to it by the investing layers of deep cervical fascia. During swallowing there is upward movement of the larynx. Any structure bound to the trachea at this level will also move up during swallowing, i.e. the thyroid gland or associated swelling. This is an important factor in clinical examination of a mass within the anterior triangle of the neck.
The gland develops as an endodermal down growth from the tongue before the end of the third week that migrates in front of the developing trachea to its permanent site in the base of the neck. The tube of cells, the thyroglossal tract, associated with thyroid migration atrophies and disappears by about six weeks. The ultimobranchial bodies developing from the fourth pharyngeal pouches become incorporated into the developing thyroid. These are the origin of calcitonin secreting C cells. By ten weeks thyroid follicles are present.
A thyroglossal duct is a remnant of the developing cord or tube of cells associated with thyroid descent. It lies in the midline from the foramen caecum of the tongue and passes via the hyoid bone to the pyramidal lobe of the thyroid, inferiorly a fibrous cord – sometimes known as the ‘levator glandulae thyroideae’ (Fig. 14.1). Epithelial remnants of the duct may proliferate and become filled with mucus i.e. thyroglossal cysts. Normally the cyst, lined by respiratory type or squamous epithelium lies above the thyroid cartilage – it may even lie at the level of or above the hyoid bone. Thyroglossal cysts elevate on protrusion of the tongue because of their association with the levator glandulae thyroideae and the hyoid bone.
Source: Rogers A W, Textbook of anatomy; Churchill Livingstone, Edinburgh (1992).
The thyroid may fail to migrate and remain embedded within the tongue – the lingual thyroid (1 in 3000 cases of thyroid disease). The patient is usually hypothyroid (70% of cases). Other sites of ectopic thyroidtissue are even rarer and may reflect well differentiated metastases from an undetected thyroid cancer.
Although T3 and T4 reach the foetal circulation from the mother, the foetus depends on its own thyroid gland for thyroid hormones. The thyroid gland is fully differentiated by approximately 11 weeks gestation, although it is probably not until about 18 weeks that thyroid hormone production commences. By 28 weeks free T4 values reach adult levels. Thyroid hormone is essential for normal differentiation and maturation of foetal tissues. A failure of thyroid gland development or hormone synthesis results in cretinism: this is gross mental retardation due to failure of brain development, and a failure of skeletal development leading to dwarfism. Maternal TSH receptor stimulating antibodies may cross the placenta; this can lead to transient neonatal hyperthyroidism. Maternal TSH receptor blocking antibodies may likewise result in foetal hypothyroidism
The normal thyroid gland has a very rich blood supply (5 ml per gram each minute). The blood flow through the thyroid may be markedly increased in thyrotoxicosis. There are four main thyroid arteries. The superior thyroid arteries, each arising from the external carotid artery, branch as they enter the upper poles of the gland and are intimately associated with a leash of veins. Together these vessels form the superior thyroidpedicles. The inferior thyroid arteries enter theposterior aspect of the mid-region of each thyroid lobe; they are branches of the thyrocervical trunk of the subclavian arteries. There are rich anastomoses between these vessels. A fifth small artery is sometimes present that enters the thyroid isthmus from below –the thyroidea ima artery arising from the brachiocephalic artery or the arch of the aorta (Fig. 14.2).
The venous drainage of the thyroid is of surgical importance. It is extensive and variable, but generally three groups are recognised. The superior thyroid veins tend to coalesce around the region of the superior thyroid artery and are ligated by the surgeon with the same tie used for the branches of the artery. Multiple inferior thyroid veins drain into the brachiocephalic veins. Veins draining the mid portion of the thyroid lobes drain either to the superior and inferior thyroid veins, or form a short venous trunk that drains directly into the internal jugular vein. This middlethyroid vein is not always present, and may sometimes be found only on one side of the neck. Careless handling of the vein during surgery can result in damage to the internal jugular vein and serious haemorrhage; the surgeon should identify and control the middle thyroidvein/s before the other thyroid blood vessels.
The recurrent laryngeal nerves (arising from the vagus) lie in the groove between trachea and oesophagus (Fig. 14.3) in close relationship to the inferior thyroid artery, parathyroid glands and the capsule of the thyroid gland. The position of each nerve may be anomalous due to ‘normal’ anatomical variation or thyroid gland pathology displacing the nerve. Their relationship to the inferior thyroid artery is variable –posterior or anterior to the artery, or between its branches. The nerve is also vulnerable to injury just before it enters the larynx below the inferior constrictormuscle: here it lies very close to the thyroid, often within a dense condensation of fascia binding the thyroid gland to the trachea – the ligament of Berry. The recurrent nerves must be regarded as vulnerable during thyroid surgery, at the very least an attempt should be made to identify the nerve and protect it at all thyroid procedures. The recurrent nerves supply the muscles of the larynx except cricothyroid, and sensation in the airway below the vocal folds. Injury to a nerve results in reduced mobility or paralysis of the vocal cord on that side as well as a sensory deficit in the larynx. Symptoms and signs that arise from unilateral nerve injury will depend upon the position of the affected vocal cord (midline or lateral) and the degree of compensation by the contralateral normal cord. The patient and the surgeon may sometimes be unaware of voice change. If the cord is paralysed in the lateral position and the gap between the cords is significant, there is hoarseness, rapid tiring, reduced voice power and a weak cough. Bilateral nerve damage affects the airway rather than the voice. If the cords lie in an adducted position there is dyspnoea and stridor. Urgent tracheostomy is required; this may be temporary or permanent depending upon the degree of recovery of nerve function.
Closely related to the superior thyroid vascular pedicle on each side of the neck is the external laryngeal branch of the superior laryngeal nerve. This may be identified on the surface of the cricothyroid muscle but in 20% of cases it lies within the muscle and in 20% intimately related to the superior thyroid artery or its branches. This nerve supplies the cricothyroid muscle which alters the tension of the vocal cord. Damage to the nerve may result in subtle changes that include voice fatigue or, a sudden decrease in the strength of the voice. The nerve should be protected as equally as the recurrent laryngeal nerve by ligation of the superior pole vessels on the capsule of the gland.
The parathyroid glands normally lie close to the inferior thyroid artery and derive their blood supply in 70% of cases from this vessel. In the remainder, parathyroid gland blood supply arises directly from the thyroid. It is of crucial importance at thyroid surgery to preserve parathyroid glands and their blood supply. To reduce risk to the recurrent laryngeal nerve/s and the parathyroid glands, branches of the inferior thyroid artery should be ligated and divided at the capsule of the gland. Approximately 30% of patients undergoing total thyroidectomy will become temporarily hypocalcaemic after surgery. Permanent hypocalcaemianecessitating lifelong treatment with calcium/vitamin D should not occur in more than 5% of patients after total thyroidectomy. Permanent recurrent laryngeal nerve injury should not occur after more than 1%of thyroid operations. All patients should be warned ofthe risks of nerve injury and hypocalcaemia as partof the process of informed consent.
Lymphatic drainage from the thyroid gland is to the trachea, to the pre-tracheal nodes inferior and superior to the thyroid isthmus, to the nodes between the trachea and oesophagus and to nodes that lie along and lateral to the internal jugular veins.
The gland is composed of follicles which are roughly spherical structures of thyroid epithelial cells surrounding colloid (principally thyroglobulin) within a lumen. In addition, parafollicular or C-cells secrete calcitonin.
Source: Symmers W S C & Lewis P D (ed), Systemic pathology 12: The endocrine system, Churchill Livingstone.
The thyroid gland incorporates iodide into its cells from plasma by an active transport mechanism in which I− follows Na+. This ‘pump’ is influenced positively by TSH (thyroid-stimulating hormone) and TSH receptor antibodies (in Graves’ disease). Iodine incorporation into the cell can be blocked or inhibited by an excess of iodide, perchlorate and thiocyanate ions and some drugs – for example, digoxin.
Within the follicular cell, iodide is quickly oxidised by thyroid peroxidase (TPO) and hydrogen peroxide and bound to tyrosine residues present in the glycoprotein thyroglobulin that is also produced within the cell. The iodinated proteins, monoiodotyrosine (MIT) and diiodotyrosine (DIT) are then transferred to the luminal colloid. MIT and DIT combine in a reaction catalysed by TPO, positively regulated by TSH to produce either triiodothyronine (T3) or thyroxine (T4) – all within the colloid. The iodination of thyroglobulin through to the production of T3 and T4 is under TSH control.
Under continued TSH control, colloid droplets are taken up by the thyroid cell via a process of endocytosis, lysosomes fuse with the droplets and proteolysis of thyroglobulin occurs. This releases MIT and DIT, T3 and T4. The MIT and DIT is deiodinated (by a microsomal enzyme) and the released iodide is re-utilised. T3 and T4 are secreted into the circulation. In the plasma the hormones conjugate with thyroxine-binding globulin (TBG) produced by the liver that binds 70% of T3 and T4, to thyroxine-binding prealbumin, and to albumin. The concentration and binding capacity of protein bound hormone in plasma varies in pregnancy, certain disease states and in the presence of certain drugs, e.g. aspirin, phenytoin, diazepam, phenylbutazone. Protein bound, T3 and T4 are inactive and thus are a ‘store’ of bound hormone allowing regulation of the levels of unbound active ‘free’ T3 and T4 available to the tissues.
Less than 1% of T3 and of T4 are in the ‘free’ state in serum; free T3 is the active hormone. Most T3 production (80%) is extrathyroidal from deiodination of T4. The half life of T3 is one day and of T4 is one week. Thus T4 appears to act as an immediately available source and regulator of T3 rather than as an hormone in its own right.
Thyroid-stimulating hormone (TSH), from the anterior pituitary, has a stimulating effect on T3/T4 production. Thyrotrophin-releasing hormone (TRH), which is stored in the hypothalamus, stimulates TSH production and release. TRH reaches the anterior pituitary via the pituitary portal venous system. Therefore, with increased TRH stimulation, TSH production is raised, with a consequent rise in T3/T4 output from the thyroid. Rising levels of T3/T4 (primarily a rising T3 concentration) have an inhibitory effect on the TRH/TSH axis. Thus there is an elegant mechanism in place for the precise control of the production and release of thyroid hormones (Fig. 14.6).
In reality the secretion of thyroid hormones is under a far greater range of control than this simple feedback arrangement. The gland itself can autoregulate according to the availability of iodine. Increasing concentrations of iodine transiently inhibit T3 formation. Thyroid autoantibodies may stimulate or inhibit thyroid function. TSH receptor antibodies may be stimulatory producing hyperthyroidism (Graves’ Disease) or have a blocking action producing hypothyroidism (atrophic thyroiditis). Anti-TPO (thyroid peroxidase) autoantibodies are found in 90% of patients with Graves’ Disease and lymphocytic thyroiditis.
T3 and T4 have major effects on the growth, development and function of most tissues. The main effects are seen on the cell membrane, on the mitochondria and on the cell nucleus. At the cell membrane level there is increased uptake of amino acids when T3 stimulation occurs. The effect on mitochondria is to increase energy production. T3 combines with T3 receptors within the nucleus, this causes increased or decreased mRNA expression with consequent effects on protein synthesis.
These are widespread and include energy and heat production, an overall catabolic effect – particularly on glucose and fat metabolism, cardiovascular and adrenergic effects, effects on production of other hormones, effects on bone, foetal development and growth. Knowledge of the actions of thyroid hormone is derived mainly from studies of the effects following in vivo administration of T3 and T4 and diseases associated with disordered thyroid function.
Heat production is brought about by the T3 effect on mitochondria: there is increased O2 uptake by the mitochondria with production of ATP in most tissues, although not in the brain. Thyroid hormone is responsible for the increase in basal metabolic rate (BMR) that occurs in hyperthyroidism, and consequently the heat intolerance described by patients.
Thyroid hormones stimulate glycogenolysis in the liver, an increase in insulin breakdown and a rise in glucose absorption from the gut. Hyperthyroidism is associated with insulin resistance and glucose intolerance, diabetes may be ‘unmasked’ or, its control in a patient with established diabetes may be more difficult.
Thyroid hormones also have a lipid lowering effect: cholesterol levels in blood are reduced in thyrotoxicosis and increased in myxoedema. The oxidation of free fatty acids contributes to the increase in heat associated with hyperthyroidism. Some of the effects on fat metabolism may be due to the potentiating effect of thyroid hormones on other hormones, including glucocorticoids, growth hormone, adrenaline and glucagon.
Thyroid hormones in excess interfere with sodium-potassium ATPase; they interact with the adrenergic system – the number of β adrenergic receptors in cardiac muscle increase and, they have an effect on the structure and function of cardiac myosin. Overall, thyroid hormones have a positive inotropic effect. In patients with thyrotoxicosis, the cardiac output and heart rate increase. β adrenergic receptor activity also increases in other tissues, including skeletal muscle. The management of the tachycardia and dysrhythmia associated with thyrotoxicosis logically includes a β adrenergic receptor blocker such as propranolol or metoprolol. In hypothyroidism cardiac output is reduced; pericardial effusions may occur.
T3 and T4 increase metabolic activity in bone, there is increased bone resorption and bone formation. The catabolic effect is predominant in thyrotoxicosis which results in a net reduction in bone density. Hypercalcaemia (rarely severe) and hypercalciuria can occur in thyrotoxicosis, PTH levels will be normal or low.
Excess circulating thyroid hormone is associated with a wide variety of behavioural, emotional and cognitive changes, movement disorders – tremor, restlessness, myopathy and, neuropathy and brisk reflexes. Thyroid hormone deficiency is associated with memory loss, tiredness and slow speech and slow or diminished reflexes.
The O2 carrying capacity of blood increases in thyrotoxic states due to an increase in 2, 3-DPG content of red blood cells, blood volume is increased, anaemia and thrombocytopaenia may occur. Hyperthyroidism is associated with an increase in sex hormone binding globulin levels in men and women; gynaecomastia and abnormal menstrual cycles respectively are commonly described. In both sexes a loss of libido is common in hypothyroidism and menorrhagia is frequently reported by premenopausal women. Skin changes in thyrotoxicosis include sweating and vasodilatation.
Thyroid function tests in routine use include TSH, free T4 and free T3. Measurement of TSH by a sensitive immunometric technique is the best single test to evaluate thyroid function. A low level of TSH and a high level of free T4 and/or free T3 will ordinarily indicate thyrotoxicosis. A high TSH combined with a low level of circulating thyroid hormone indicate a hypothyroid state.
There are normal variations in thyroid function during life. In pregnancy there is a rise in TBG with a consequent rise in total T3 and T4 levels: however, the free T3 and T4 levels are little changed. In very early pregnancy the free T3 and T4 levels may increase due to the effects of hCG. The thyroid gland often increases in size during pregnancy. Post-partum thyroid dysfunction is common (15%).
In children, free T4 levels reach the normal adult range by the end of the first year. Free T3 levels remain high in childhood and early adolescence. In sick patients with non thyroidal illness, a transient rise in TSH and low free T4 and free T3 is often seen. With recovery from the illness, thyroid function tests return to normal.
Thyroid autoantibody status should also be determined. In patients with Graves’ disease TPO antibodies are positive in approximately 80% of patients. Approximately 90% of patients with Hashimoto’s disease have positive TPO antibodies. It should be remembered that in itself positive antibody status does not constitute a diagnosis of thyroid disorder as at least a third of the normal population will have a positive antibody titre.
The ability of the thyroid to take up iodine is sometimes utilised in the investigation of patients with thyroid dysfunction. Radionuclide uptake with 123I (iodine) or 99mTc (technetium) is indicated when the cause of hyperthyroidism is not clear.
Thyroglobulin is measured in the serum of patients with differentiated (papillary or follicular) thyroid cancer who have undergone complete eradication of thyroid tissue by the combination of surgery and postoperative radioactive iodine therapy. A rise in thyroglobulin levels indicates persistent or recurrent disease.
Calcitonin is measured in patients with suspected or proven medullary thyroid cancer (MTC); it is a sensitive diagnostic test for MTC (a tumour that arises from thyroid C cells). Calcitonin levels are also measured in patients who have undergone surgery for MTC; a raised or increasing level of calcitonin indicatesresidual or recurrent disease.
The distinction of benign from malignant thyroid enlargement is aided by the examination of a representative sample of thyroid cells (cytology) obtained by fine needle aspiration (FNA). The same technique can distinguish solid from cystic thyroid enlargement. Ultrasound of the thyroid is very sensitive at detecting abnormal thyroid tissue but not specific, and rarely contributes to the diagnosis of thyroid swellings. It is a useful aid to targeted FNA and reduces the number of unsatisfactory needle aspirates. Thyroid CT and MRI can delineate the extent of thyroid enlargement in the neck and chest as well as the encroachment/invasion of adjacent structures in benign and malignant disease.
The reader is reminded that this text is not designed to give a comprehensive knowledge of thyroid disease. Some of the more important physiological – and pathophysiological – aspects of thyroid disease are outlined below.
Knowledge and understanding of the homeostatic control of thyroid function is essential for the interpretation of thyroid function tests. The patient who presents with symptoms and signs of hypothyroidism, a low free T4 and low TSH, has a problem at the pituitary (secondary hypothyroidism) or hypothalamic level (tertiary hypothyroidism). A problem with the thyroid gland causing a low free T4 is associated with a high TSH (primary hypothyroidism). It would be totally inappropriate to treat a secondary hypothyroid patient with thyroxine alone when the cause of the thyroxine deficiency was, for example, an infiltrating or expanding tumour of the pituitary causing a failure of TSH production. A patient who presents with signs and symptoms of thyrotoxicosis, a high free T4 and suppressed TSH levels, has a problem arising in the thyroid gland (primary hyperthyroidism).
This is defined as a hypometabolic disorder caused by a deficiency of or resistance to thyroid hormone. The many causes of hypothyroidism may be congenital or acquired. Primary hypothyroidism is the cause of 95% of adult cases; Hashimoto’s disease (chronic lymphocytic thyroiditis) is responsible for 70% of these. Myxoedema, the end result of severe long standing hypothyroidism, is associated with marked symptoms and signs, characteristic skin changes and in extreme cases, confusion and coma associated with a very high mortality. The patient has profound hypothermia, and may demonstrate hypoglycaemia, water retention, and hypoventilation. In generalised myxoedema there is accumulation of glycosaminoglycans within soft tissues, and facial and cutaneous oedema (containing mucopolysaccarides, hyaluronic acid and chondroitin sulphate). Patients with hypothyroidism sometimes present with a goitre to surgeons. The combination of abnormal thyroid function tests, positive TPO autoantibodies and sometimes aspiration cytologyis sufficient to confirm the diagnosis. Lifelong thyroxine is the treatment of choice and in most cases is associated with a reduction in size of the goitre as TSH levels fall. Thyroid lymphoma is more common in patients with lymphocytic thyroiditis. A nodule or continued enlargement of the thyroid in a patient with Hashimoto’s disease despite thyroxine treatment must be viewed with suspicion and aggressively investigated.
The surgeon should be aware of the many manifestations of hypothyroidism. Some patients will be asymptomatic despite significant degrees of biochemical dysfunction. The patient who presents with constipation without an obvious mechanical cause requires thyroid function tests. Other risk groups the surgeon should consider are individuals who have previously undergone thyroid surgery who may become hypothyroid as a delayed consequence of surgery or, as a result of failure to take thyroxine medication.
This is defined as thyroid over activity with a sustained increase in production of thyroid hormones. Thyrotoxicosis is the clinical syndrome that results from an increase in the serum concentration of thyroid hormones. The commonest cause of thyrotoxocosis is Graves’ disease (60%), an autoimmune condition in which TSH receptor antibodies are present which stimulate thyroid cell activity and growth. Other common causes of hyperthyroidism include toxic multinodular goitre and toxic adenoma. The clinical features of thyrotoxicosis include diffuse or nodular thyroid enlargement, and systemic manifestations of raised blood thyroid hormone levels. In Graves’ disease, eye signs (thyroid associated opthalmopathy: TAO) occur that may be clinically inapparent but are evident on screening in up to 90% of patients. Signs of TAO, unilateral in 10% of cases, include lid retraction, lid lag and proptosis. Less than 10% of patients will develop severe eye changes that include diplopia, opthalmoplegia and sight loss. The histological findings in the soft tissues within the orbit in TAO include oedema, lymphocyte infiltration, glycosaminoglycan deposition and inflammatory changes in the extra ocular muscles with fibrosis. The aetiology of TAO is unclear, predisposing factors include male sex and smoking, immunogenetic factors have little if any effect. Radioiodine leads to a worsening of eye disease in some patients. Patients with Graves’ disease may develop pretibial myxoedema (thyroid associated dermopathy) and thyroid acropachy.
The thionamides – carbimazole and propylthiouracil (PTU) are most commonly used. They block thyroid peroxidase activity (inhibition of iodine organification and iodotyrosyl coupling); in addition PTU inhibits deiodination. Thionamides also have an immunomodulatory effect on the disease process, probably as a result of a direct action on thyroid cells. They control thyroid hormone production as long as they are continued and are used as primary treatment in Graves’ disease. They can be given either to partially reduce thyroid hormone production to achieve a euthyroid state (titration regimen) or at a high dose to render the patient hypothyroid; thyroxine is then introduced (block and replace regimen). Patients remain on treatment for a variable period of time – at least six months, sometimes a year or more, medication is then discontinued. Approximately 40% of patients with Graves’ have a sustained remission after antithyroid drug treatment. A higher chance of relapse can be predicted in patients with large goitre, severe hyperthyroidism and a long duration of symptoms.
Beta blockers are prescribed to thyrotoxic patients to control symptoms whilst waiting for antithyroid drugs to work. Carbimazole and propylthiouracil, if given in high dose may block foetal thyroid function; PTU is the drug of choice in pregnant women with hyperthyroidism.
Patients with Graves’ disease who relapse after a course of antithyroid drugs or who cannot tolerate them because of side effects require some form of definitive treatment. Patients with toxic multinodular goitre or toxic adenoma become euthyroid with thionamides, but these drugs do not alter the natural history of the disease.
Iodide is removed from plasma largely by the kidneys and the thyroid. Salivary tissue and gastric mucosa to a much lesser degree also transport iodide. This property enables interstitial irradiation to be delivered by 131Iodine to thyroid cells from within. Its use in the treatment of thyrotoxicosis is more prevalent in the USA than in the UK. It is the treatment of choice when relapse occurs after surgery, in patients who have completed their families and in patients over 55. It must not be used in pregnancy – male and female patients are advised to avoid conception for six months after treatment. TAO and large goitres are relative contra indications to its use. Depending on the dose given, there will be restrictions on social contact between the patient, pregnant women and children. When an adequate dose (500–600 MBq) is given to treat thyrotoxicosis, around 65% of patients will be hypothyroid at a year. The rate of hypothyroidism increases with time.
This should be considered when radioiodine is contraindicated, when there is a possible associated thyroid cancer, the patient prefers to avoid radioidine, and in patients who have relapsed after radioiodine treatment. Knowledge of thyroid physi-ology is crucial in planning a safe operation; surgery on an uncontrolled thyrotoxic patient is unacceptable and avoidable.
The patient should be euthyroid following the use of antithyroid drugs. In non-compliant toxic patients who require surgery, treatment with anti-thyroid medication, beta blockers and iodine can be given under in-patient supervision. Iodine administration transiently inhibits T3 formation (the Wolff–Chaikoff effect) and deiodination, as well as reducing the thyroid vascularity that is increased in thyrotoxicosis.
For patients with Graves’ disease and those with toxic multinodular goitre, total thyroidectomy or near total thyroidectomy is the treatment of choice. Total lobectomy alone is required for patients with toxic adenoma (who can be as well treated with radioiodine).
Thyroid enlargement may be physiological (puberty, pregnancy) or pathological (due to iodine deficiency, goitrogens, genetic disorders of thyroid hormone synthesis or action or, benign neoplasia). Clinical examination categorises gland enlargement as diffuse or nodular. Nodular enlargement (which may be solid or cystic) is further categorised as solitary, multinodular or domin-ant (a larger nodule in a background of multiple nodules) nodular change. Investigations as described above are performed, surgery is indicated if the nodule/gland is large and/or causes compressive symptoms of the trachea or oesophagus, if enlargement is retrosternal, or there is suspicion of malignancy. Total lobectomy or total thyroidectomy is performed depending upon whether the abnormality is unilateral or bilateral.
Papillary cancer is the commonest tumour (70%), the peak incidence is around the third decade. The patient usually presents with a lump in the thyroid gland or, with an enlarged lymph node in the neck. It may be identified as an incidental finding after thyroid surgery for an unrelated condition. It is often multifocal within the thyroid; early spread to pre- and para-tracheal nodes can occur. It is, however, an indolent disease in most young adults if treated appropriately. It is more aggressive in children and the elderly.
Follicular cancer (20%) presents more commonly in the fourth and fifth decades. Thyroid cytology cannot distinguish benign follicular lesions (hyperplasia, adenoma) from malignant follicular lesions. The diagnosis of malignancy requires histological evidence of capsular and/or vascular invasion. Patients generally present with a lump in the thyroid.
The prognosis of the differentiated thyroid cancers is good – particularly for the papillary tumours. Adverse factors include increasing age at presentation, male sex, increasing lesion size, extrathyroidal invasion, incomplete tumour resection, distant metastases (lungs and bone).
Total thyroidectomy is the recommended initial treatment for most patients with differentiated thyroid cancer. Patients with small (less than 2 cm) low risk cancers are sometimes treated with thyroid lobectomy alone. The subsequent treatment of patients with differentiated thyroid cancer is consequent to three principles of thyroid physiology.
Firstly, differentiated thyroid cancer cells, in common with normal thyroid cells, usually take up iodine – particularly when TSH levels are markedly increased. After total thyroidectomy, the patient is given T3 as thyroid hormone replacement (it has a shorter half life than T4). This is stopped and two weeks later, TSH levels are checked. If the TSH is markedly elevated an ablation dose of 131I is given whilst the TSH drive is high. The ß-particles emitted by the radio-active iodine will destroy residual thyroid and thyroid cancer cells.
Secondly, TSH is a potent growth stimulus to benign and malignant thyroid cells. Suppression of TSH levels by the lifelong administration of higher doses of thyroxine than are given to patients with benign disease as replacement therapy reduces the risk of tumour recurrence.
Thirdly, patients who have undergone total thyroidectomy and post-operative radioiodine ablation should have very low or undetectable serum thyroglobulin levels. Recurrent disease is associated with a rise in thyroglobulin. In at risk patients, suppressive thyroxine is stopped temporarily until TSH rises. The measurement of serum thyroglobulin after thyroxine withdrawal is a sensitive way of detecting tumour recurrence. Alternatively, recombinant human TSH can be used to stimulate thyroglobulin. This avoids the need for thyroxine withdrawal and associated hypothyroid symptoms.
Poorly differentiated tumours and sub-types that include insular cancer, and diffuse sclerosing papillary cancer have a worse prognosis. Anaplastic cancer usually affects the elderly. Prognosis is very poor. Thyroid lymphoma usually arises in patient with pre-existing Hashimoto’s disease. When the diagnosis is made by FNA and core biopsy, treatment is non-surgical.
Medullary thyroid cancer (MTC) represents 5%–10% of thyroid cancers and arises from thyroid C cells (parafollicular cells). In 75% of cases it is sporadic and in 25% inherited as part of a genetic syndrome (MEN 2A, MEN 2B, FMTC). An apparently sporadic case of MTC may represent the index case of a previously unknown familial syndrome – see below under multiple endocrine neoplasia (MEN). All patients with MTC should undergo biochemical testing to exclude an unsuspected phaeochromocytoma prior to surgery and be appropriately counselled to undergo genetic testing. Onset of sporadic disease may occur at any age but is mainly in the fifth decade. The patient presents with a thyroid nodule, diffuse thyroid mass or lymph node enlargement. The tumour secretes calcitonin which appears to have no physiological effect, and other peptides which cause diarrhoea in advanced disease. Diagnosis is confirmed by FNA and elevated calcitonin levels in blood. Treatment is total thyroidectomy and lymph node dissection. Disease relapse and progression can be ascertained by serial calcitonin measurements. Since MTC is derived from C cells which are of neural crest origin and not from thyroid follicular cells, radioiodine therapy and TSH suppression have no role in this disease; there is currently no effective systemic treatment for MTC. The prognosis is highly variable; many patients live for years with metastases in liver, lung and bone.