The thyroid gland is situated in the anterior triangle of the neck, weighs approximately 20 g and consists of two lateral lobes (right and left), joined together by a midline isthmus. The small pyramidal lobe of Lalouette, of variable size, commonly joins the isthmus at its junction with the left lateral lobe by a fibrous band or strand of muscle fibres known as the levator glandulae thyroideae. The lobes measure approximately 5 × 3 × 1.5 cm (slightly larger in women) and extend from the middle of the thyroid cartilage above to the sixth tracheal ring below. Each lobe fills the space between the trachea and oesophagus medially and the carotid sheath laterally. A strong condensation of vascular connective tissue, known as the suspensory ligament of Berry, binds the gland firmly to each side of the cricoid cartilage and it is this ligament, together with the pretracheal fascia which splits to invest the gland, which makes the thyroid move up and down on swallowing. The fascia (false or surgical capsule) sends fibrous septa into the gland substance, dividing it into numerous lobules. Each lobule consists of 30 to 40 follicles that contain colloid; these are the main secretory and storage elements.

The thyroid gland develops from two distinct embryological structures: the primitive pharynx and the neural crest. A median pharyngeal downgrowth migrates between the first and the second arch components of the tongue and descends in a caudal direction along a line extending from the foramen caecum at the back of the tongue to the pyramidal lobe of the thyroid. In doing so, the track passes ventral to the hyoid bone and then loops behind it (Fig. 1) 739. The track usually becomes obliterated but part occasionally persists, giving rise to a thyroglossal cyst or fistula. Rarely the thyroid bud fails to descend but develops in situ at the back of the tongue (lingual thyroid). Conversely, it may descend too far, causing a primary mediastinal or retrosternal goitre. Even less commonly the thyroid bud may fail to divide in two and appear as one lateral lobe, the left usually being absent. The parafollicular or C cells scattered between the cuboidal epithelial cells that line the thyroid follicles, are derived from the neural crest. They first migrate to the ultimobranchial bodies of the fourth and fifth branchial pouches and then to the thyroid (Fig. 2) 740. These are the cells which in later life have the potential to undergo hyperplastic and malignant change, resulting in calcitonin-producing medullary carcinoma of the thyroid.

The vascular supply of the gland is impressive and becomes more so in hyperactive thyroid states. The main supply is via two paired arteries; a third vessel occasionally supplies the lower pole of one or other lobe. The superior thyroid artery, the first branch of the external carotid, runs downward on the inferior constrictor to reach the apex of the lateral lobe, where it divides into a large anterior branch and a usually smaller, but important, posterior branch. Occasionally a tributary leaves high on the left to supply the pyramidal lobe near the midline. The inferior thyroid artery is generally much larger than the superior thyroid artery but is less constant, being absent or duplicated on one side or the other in 10 per cent of individuals. It arises from the thyrocervical trunk and passes upwards for a variable distance before looping down, running medially behind the carotid sheath to reach the posterolateral aspect of the gland at the junction of the middle and lower thirds. Numerous unnamed accessory arteries arise from the oesophagus and trachea, but the most frequently encountered is the thyroidea ima (Neubauer's artery), which courses up anteriorly on the trachea to reach the isthmus or one of the lower poles and originates from the aorta or brachiocephalic artery. In the absence of the inferior thyroid artery on one side, the thyroidea ima may be the principal source of blood supply to the lobe and therefore substantial. The named thyroid veins, although three in number like the arteries, are subject to greater variation. The superior thyroid vein, formed by a confluence of vessels from the upper pole, crosses the common carotid artery high in the neck to drain into the internal jugular. The middle thyroid vein, which overlies the inferior thyroid artery, also ends in the internal jugular vein after crossing the common carotid artery. The inferior thyroid veins descend from the isthmus and inferior poles of the lateral lobes to join the internal jugular or brachiocephalic veins in the anterior mediastinum and are intimately associated with the thyrothymic ligaments, which expand inferiorly as the lobes of the thymus.

The thyroid is generously supplied with lymphatics and a rich network ramifies throughout the gland. They drain primarily into mediastinal nodes inferiorly, tracheo-oesophageal nodes laterally, and the midline delphian nodes superiorly. Studies performed following injection of dye suggest that the majority of lymph from the thyroid returns to the thoracic duct without passing through the deep cervical lymph node chain or the nodes of the posterior triangle, although these pathways may open up secondarily (Fig. 4) 742. This has implications for the assessment of patients with carcinoma of the thyroid, who may develop lymph node deposits outside the primary drainage areas, even on the contralateral side.

There are several structures closely related to the gland with which a surgeon must be familiar. The most important of these is the recurrent laryngeal nerve on each side, which is a branch of the vagus. The latter, having entered the mediastinum, gives off the recurrent nerve, which returns to the neck having circled around the arch of the aorta on the left and the right subclavian artery on the right. It ascends in the tracheo-oesophageal groove and has a variable relationship with the inferior thyroid artery on each side (Fig. 6) 744. Occasionally the nerve itself divides early and branches around the artery (10 per cent of individuals). In approximately 0.25 per cent of individuals the recurrent laryngeal nerve on the right is non-recurrent but passes directly from the vagus to the cricothyroid muscles. As it takes the same course as the inferior thyroid artery, it is particularly vulnerable if its presence is unrecognized when this vessel is routinely ligated laterally. Whichever course the nerve takes, it ultimately enters the larynx posterior to the cricothyroid articulation passing under or through Berry's ligament. The nerve supplies all the intrinsic muscles of the larynx together with some sensory supply to the mucosa below the vocal cords. The principal effect of division of this nerve is paralysis of the vocal cord on that side.

This also arises from the vagus (inferior ganglion) and divides at the level of the hyoid bone into a large internal laryngeal nerve and a smaller external laryngeal nerve. The latter runs close to the superior thyroid artery but at a deeper plane, immediately above the superior pole of the thyroid. It terminates as the nerve supply to the cricothyroid muscle which acts as a tensor of the vocal cords on the same side.

This underlies the carotid sheath just medial to the vagus on the prevertebral fascia and is in close proximity to the inferior thyroid artery as it arches around medially.

There are normally four parathyroid glands, the upper pair of which lie in close proximity to the dorsal aspect of the thyroid. They are usually found just above and medial to where the recurrent laryngeal nerve crosses the inferior thyroid artery, frequently tucked round behind its branches (Fig. 7) 745. The lower parathyroid gland on each side is situated within a 2-cm radius of the lower pole of the thyroid typically on its surface anterolaterally and at a level below and medial to where the recurrent laryngeal nerve crosses the inferior thyroid artery (Fig. 8) 746.

The thyroid, the largest endocrine gland in the body, produces three hormones, thyroxine (T&sub4;), tri-iodothyronine (T&sub3;) and calcitonin. T&sub4; and T&sub3; are both stored in the colloid, consisting primarily of thyroglobulin which is an iodinated glycoprotein. Thyroglobulin stores are dependent on adequate dietary iodine intake, which is essential for T&sub3; and T&sub4; synthesis. Iodine is derived mainly from milk and dairy products with a smaller proportion from salt water fish and iodized salt. An average diet in the United Kingdom gives an intake of 100 to 150 &mgr;g of iodide daily—this is higher in North America, where iodine is added to a wider range of foodstuffs. Plasma levels therefore vary widely, depending on geographical locality. Iodides are absorbed in the stomach and upper gastrointestinal tract; approximately two-thirds is excreted via the kidneys, and one-third is trapped in the thyroid, where 95 per cent of the body stores of iodine are found. Hormone synthesis takes place only after the iodide has been oxidized to an active form by a peroxidase enzyme system, which is in turn generated by one of the cytochrome reductase systems. The activated iodine is bound covalently to tyrosine or monoiodotyrosine. The peroxidase system is also responsible for the coupling of iodotyrosines to produce iodothyronines. Antithyroid drugs, notably carbimazole, are rapidly converted to methimazole, which specifically prevents iodine becoming trapped by inhibiting the peroxidase system within the thyroid.

The release of thyroid hormones from the colloid begins when microvilli on the surface of the thyroid cell engulf droplets of colloid by pinocytosis; these then fuse with lysosomes containing proteolytic enzymes, which hydrolyse the colloid. The iodotyrosines are rapidly converted to iodide and thyroxine, which enters the blood stream via the thyroid capillaries (Fig. 9) 747. A small quantity of unhydrolysed thyroglobulin returns to the circulation via the thyroid lymphatic system. The iodide released from the thyroid contributes to a much larger circulating iodide pool than the quite separate dietary iodide pool which delivers the element to the gland. Turnover is also slower.

Thyroid stimulating hormone (TSH) produced by the thyrotrophic cells of the anterior pituitary control the complex enzymatic reactions that trap iodine, convert it to T&sub3; and T&sub4; and release them into the circulation. When T&sub3; and T&sub4; levels rise above the normal range TSH production is shut down by a negative biofeedback loop (Fig. 10) 748. Release of TSH is regulated by thyrotrophin releasing hormone (TRH), which is produced in the hypothalamus. TRH enters the capillary bed of the stalk median eminence passing via the portal veins and sinusoids to bathe the anterior pituitary cells. TSH biosynthesis shows a circadian rhythm, its secretion being maximal in the evening before the onset of sleep, remaining high overnight and falling to a low around midday. The pineal gland may be responsible for this rhythm.

The role of calcitonin in normal thyroid physiology has not been established in man, but it may be involved in the regulation of plasma calcium and phosphate concentration. However thyroidectomy which removes nearly all the parafollicular C cells causes no disturbance of calcium homeostasis. Medullary thyroid carcinoma, a tumour of the C cells which frequently results in gross hypercalcitoninaemia also rarely disturbs calcium levels in the plasma. The rise in plasma calcitonin which occurs during pregnancy and lactation appears to have no effect on the maternal skeleton, but calcium resorption may be prevented by a concommitant increase in the level of circulating cholecalciferol.

Nearly all disorders of the thyroid result in some swelling of the gland itself and the non-specific term ‘goitre’ embraces them all. In clinical practice a working classification based on whether the gland is toxic or not and the nature of the enlargement is helpful. This enables a diagnosis to be made and appropriate action taken in the majority of patients (Fig. 11) 749.

Enlargement of the thyroid is common during puberty and pregnancy, and at the menopause. This may be the result of increased physiological demand for thyroid hormone or as a response to growth hormone and variation in oestrogen levels. Increased levels of TSH are believed to be involved in the process but are not readily detectable in euthyroid patients.

The majority of ‘endemic’ goitres are due to low dietary intake of iodine (less than 100 &mgr;g a day). The worldwide geographical distribution of endemic goitre corresponds closely to alpine areas where glacial action has leached iodine from the soil and carried it away to the sea: endemic goitres are rarely seen in coastal areas. The response of high-risk populations to the addition of iodine to table salt or drinking water or to a depot injection of intramuscular lipiodol suggests that some patients with endemic goitres also have a metabolic defect in thyroxine synthesis which only declares itself when iodine is scarce.

Some endemic goitres are due to substances in the diet (goitrogens) which interfere with the trapping of iodine or the synthesis of thyroxine. These include the thioureas in uncooked vegetables of the brassica family—turnips, swedes, cabbages, Tasmanian weeds (used for cow feed), and soya beans. Excess dietary fluoride has been incriminated in the aetiology of goitre in the Punjab, while calcium excess has been implicated in Columbia, Cape Province, Burma, and Western China.

The drugs most commonly responsible for thyroid enlargement of this type are the thioureas, especially when over-used in the treatment of thyrotoxicosis. Other drugs, including thiocyanates, iodine, p-aminosalicylic acid, resorcinol, lithium, and phenylbutazone, may all cause goitre if administered over a long period.

In a small proportion of patients the susceptibility to goitre formation is due to an autosomal non-sex-linked partially recessive gene defect. Five distinct biochemical defects resulting from the inheritance of a single gene abnormality have been described.

2.Inability to bind iodine which if total results in congenital hypothyroidism. In some cases congenital deafness may be associated (Pendred's syndrome);

3.Inability to couple iodotyrosines to form iodothyronine (peroxidase and dehalogenase deficiency);

5.Inability to retain iodine in iodotyrosines due to the lack of the deiodinase enzyme. This results in loss of iodine in its organic form in the urine;

4.Abnormal protein binding of iodine in the plasma which is then unavailable to the normal process of hormone synthesis.

Although of academic interest it is not usually practical or helpful to investigate which of the above defects is responsible for a congenital goitre. All of the above causes of dyshormonogenesis cause compensatory hypertrophy of the gland in an attempt to maintain physiologically appropriate serum levels of thyroid hormone. Under the influence of increased TSH stimulation the acini multiply in an even fashion throughout the gland, producing what is sometimes described as a parenchymatous goitre. When the process is controlled or the demand for thyroid hormone ceases colloid may collect in previously hyperplastic acini, resulting in a colloid goitre. This process is typically patchy, causing nodularity.

This type of thyroid enlargement most commonly affects middle-aged women and occurs sporadically: it may represent an acquired enzyme defect due to ageing. Many multinodular goitres develop from simple goitres, especially if iodine intake or availability is compromised. The initial diffuse hyperplastic process then becomes localized to one or several areas of disorganized thyroid metabolism in which the hyperplastic acini undergo colloid involution while others show haemorrhage, cystic degeneration, or necrosis. Fibrosis and calcification may supervene: a typical multinodular goitre shows all these macroscopic features.

Fifty per cent of goitres assessed clinically to be of this type are found to be multinodular on scanning or at surgery. Truly solitary nodules may be cystic or solid. The pathogenesis of solitary cysts is uncertain, but a minority are due to degeneration of a papillary carcinoma. A solitary solid nodule may be an adenoma, a degenerative nodule, a carcinoma, or may occasionally be secondary to thyroiditis. Four times as many females as males are affected, with a peak incidence in middle age. Ninety per cent of solitary nodules in this age group are benign, but at the extremes of life over 50 per cent are malignant.

This may occur after surgery for multinodular goitres or solitary nodules and usually represents progression of the original underlying process. It may be modified or prevented by administration of thyroxine to stop TSH release and suppress gland function.

The increase in size of the gland seen in patients with Graves' disease is typically due to epithelial proliferation, an increase in stromal vascularity, and lymphocytic infiltration. This may be due to a focal thyroiditis reflecting the production of autoantibodies. Occasionally this condition progresses with increasing fibrosis to become Hashimoto's disease. Graves' disease is not simply the result of the action of increased TSH levels secondary to a primary defect in the hypothalamus or pituitary, as was once thought. Genetic predisposition and psychological trauma have a role, and seasonality of the disease may result from variation in dietary intake of iodine. In populations with a high dietary iodine intake such as in the fish-eating Japanese, Grave's disease is more common. There is now general agreement that the hyperthyroidism and goitre of Graves' disease is caused by antibodies directed against the TSH receptor on the thyroid membrane: these increase the action of TSH acting via the adenyl cyclase—cAMP system. This thyrotrophin receptor antibody was first isolated in 1956 from the serum of patients with Grave's disease as a substance which, on injection into guinea pigs pretreated with ¹³¹I caused prolonged stimulation of radioiodine release. The nature of its action resulted in the name long-acting thyroid stimulator (LATS); this has subsequently been identified as a 7 S IgG molecule produced by lymphocytes. The presence of IgG, IgM, and IgE in the thyroid, the lymphocytic infiltration of the gland, the generalized lymphadenopathy frequently seen in Graves' disease and the IgG nature of the thyrotrophin receptor support its recognition as an autoimmune process. There is strong evidence of a genetic predisposition associated with the HLA-A1, B8, and DW3 antigens in Caucasians; Class II antigens of the D locus on chromosome 6 are believed to be associated with the gene coding for the abnormal immune response.

Patients with long-standing nodular goitres often develop thyrotoxicosis. Excess thyroid hormones may be produced by the nodules themselves, by the paranodular tissue, or by a combination of both. Eye signs are usually slight and cardiac arrhythmias and cardiac failure more common than in Graves' disease; the reason for this is not known.

The distinction between multinodular and solitary nodular toxic goitres may be unnecessary but in approximately 5 per cent of thyrotoxic patients a single nodule consisting of hyperplastic epithelia and surrounded by acini in the resting phase is found. There is good correlation between the size of the nodule and the degree of hormone overproduction: overproduction of T&sub3; but not T&sub4; is common (T&sub3;-toxicosis). Women are more likely than men to be affected with this type of goitre, and its maximum prevalence occurs between the ages of 40 and 60, although children may also be affected.

Nodules associated with hormone overproduction may occur after thyroidectomy, suggesting that the causal factors are still prevailing.

This term embraces a group of conditions that have in common the presence of circulating antithyroid antibodies; these may or may not have a causal relationship with the thyroiditis. Glandular enlargement due to lymphocytic infiltration is common.

This characteristically affects middle-aged women: the female to male ratio is approximately 15:1. Very high titres of thyroglobulin and antimicrosomal antibodies are common and the latter are usually associated with thyroid failure. The degree of lymphocytic infiltration of the thyroid correlates well with levels of these antibodies, especially in the fibrous variant, suggesting long-standing hyperimmunization. Microscopically the epithelial cells are enlarged and eosinophilic—these so-called Askenazy cells have been compared to hepatocytes. Lymphocytic infiltration of the stroma is intense, with the formation of lymphoid follicles. It seems probable that sensitization of these lymphocytes to thyroglobulin, mitochondria, and microsomes leads to the destructive fibrosis. A subacute variety of the condition causes transient pain and tenderness of the thyroid but in the majority of patients the thyroid enlargement changes over time from a rubbery consistency to stony hardness, associated with progressive hypothyroidism. The risk of lymphoma and primary thyroid neoplasia developing in a Hashimoto's gland is now considered to be low. Hashimoto's disease is not associated with antigen HLA-DR3 but is weakly associated with HLA-DR5; antithyrotrophin receptor antibodies are sometimes present and are likely to be responsible for the thyroid hyperplasia which is commonly seen. Some of these antibodies are biologically active, causing hormone overproduction.

This condition is rare in Europe but is becoming more common in North America. The slightly tender thyroid enlargement is frequently preceded by an infection of the upper respiratory tract or by a viral illness such as mumps or coxsackie virus infection, suggesting an infective aetiology. Women in the 20- to 50-year age group are most commonly affected. Disruption of epithelial cells and extrusion of nuclei causes a pseudo-giant cell appearance. Inflammatory infiltration of the stroma by polymorphs, mononuclear cells, and lymphocytes can result in microabscesses and later fibrosis. Subsequent hypothyroidism is rare.

This is an extremely rare condition, and some even doubt its existence as a separate entity distinct from Hashimoto's and de Quervain's thyroiditis, both of which can produce a very hard and fibrotic gland. If the fibrosis is particularly dense and extends beyond the thyroid, tethering it to the trachea and strap muscles, the diagnosis of thyroid carcinoma must be considered. The cause is unknown but is probably one of a group of conditions, including fibrosing mediastinitis, retroperitoneal fibrosis, sclerosing cholangitis, and orbital pseudotumour, all of which are characterized by multifocal midline fibrosis.

This condition is now rarely seen due to the widespread use of antibiotics. The thyroid is usually infected by Streptococcus pyogenes or Straphylococcus aureus, originating from the bloodstream or from adjacent structures. The gland is enlarged, exquisitely tender, and there is surrounding induration. If not treated promptly with antibiotics the patient becomes acutely ill and an abscess will form. There is no disturbance of thyroid dysfunction, normal thyroxine and autoantibody levels being maintained.

Malignancy of the thyroid is rare but the incidence appears to be rising: in the United Kingdom 25 cases occur per million of the population each year, with a death rate of six per million. Areas with a incidence of high endemic goitre (notably Columbia) also report a high prevalence of thyroid carcinoma, but there is no clear aetiological relationship. External radiotherapy administered to the head and neck in children (used in the past for the treatment of acne and tonsillitis) undoubtedly increases the risk of subsequent thyroid carcinoma (notably papillary) with an average latent interval of 10 years. Radioiodine therapy in children has also been associated with the subsequent development of low-grade malignant nodules. Papillary carcinoma is the most common malignancy in individuals exposed to modest radiation doses following atomic explosions. Familial thyroid carcinomas are rare. Intake of high levels of iodine predisposes to papillary carcinoma; and some races are more at risk. Follicular carcinoma, on the other hand is more common in areas where iodine intake is low; it appears to be TSH induced. The existence of an association between Hashimoto's thyroiditis and thyroid neoplasia is controversial; an important prospective study has not established a high incidence of the two conditions coexisting. Malignant thyroid tumours may be classified as primary and secondary, and their prevalence, major features, and prognosis are summarized in Table 1 251.

Papillary carcinomas account for 80 per cent of thyroid tumours in patients under the age of 40, reflecting its tendency to affect teenagers and young adults with a 2:1 female:male sex ratio.

In older patients this tumour may be associated with follicular lesions; in this case the papillary pattern of behaviour predominates, with a better prognosis. The typically unencapsulated pale homogeneous primary tumour (which commonly undergoes cystic degeneration) spreads via the lymphatics. If the whole of the gland is examined, micrometastases are present in 90 per cent of affected individuals. Multiple macroscopic deposits are found at operation in 20 per cent and spread to the regional lymph nodes occurs in 50 per cent of patients. Occasionally, the tumour within the thyroid is impalpable and less than 1.5 cm in diameter (‘occult’). It may even be difficult to locate histologically. Whether or not a primary thyroid tumour is palpable the first evidence of a papillary lesion is frequently an enlarged deep cervical or posterior triangle lymph node, previously erroneously described as a lateral aberrant thyroid. Histologically, these tumours are characterized by papillary processes arranged like a Christmas tree, with variable colloid and follicular architecture. Laminated calcium-containing structures called psammoma bodies are often seen in well-differentiated papillary tumours.

This tumour affects three times as many women as men. It is associated with lack of iodine, and is therefore probably induced by TSH; this accounts for the fact that the tumour is more common in areas with a high incidence of endemic goitre. Macroscopically, the tumour is unifocal and encapsulated, with a pinkish cut surface which bulges. Capsular invasion is occasionally evident, and nodular components may develop to affect the whole lobe of the thyroid. Cystic degeneration is rare. The malignant potential of follicular carcinoma is dependent on the extent to which its capsule has been breached and the blood vessels invaded. This can only be assessed by examining the whole lobe with paraffin sections. Spread occurs via the bloodstream and the most common distant sites to be affected are the lung, bones, and brain. Lymph node involvement is unusual.

This tumour is noted for its speed of growth, local invasiveness, and early dissemination, but is fortunately rare. Its follicular cell origin is supported by the presence of small areas of differentiated thyroid carcinoma in a proportion of anaplastic carcinomas and probably accounts for its high prevalence in endemic goitrous areas. The histological appearance is varied, with spindle cell and giant cell patterns. If a patient diagnosed as having a anaplastic thyroid carcinoma survives for more than 1 year the histology should be reviewed: the diagnosis will invariably be revised to lymphoma.

This occurs mainly in elderly women and grows rapidly. Its association with long-standing Hashimoto's disease is now discounted. Histologically malignant lymphona may be confused with small round cell anaplastic carcinoma of the thyroid; this is resolved by monoclonal antibody studies.

This tumour has attracted considerable interest since it was first described in 1959, and now that clinical awareness has been aroused diagnosis is more frequent. It arises from the parafollicular C cells, which are distributed throughout the gland but are present in highest concentration in the upper poles, where most medullary thyroid carcinomas occur. If the tumour is solitary the disease is likely to be sporadic (80 per cent); if tumours are multiple the familial form is more likely (20 per cent). The latter shows a predominantly autosomal pattern of inheritance and men and women are equally affected; successive generations tend to develop tumours at a progressively earlier age. A chromosomal abnormality affecting chromosome 10 has been identified in individuals with the familial form of the disease and should prove helpful in identifying affected individuals in the future. Familial medullary thyroid carcinoma is also associated with tumours of the adrenal medulla (phaeochromocytoma) and with parathyroid hyperplasia—an endocrine triad categorized as multiple endocrine neoplasia Type IIA, or Sipple's syndrome. A distinct group of patients have a phenotypically different disease, characterized by medullary thyroid carcinoma and phaeochromocytoma but without parathyroid disease. This syndrome, called multiple endocrine neoplasia Type IIB, is also associated with characteristic facies, Marfanoid habitus, and submucosal neurofibromata of the tongue, eyelids, and lips (Fig. 12) 750. This type is more aggressive in its behaviour than Type IIA and often rapidly fatal. The C cells of both sporadic and medullary carcinoma produce a near-specific tumour marker, calcitonin, which helps in its diagnosis and management.

Very rarely breast, renal, ovarian, and gastrointestinal cancers metastasize to the thyroid, where they present as a solitary nodule. It is surprising that metastases to the thyroid are not more common, considering the high percentage of the cardiac output relative to unit volume which circulates through the very vascular gland which must be considered a protected site.

There is no substitute for good history taking and careful clinical examination in the assessment of thyroid disorders. None of the available tests is infallible and misleading results may be obtained, especially if the patient is taking medication or has altered physiology, for example in pregnancy. Nevertheless major advances in the accurate measurement of hormones and antibodies either produced by or acting upon the thyroid have resulted in the development of an impressive array of tests to help confirm the clinical diagnosis and elucidate the more difficult diagnostic problems.

This measures the total protein-bound thyroxine and, provided that the patient is not on any drug or in a condition which might affect the serum levels of binding proteins, offers a good basic test for thyroid function, especially when myxoedema is suspected. Low levels are seen in patients with the nephrotic syndrome and falsely high levels occur in pregnancy and in those taking oral contraceptives. Some drugs, notably salicylates, phenytoin, and phenylbutazone, compete with T&sub4; for protein binding, resulting in falsely low levels.

Serum levels of T&sub3;, are also affected by changes in the thyroid binding proteins and are therefore subject to the same limits of interpretation. Serum T&sub3; falls more profoundly than T&sub4; in the elderly and in patients with non-thyroidal diseases. Enhanced secretion of T&sub3; is seen when the thyroid is deprived of iodine, making this assay unhelpful for the assessment of patients treated with drugs which block iodine uptake. The test is most useful in the confirmation of hyperthyroidism, especially when the clinical picture strongly supports a diagnosis of thyrotoxicosis but the levels of serum T&sub4; are normal.

Since the introduction of a radioimmunoassay in kit form, it is now possible to measure the biologically active unbound circulating T&sub4; with precision and at relatively low cost. Drugs such as oral contraceptives or phenytoin have no effect on the results since protein binding is not a factor. Levels of free T&sub4; do not appear to vary with age in healthy individuals.

The free T&sub3; imino radioimmmunoassay has the same merit as the free T&sub4; assay, and is the best single test in the assessment of hyperthyroidism, providing the patient is not suffering from severe non-thyroidal illness. It is not helpful in the diagnosis of hypothyroidism.

Routine TSH assays lack sensitivity and cannot identify patients who may have subclinical hypothyroidism and might benefit from replacement therapy. New sensitive immunoradiometric assays (IRMA) probably represent the most helpful confirmatory test for both hypothyroidism when levels are high and hyperthyroidism when levels of TSH are undetectable. In severely ill patients or those in early pregnancy, however, falsely low TSH levels may be recorded, and hyperthyroidism can be missed.

Following the intravenous administration of 200 mg of thyrotrophin the patient's TSH levels are then measured in blood samples taken after 0, 20 and 60 min. An exaggerated response producing levels greater than 20 &mgr;U/l at 20 min is seen in patients with hypothyroidism. Little or no response (<1.8 mU/l) is seen in hyperthyroid patients. The test is being superseded by the immunoradiometric assay for TSH where this is available.

Uptake measurements combined with thyroid scanning provide information about thyroid activity and also providing graphic information about the size and extent of the gland. This method is particularly helpful in showing the retrosternal extent of the gland (Fig. 13) 751 and identifying which part of the gland is hyperactive (hot nodules) (Fig. 14) 752. In North America, where radio-iodine therapy is more commonly employed for the treatment of thyrotoxicosis, a radio-isotope uptake study may identify clinically thyrotoxic patients with silent thyroiditis but low radio-iodine uptake. Ablative therapy should be avoided in such patients.

T&sub3; administration normally suppresses pituitary TSH secretion and therefore reduces radio-iodine uptake in normal patients. Radio-iodine uptake is not so reduced in patients with Grave's disease, in whom the thyroid is being stimulated by antibodies rather than by TSH. The test is useful in distinguishing high radio-iodine uptake associated with iodine deficiency from that of hyperthyroidism, but can precipitate cardiac failure in the elderly. It has largely been superseded by the TRH test or immunoradiometric TSH assay.

Very high titres of antithyroglobulin antibodies are seen in patients with Hashimoto's thyroiditis, especially in those with long-standing disease, when their presence strongly supports the diagnosis. Surgery should not usually be undertaken in patients with Hashimoto's thyrotoxicosis. The presence of antithyroglobulin antibodies in a hyperthyroid patient without eye signs suggests the diagnosis of Graves' disease. The presence of anti-microsomal antibodies indicates autoimmune thyroid disease of Hashimoto's type, and when found in patients who have already received thyroxine makes a presumptive initial diagnosis of thyroid failure more likely. This antibody is also seen in patients with thyroid malignancy.

The ESR is often modestly raised (>90 mm/h) in many patients with myxoedema and Hashimoto's thyroiditis, and is markedly elevated in de Quervain's thyroiditis.

¹²³I has a half life of 13 h and is a gamma ray emitter; it gives a low radiation dose and is the isotope of choice. Areas of high uptake (hot nodules) are almost invariably benign. More than 50 per cent of nodules have low uptake rates, but only 10 per cent are subsequently shown to be malignant. The test discriminates poorly and is therefore hard to justify. The principal benefits of isotope scanning, other than those already mentioned, is to identify metastases or residual local disease after total thyroidectomy for follicular carcinoma (Fig. 15) 753.

This technique is helpful in identifying impalpable multiple nodules (multinodular goitre) which are much less likely to be malignant than is a solitary nodule. Justification for the use of this technique in the diagnosis of malignancy is, however, poor.

This technique promoted by the Karolinska Institute in Sweden for over 40 years, has only recently gained wider acceptance. A 25 gauge disposable needle on a 10-ml syringe enables cells to be aspirated from any suspicious area of the thyroid (Fig. 16) 754. The procedure can be performed quickly and painlessly in the outpatient department without the need for local anaesthetic, providing a smeared specimen which is fixed and stained on a microscope slide. A high level of diagnostic accuracy can be achieved for the majority of thyroid conditions when the clinician and cytologist are experienced. The technique cannot distinguish benign from malignant follicular lesions since no information is available about capsular and vascular invasion; these lesions are best excised.

Elevated basal levels of this hormone produced by the parafollicular C cells are diagnostic of medullary thyroid carcinoma; serial measurements are also useful in predicting complete removal of the tumour or recurrence. Patients with Type II multiple endocrine neoplasia who have occult or premalignant medullary thyroid carcinoma (C cell hyperplasia) can be identified by a provocation test using a combination of pentagastrin (0.5 &mgr;g/kg body weight) and calcium gluconate (2.5 mg/kg body weight) infused IV over 30 s. Blood samples are drawn for calcitonin estimation prior to infusion and at 2, 5, 10, and 15 min post-infusion in a fasted subject. The test is safe and can be carried out in the out-patient department.

In patients who have undergone total thyroidectomy with or without radio-iodine therapy for differentiated thyroid carcinoma, levels of thyroglobulin above 50 &mgr;g/l indicate probable residual or recurrent tumour. Levels above 100 &mgr;g/l strongly suggest the presence of pulmonary or skeletal metastases.

Measuring the nuclear DNA content by flow cytometry offers the prospect of identifying diploid tumours, which have a good prognosis and aneuploid tumours, which have a poor prognosis . Data which have been accumulated from patients with papillary tumours correlate well with predicted outcome and should help decide the scale of surgical intervention.

There are two broad categories of symptoms related to thyroid disease: those occurring as a result of the enlargement of the gland itself and those related to its disordered endocrine activity. The history will establish whether one or both classes of symptoms are present, and examination then aims to elicit the relevant physical signs.

Nearly all goitres grow slowly and are painless; the patient only visits the clinician when the mass becomes a cosmetic problem. A rapid change in size of all or part of the thyroid may be caused by haemorrhage into a necrotic nodule, a fast growing carcinoma, or by one of the varieties of thyroiditis. When haemorrhage is the cause of a lump its appearance is invariably sudden (within 24 h) and it is usually painful. Malignant tumours only cause pain when local structures are involved. This occurs within weeks of development of an anaplastic carcinoma or within months or years for a papillary or follicular tumour.

Thyroid swellings make swallowing uncomfortable but rarely obstruct the oesophagus, which easily moves out of the way or becomes stretched. Thyroiditis causes extreme pain on swallowing, radiating up into the jaw and ears. True dysphagia as a result of thyroid disease is a sinister symptom indicative of aggressive anaplastic carcinoma.

This most commonly arises as a result of deviation and compression of the trachea caused by asymmetrical thyroid enlargement. It may be accompanied by stridor when the patient has the head flexed forward or laterally to the side of the enlarged lobe.

This symptom in association with a goitre is sinister and until proven otherwise should be considered secondary to a malignant process of the thyroid involving one of the recurrent laryngeal nerves. The hoarseness seen in hypothyroid patients derives more from mucus on the vocal cords than an inability to phonate.

All bodily systems can be affected by altered thyroid activity. In hyperthyroidism increased metabolism is usually reflected in heat intolerance with a preference for cold weather coupled with increased sweating. The principal systemic symptoms of hyperthyroidism are shown in Table 2 252; hypothyroid symptoms are best summarized as the exact opposite.

Since examination traditionally follows functional enquiry the clinician will usually have a fairly strong impression of the patient's thyroid status and will know that attention needs to be directed primarily towards the thyroid itself. In those with thyroid dysfunction more specific signs need to be elicited.

Euthyroid patients appear normal, apart from possible signs in the neck. Hyperthyroid patients are frequently noisy, agitated, and clearly nervous, but may be apathetic. Hypothyroid patients show little response to their environment, being subdued, slow in their movements, and frequently overweight. They typically have thickened and expressionless features and a ‘peaches and cream’ complexion (Fig. 17) 755.

The hands provide a wealth of clues about a patient, and this is certainly true in thyroid disease. The hands of a hyperthyroid patient usually show a fine tremor, which is accentuated by placing a sheet of paper on the back of the hand with the arms outstretched. Patchy depigmentation of the skin (vitiligo) surrounded by areas of increased pigmentation may be apparent (Fig. 18) 756. Patchy subperiosteal deposition of new bone, simulating clubbing (thyroid acropathy) can occur. On shaking hands with the patient one is aware of increased temperature and sweating. Pulses at the wrist and at the bases of the fingers are easily felt due to increased systolic pressure; this is often accompanied by tachycardia greater than 80/min and irregularity.

The hypothyroid patient has cool, dry hands, and the palms are often pale yellow in colour. The increased bulk of the subcutaneous tissues cause the hands to look puffy and spadelike, and rings become tight. The nails are often fissured and cracked becoming separated from the nail bed (onycholysis or Plummer's nails). Bradycardia and a low volume pulse difficult to detect is characteristic of hypothyroidism.

Confirmation that a swelling in the neck is arising from the thyroid is based on two observations—the site is anatomically correct and the swelling moves up and down on swallowing. Offering the patient a drink of water is helpful at this stage and subsequently aids more detailed examination by palpation. Much can be learned by simple inspection with the patient's neck properly exposed and with a good light source on one side. Prominent neck veins may indicate superior vena caval obstruction secondary to retrosternal extension of the goitre. Puckering of the skin, accentuated on swallowing, is seen with locally invasive thyroid cancer. Erythema of the skin is often present in patients with de Quervain's thyroiditis or suppurative thyroiditis. Deviation of the thyroid cartilage suggests asymmetrical enlargement of the thyroid.

Palpation should be undertaken with the patient sitting comfortably in an upright chair with all clothes removed from around the neck. Standing behind with the thumbs placed on the patient's occiput to flex the head forward slightly, the clinician's hands encircle the neck and the right hand draws the sternomastoid muscle on the same side laterally whilst the fingertips of the other hand scan the surface of the underlying lobe (Fig. 19) 757. The position of the hands is then reversed to evaluate the left lobe. The normal trachea should be in the midline of the suprasternal notch and not obscured by the thyroid isthmus. If there is any doubt about the relationship between anatomical features and any lump, or difficulty feeling below the lower pole of the lobe, the patient is asked to swallow. This will confirm whether the lump is part of the thyroid or whether retrosternal extension is likely to be present. If the head and neck becomes suffused (Fig. 20) 758 with or without the onset of stridor, when the patient raises his arms above his head, retrosternal extension is present. In a patient with thyrotoxicosis careful palpation may detect a thrill. The overall neck circumference and precise measurements of any nodules should be recorded to provide a baseline if longer-term surveillance is indicated. The lymph nodes draining the thyroid should also be checked for any enlargement (see Fig. 4 742).

A systolic bruit may be heard in Graves' disease and is an important sign of toxicity. It should not be confused with a transmitted systolic murmur secondary to aortic or pulmonary stenosis or from a venous hum that can be eliminated by pressure on the internal jugular vein at the level of the hyoid bone.

The skin is characteristically dry and flaking with hyperkeratosis over the flexures. Coarsening of features and subcutaneous thickening, notably across the back of the neck and hands, are due to deposition of hygroscopic hyaluronic acid. This mimics oedema but does not pit on pressure. The hair is coarse, brittle, and falls out easily; loss of the outer one-third of the eyebrows is an unreliable sign of hypothyroidism, and is often seen in normal perimenopausal women. Macroglossia is often present and impairs speech. The reflexes are sluggish and their relaxation period is prolonged.

There are two main groups of physical signs, other than those affecting the thyroid: those confined to the eyes, and more general signs.

Swelling of the eyelids without exophthalmos is an indicator of dangerous congestive ophthalmopathy. Conjunctivitis and chemosis (Fig. 21) 759 may be induced by a reduction in blinking rate and by an inability fully to close the eyelids whilst asleep. The conjunctivae are inflamed and prominent vessels are seen, especially at the lateral canthi. When oedema occurs (chemosis) the conjunctiva becomes thickened and wrinkled, and may actually prolapse between the lids. Excessive watering and photophobia occur.

Exophthalmos is caused by the eye ball being pushed forward by an increase in retro-orbital contents. In Graves' disease this is due to an increase in fat and bulkiness of the extrinsic muscles secondary to deposition of water and mucopolysaccharides combined with lymphocytic infiltration. The eyes may be affected asymmetrically. The single most crucial observation relates to the appearance of the white sclera below the inferior limbus of the cornea on forward gaze (Fig. 22) 760. Accurate measurement of the degree of exophthalmos requires an exophthalmometer: an absolute reading of 18 mm or more or a difference of 2 mm between the eyes is considered significant. Looking down directly over the patient's forehead and observing the cornea in front of the supraorbital ridges is an easy bedside means of assessment but only reveals gross exophthalmos. The same applies when the patient can look upwards without wrinkling the forehead.

Lid retraction is the result of spasm of the levator palpebrae superioris muscles, which causes the white sclera to appear between the upper lid and upper limbus of the cornea in all positions of gaze (Fig. 23) 761. It prevents apposition of the eyelids during sleep and is a cause of conjunctival irritation and ulceration. This same spasm allows the sclera to become visible between the upper lid and cornea (lid lag) as a patient's eye follows the examiner's finger downwards (ideally an arm's length away from the patient's head). This test of lid lag is poorly reproducible and unreliable.

Disturbance of vision occurs as a result of oedema and lymphocytic infiltration affecting the extrinsic muscles of the eye, notably the superior rectus and inferior oblique. Diplopia commonly occurs on upward outward conjugate gaze, but upward inward gaze may also be affected. Both of these movements should be checked by asking the patient to follow the examiner's finger appropriately.

1.Proximal myopathy, producing wasting of the muscles of the shoulder girdle and pelvic girdle, may result in difficulty getting up from a chair or inability to carry a heavy shopping bag.

2.Hyper-reflexia.

3.Fine tremor of the tongue may also be present.

4.Pretibial myxoedema is seen in approximately 5 per cent of patients with Graves' disease, especially those with eye signs, and is due to deposition of mucopolysaccharides and hyaluronic acid. The skin is thickened, livid, with ‘peau d'orange’ appearance, typically extending over the front of the shins and occasionally over the dorsum of the feet (Fig. 24) 762.

5.Splenomegaly is rare, but may be associated with generalized lymphadenopathy.

The incidental finding of a small soft goitre, especially if ‘physiological’ (see under pathophysiology), requires no treatment. Goitres occurring as a result of primary or secondary iodine deficiency rarely present until the condition is well established, but those detected at a small size may regress in response to iodine or eradication of the offending goitrogen in the diet. This process may be accelerated by giving thyroxine, which depresses the TSH drive to the gland. If there is no response partial thyroidectomy may be indicated on cosmetic grounds.

Large goitres of this type may well cause cosmetic disfigurement, pressure symptoms, and discomfort. All of these are good indications for surgery, the extent of which is dependent on the size and number of nodules present. Following surgery a small dose of thyroxine (0.1 mg daily) reduces the risk of recurrence.

Because of the high prevalence of solitary nodules (and even though over 50 per cent of those thought to be solitary are in fact part of a multinodular process) a policy of removing all of them surgically, although sound, is simply not practical. Fine-needle biopsy (aspiration biopsy cytology) has helped to reduce the incidence of surgical exploration of thyroid nodules by 25 per cent. It allows benign and malignant lesions to be identified with a high degree of specificity and sensitivity, and has the merit of being quick, painless, and easily performed as an outpatient procedure. All biopsy techniques are limited by the skill and ability of the operator to obtain a truly representative sample and by the experience and accuracy of the cytopathologist examining the specimen. The only serious limitation of this technique is failure to differentiate between a follicular adenoma and a follicular carcinoma: this can be done only by studying the overall histological pattern and, in particular, the presence or otherwise of capsular and vascular invasion. Unless the surgeon can depend on a cytology service which has a very low false-negative rate, total lobectomy (Fig. 25(a)) 763 is advocated for all cases, especially in children and males under 40. Fine-needle biopsy quickly identifies a cystic nodule or simple cyst and, if less than 2 cm in diameter, drainage may be curative. Ideally the cyst wall should also be biopsied to ensure that a papillary carcinoma is not missed.

There are three methods of treatment for this condition—anti-thyroid drugs, radio-iodine, and surgery. Over 50 years fashions have waxed and waned but a marked preference for radio-iodine persists in North America, while its use is more selective in the United Kingdom. The different treatments have their own advantages and disadvantages (Table 3) 253. Ultimately it is for the patient to decide which treatment is most acceptable.

The thyroid function of patients with large toxic multinodular goitre or classical Graves' disease is often very labile during treatment with antithyroid drugs, and relapse rates following withdrawal of medication are greater than 50 per cent. Unfortunately there is no reliable test to identify patients likely to relapse, although attempts to do so have been made on the basis of HLA status and levels of thyroid stimulating antibody. Radioactive iodine treatment is least suited for Plummer's disease as drug uptake is variable, there is minimal impact on the size of the gland, and response is slow. Surgery is best carried out sooner rather than later to avoid compromise of the airway and the cardiovascular system. The specific surgical procedure is a near total thyroidectomy, with the removal of at least 85 per cent of the gland (Fig. 25(b)) 763, notably those parts shown to be ‘active’ on radio-iodine scanning.

Patients affected with this condition are likely to have florid disease and cosmetic embarrassment. Prompt elective surgery should be performed after a course of treatment with antithyroid drugs and &bgr;-blockers. It is more debatable whether surgery should be undertaken when the gland is small, since the risks of hypothyroidism are greater than when a bulkier gland is the target. However, in women, especially those in their reproductive years, who have relapsed after 12 to 18 months' treatment with antithyroid drugs, or in those in whom medication has proved impractical due to poor compliance or unacceptable side-effects, surgery is the first choice, providing it is acceptable to the patient and the necessary surgical skills are available. A sub-total thyroidectomy should be performed, which aims to leave one-eighth of the total mass (approximately 4 g) of thyroid tissue on each side.

Surgical resection of the physiologically hyperactive part of a thyroid gland (demonstrable on radio-iodine uptake scan) is so straightforward that the other methods of treatment need not be seriously considered unless the overall medical state of the patient makes surgery inadvisable. Antithyroid drugs have the disadvantage of having to be taken for life, and radio-iodine therapy runs the risk of exposing surrounding normal tissue to irradiation. In addition, the nodule usually persists. The operative procedure indicated is subtotal lobectomy or isthmusectomy (Fig. 25(c)) 763, depending on the location of the active nodule.

Children with hyperthyroidism are prone to relapse after withdrawal of medical therapy and radio-iodine therapy is contraindicated due to the high incidence of benign and malignant nodules arising as a result of exposure to radiation. Unless medical therapy is effective quickly, surgery is the treatment of choice. Hypertrophy of thyroid remnants and recurrent thyrotoxicosis is common in children, and surgery therefore needs to be more radical. A surgeon experienced in operating on the thyroid gland in children can perform the operation avoiding high myxoedema rates and complications. Long-term follow-up is essential.

This is rare, affecting 0.2 per cent of pregnancies, but can present a difficult management problem. Antithyroid drugs given to the mother cross the placental barrier and may cause hypothyroidism and goitre in the foetus (iatrogenic cretinism). Excretion of anti-thyroid drugs in the milk is at a level too low to cause comparable effects. Radio-iodine is never given in view of its possible teratogenic effects, especially in the first trimester or at the time when the fetal thyroid is trapping iodine. If maternal thyrotoxicosis is moderate or severe, and especially if cardiac symptoms herald possible cardiac failure late in pregnancy, elective subtotal thyroidectomy should be undertaken in the middle trimester, when it is safe and effective.

A small goitre of this type in a euthyroid patient may require no treatment. As the goitre enlarges symptoms of pressure on the trachea and oesophagus are common; these may be relieved by exogenous thyroxine (0.1–0.2 mg/day) and prednisolone (20 mg/day). If there is still no response removal of the affected lobe or isthmus is indicated. Such goitres are relatively avascular and easily separable from the false capsule. Total lobectomy or total thyroidectomy is indicated in any patient with Hashimoto's disease in whom malignancy is suspected on clinical or cytological grounds.

The acute pain associated with this condition can be alleviated by aspirin and a &bgr;-blocker. If this fails, 20 to 30 mg of prednisolone daily in divided doses for 1 month usually provides rapid relief. Thyroxine replacement may be required if hypothyroidism develops, but this is usually transient and treatment should be stopped after 6 months. Surgery is only required if the diagnosis is uncertain or equivocal on fine-needle biopsy.

Surgery is almost invariably required to exclude malignancy and to relieve the severe constriction of the airway. Relief can be obtained by dividing the thyroid isthmus, which is hard and brittle and can literally be snapped off the trachea with the fingers. Hypothyroidism frequently arises as the fibrosis progresses and needs to be treated indefinitely with thyroxine.

Cysts less than 2 cm in diameter are treated by aspiration: the fluid should be examined cytologically, and the patient's condition monitored. Larger cysts are likely to recur and may well be cosmetically unacceptable. These carry a risk of sudden airways obstruction due to intracystic haemorrhage and are, therefore, best dealt with electively by thyroid lobectomy or isthmusectomy, according to site.

The indications for and extent of surgery in carcinoma of the thyroid depend primarily on the histological type, but the age of onset and the mode of presentation will also influence management.

There is controversy about the extent of surgery required. The conservative approach to a solitary macroscopic tumour with no lymph node disease is a total lobectomy on the side of the tumour. The prognosis for the majority of patients is excellent if TSH is permanently suppressed by thyroxine (usually 0.1 mg/day). Total thyroidectomy is reserved for patients with macroscopic multifocal disease and/or demonstrable lymph node disease. Those who advocate a more aggressive strategy perform total or near-total thyroidectomy (Fig. 25(d)) 763 for all cases, accepting the greater morbidity and higher incidence of hypoparathyroidism. The advantage of this approach is that multifocal tumour throughout the gland is always removed, the risk of anaplastic change in residual foci is excluded, and postoperative surveillance may be possible through serial thyroglobulin estimation. Deciding between the two strategies may be resolved by a scoring system devised to identify low- and high-risk patients based on four variables: age, grade, extent, and size (AGES); a higher score on each is associated with a poorer prognosis and the need for more radical surgery. DNA flow cytometry (possible on samples obtained at fine-needle aspiration) will also provide guidance on treatment, when the technique becomes more readily available. Surgery for papillary carcinoma should always include clearance of nodes in the primary lymphatic drainage zone. The thymus need not be disturbed unless obviously involved in the disease process, as ectopic parathyroids are frequently located in the thyrothymic ligament. Disease affecting lymph nodes in the secondary drainage areas may be suspected by their blue/black discoloration and often fleshy or cystic appearance. Clearance of all such nodes should be carried out by a modified neck dissection, only sacrificing the internal jugular vein and sternomastoid muscle if these are directly involved. The classical radical block dissection has been shown to confer no benefit in terms of reduced tumour recurrence rates or improved survival and leaves the patient disfigured and at risk of lymphoedema of the face. When disease recurs in lymph nodes, often years later (less than 10 per cent of cases treated by total lobectomy), the nodes are well encapsulated and can easily be excised ‘berry-picking’. Even patients treated in this way for successive recurrences do not appear to have a compromised survival. When local invasion or distant spread not amenable to surgery occurs, radio-iodine may show uptake in approximately 20 per cent of papillary metastases and then the option of therapeutic radio-iodine can be considered.

This tumour typically presents as a non-toxic solitary nodule, and distant metastases rarely occur without a clinically impressive primary lesion. Most cases will be suspected on fine-needle biopsy and confirmed on examination of frozen sections after total lobectomy, as for papillary carcinoma. If there are unequivocal malignant features of capsular and vascular invasion, total thyroidectomy is the treatment of choice. Frequently, however, the pathological appearances are not clear-cut, and malignant features are easily missed because of sampling error, in which case it is best to wait until definitive paraffin sections are available. If these show minimal invasion suppression of TSH with thyroxine is all that is required. If, however, overt vascular or capsular invasion is seen, re-operation is strongly advised: total thyroidectomy should ideally be carried out within 7 to 10 days; beyond that time surgery becomes difficult due to new vessel growth and fibrosis. Although multifocal disease is not common, removal of the main ‘iodine trap’ enables distant metastases to be identified and ablated using radio-iodine. The usual routine is to withhold thyroxine after thyroidectomy until the patient becomes hypothyroid, usually within 3 to 6 weeks. The increased TSH drive then makes the secondaries avid for iodine and therefore more likely to be identified.

Surgery has little to offer for most patients, who are usually elderly, female, and infirm. The rare middle-aged patient may benefit from total thyroidectomy followed by external radiotherapy, although tumour cells may be implanted in the surgical incision. The surgeon's role is therefore mainly to establish the diagnosis beyond doubt. In view of the bulky nature of most anaplastic tumours a good representative sample can be obtained using a Trucut needle and local anaesthetic. Pressure on the trachea can sometimes be achieved by removal of the isthmus, but local radiotherapy often offers the only prospect of worthwhile palliation. The 12-month survival rate is zero and chemotherapy has so far failed to improve the dismal prognosis.

Some of these tumours, which mimic anaplastic carcinoma in their presentation and histology, arise in pre-existing Hashimoto's disease or as part of a generalized lymphomatous disease. Most are radiosensitive and regress following external beam radiotherapy; good 5-year survival figures have been reported. Chemotherapy is reserved for patients with disseminated disease. The role of surgery is therefore diagnostic and attempts to remove the lymphoma are rarely appropriate.

Total thyroidectomy is the procedure of choice in view of the high incidence of multicentric lesions in patients with both familial and sporadic disease. The upper poles and in particular the primary lymphatic drainage areas must be completely resected. The resection of lymph nodes in the central compartment should extend from the hyoid bone to the innominate vessels, since up to 75 per cent of them will be found to contain metastatic disease. Lymph nodes in the secondary drainage areas should be sampled and, if positive, removed in accordance with the modified dissection described for papillary carcinoma. When the diagnosis is suspected from the family history or confirmed by fine-needle biopsy a co-existing phaeochromocytoma or parathyroid tumour needs to be excluded: failure to attend to these endocrine tumours first may be catastrophic. A serial rise in serum calcitonin after thyroidectomy is a strong indicator of recurrent disease; this is detectable by pentavalent DMSA scanning. Metastases may be treated by surgery, radiotherapy, radio-iodine, or chemotherapy. Results are, however, often disappointing and calcitonin levels rarely return to normal.

Although rare, these most commonly arise from breast, kidney, ovary, or colon. Thyroidectomy may be indicated if the secondary deposits are confined to the thyroid and if the primary tumour is under control.

Preparation is directed to ensure safe induction of anaesthesia and a trouble free intra- and postoperative course. Haemoglobin estimation, chest radiology, and an ECG are mandatory. Blood transfusion is rarely required: grouping and saving of serum is all that is required. If thyroid enlargement is massive or retrosternal, and if the patient shows clinical signs of respiratory embarrassment or superior vena caval obstruction, a CT scan of the neck and thoracic inlet (Fig. 26 (a) and (b)) 764 will indicate the possible need to enter the chest and potential problems which may be encountered on intubation. The vocal cords should always be examined by indirect laryngoscopy; this is especially important when the voice is compromised, malignancy is suspected, or when previous thyroid surgery has been undertaken. A small proportion of patients have unsuspected recurrent laryngeal nerve palsy; it is of clinical and medicolegal importance to both the patient and the surgeon to determine before surgery whether or not the vocal cords are moving normally. Thyrotoxic patients need to be rendered euthyroid or the peripheral effects of high circulating levels of thyroxine blocked. The majority of thyrotoxic patients referred for surgery have already received one or more courses of antithyroid drugs, but their condition remains unstable. Where residual toxicity is modest and surgery can be undertaken quickly it is standard practice in many centres to stop antithyroid drugs 10 days prior to operation and switch to oral propranolol in a dose of 30 to 120 mg every 6 to 8 h. The dose is adjusted to keep the patient's sleeping pulse at around 70 beats/min. Since the effective duration of action of propranolol is approximately 6 h it is important to administer medication right up to induction of anaesthesia and to continue treatment thereafter, especially if the patient develops tachycardia. &bgr;-Blockers are contraindicated in patients with bronchial asthma, sinus bradycardia, or congestive heart failure. Patients with severe thyrotoxicosis who require relatively early surgery should receive a 6- to 8-week course of carbimazole (Neomercazole 10–15 mg 8-hourly). In the event of an adverse drug reaction propylthiouracil (100 mg three times daily) may be substituted for carbimazole. Extended use of thiourea drugs may cause prothrombin deficiency (hence the advisability of stopping the drug 10 days prior to surgery), leucopenia, or profound bone marrow depression. Full blood count and INR estimation should be checked if reduced resistance to infection or impaired haemostasis is suspected.

The patient should be placed comfortably on the operating table and the surgical diathermy indifferent electrode securely attached to the thigh prior to placement of the surgical drapes. Good access to the anterior compartment of the neck is facilitated by placing a pillow under the shoulders to extend the cervical spine while supporting and stabilizing the head on a rubber ring or horseshoe. Failure to do so may result in severe postoperative pain and headache, especially in elderly patients with cervical spondylitis. In patients with a short stocky neck or a large goitre it is helpful to depress the shoulders by exerting gentle traction on the arms alongside the body and securing their position with foam wedges (Fig. 27) 765. The table is then tilted 15° head-up to reduce engorgement of the neck veins. A flat board or magnetic pad supported by pillows placed on the lower chest and upper abdomen provides a convenient instrument tray. The skin is prepared with a suitable antibiotic solution and the operative field draped after gauze packs have been pushed well down into the recesses between the head support and the shoulder pillow on each side. These absorb blood loss at the lateral extent of the surgical excision and provide a good anchor for towel clips. The skin to be incised is now rarely infiltrated with 1 : 1000 adrenaline in saline solution, since much of the bleeding at the skin edge stops spontaneously. More persistent points of loss are best recognized and dealt with immediately, since extensive bruising and wound haematoma can develop after the vasoconstrictive effects of adrenaline have worn off.

The majority of thyroid procedures can be carried out through a Kocher collar incision which is placed in one of the natural skin creases (Langer's lines), approximately two finger breadths above the supraclavicular joint (Fig. 28) 766. This may conveniently be marked before incision with a length of silk held taut against the skin around the convexity of the neck. The incision should be symmetrical: when the collagen in the scar matures it may contract unevenly if the stress lines are unequal, leading to a poor cosmetic result. Symmetry can be checked by the surgeon standing at the head of the table and looking down on the proposed incision directly from above. Matching the skin flaps at the end of the operation is rarely a problem for an experienced surgeon, and the practice of cross-hatching the incision line with a needle, which carries the risk of provoking a keloid reaction, is undesirable. Deepening the incision through the subcutaneous fat and platysma muscle discloses the deep cervical fascia, investing the strap muscle centrally and the sternomastoid laterally. The anterior jugular veins course beneath the fascial layer on the anterior surface of the thyroid and, provided that the surgeon is careful and keeps to the plane between the platysma and fascia, blood loss is minimal. Mobilization is extended superiorly to the prominence of the thyroid cartilage and inferiorly to the suprasternal notch. The diamond-shaped surgical field is held open with a self-retaining retractor and the deep cervical fascia is then incised through the midline raphe from top to bottom. Defining the planes beneath the strap muscles which extend over the surface of the thyroid lobes laterally requires care: the sternothyroid muscle may be extremely thin due to compression by a greatly enlarged thyroid. Adherence of these layers is a feature of the inflammatory process seen in autoimmune thyroiditis and when thyroid malignancy extends outside the gland. Further exposure of the thyroid requires delivery of each lobe into the wound after division and ligation of the middle thyroid vein on each side. In most patients the strap muscles present no impediment to the forward dislocation of the lobes; if they do they should be divided since division or removal causes no detectable functional disability. In practice, a pair of long straight artery forceps inserted under the strap muscles at the junction of their upper one-third and lower two-thirds can define their lateral margin against the sternomastoid, allowing identification and preservation of the nerve of supply (the ansa hypoglossi) before the muscle is divided. Stay stitches to the upper and lower muscle flaps hitched over the joints of the self-retainer can act as a convenient retractor (Fig. 29) 767.

The aim of this operation to remove sufficient thyroid tissue to cure hyperthyroidism yet preserve a posterior remnant of the gland on each side sufficient to maintain the patient in a euthyroid state. Most surgeons prefer to stand on the opposite side of the table to the lobe being delivered. Following mobilization of the lobe the upper pole vascular pedicle is identified below the adherent sternothyroid muscle. A thyroid director is then passed between the larynx and the thyroid pedicle just above the suspensory ligament. Damage to recurrent laryngeal nerve and the superior laryngeal nerve is avoided if the point of the director is aimed upwards and laterally; finger-tip pressure is sufficient to ensure that the point of the director is passing behind all of the upper lobe tissue, but nothing else (Fig. 30) 768. With the director in place the pedicle is doubly ligated with a transfixion non-absorbable suture. The lobe is then grasped with a pair of tenaculum forceps and rotated medially. The inferior thyroid artery, identified by blunt dissection of the space between the trachea and common carotid artery, is under-run cleanly and precisely with a ligature mounted on an aneurysm needle. If this is placed laterally it is ready for tying in continuity avoiding involvement of the recurrent laryngeal nerve and parathyroids. Gentle traction on this ligature often throws the recurrent laryngeal nerve into prominence as it runs up at an acute angle from the mediastinum to reach the tracheo-oesphageal groove before assuming its intimate relationships with the branches of this artery. When the nerve is not evident an aberrant course should be suspected; this may be lateral or anterior to the trachea or even non-recurrent. The nerve can confidently be identified by its white colour, fine longitudinal surface vein, lack of pulsation, and lack of elasticity. Proceeding with the operation without having identified the nerve is hazardous. The thyroid lobe is freed inferiorly by isolating and dividing between ligatures the inferior thyroid veins, and the thyroidea ima artery where present. During this manoeuvre the recurrent laryngeal nerve should be kept in view and avoided at all times. The inferior parathyroid gland may be seen at this stage, especially if ectopic, lying in the thyrothymic ligament. This and its blood supply will be preserved if the veins are swept medially and secured close to the gland. In this form of thyroidectomy the parathyroids are not specifically identified; attempting to do so may jeopardize their blood supply. If a parathyroid gland seems to be inadvertently excised or devascularized it can be diced into 1 mm cubes and autotransplanted into the adjacent sternomastoid muscle. The surgeon then decides how much thyroid tissue to leave behind. The empirical formula of resecting seven-eighths and leaving one-eighth of the gland renders a large number of patients euthyroid. The merit of this approach is that it requires no modification for varying sizes of gland, but it has the disadvantage that it does not take into account the age of the patient (generally the younger the patient the more radical the resection needs to be) or the presence of antithyroid autoantibodies (which call for less radical excision). Attempts to standardized the size of the thyroid remnant to 3 to 4 g of tissue on each side, assessed by linear measurement or dental wax impressions, are not only highly inaccurate but meaningless. Having decided on the size of the thyroid remnant, small artery forceps are placed along the line of the incision on the posterolateral aspect of the surgical capsule of the gland. Placement above the level defined by the anterior surface of the trachea allows injury to the recurrent laryngeal nerve and parathyroids to be minimized. The gland is then incised with a scalpel blade directed obliquely down towards the trachea (Fig. 31) 769. This procedure is then performed on the opposite side of the neck. Both lobes and isthmus having been freed the gland now remains attached only by the pyramidal lobe or fibrous remnant of the thyroglossal tract. This requires careful dissection upwards so that no additional thyroid tissue or blood supply is overlooked. The thyroid remnants are then sutured to the pretracheal fascia with a continuous absorbable suture in a herringbone fashion, picking up the surgical capsule and rolling the gland towards the midline and away from the recurrent laryngeal nerves (Fig. 32) 770. As well as having an haemostatic effect, this ensures that the fibrotic reaction around the thyroid is well away from important structures, the neck requires further exploration at a later date. The thyroid bed should usually be drained on each side: where the dead space is modest a suction drain is ideal. After flexing the head the strap muscles, if divided, are rejoined by interrupted sutures and then approximated in the midline. Finally the platysma is closed and then the skin closed either with clips or a subcuticular suture.

This procedure is appropriate when a large multinodular goitre needs to be reduced in size. The standard exposure of the thyroid and subtotal excision is performed as described above. As much normal tissue as possible is left, consistent with a modest lateral remnant on each side which is not evident when the patient swallows. The isthmus or pyramidal lobe should be removed, even if apparently normal, since compensatory hypertrophy at that site is particularly unacceptable cosmetically.

Nearly all retrosternal goitres can be removed via a cervical incision, which should be placed lower than the conventional incision already described. However if preoperative symptoms and investigations indicate that the chest may need to be opened then the anterior chest wall is prepared and draped accordingly. In this instance the services of an experienced anaesthetist are imperative, especially if the airway is severely compromised. It is often safer to withhold sedative premedication and to rely on rapid intubation of the conscious patient, after spraying the vocal cords with local anaesthetic. Wholly or partially intrathoracic goitres derive their arterial supply from the superior and inferior arteries in the neck, and these should be secured in the usual way. Once the upper pole has been freed an attempt should be made to dissect the retrosternal portion of the lobe with the index finger, generally easing it upwards. Minimal force should be used to avoid damage to the recurrent laryngeal nerves, which cannot always be visualized. If this manoeuvre fails intracapsular enucleation of the retrosternal goitre may be appropriate; if retrosternal thyroid malignancy is suspected or if surgery is being performed for a recurrent goitre, formal splitting of the sternum is appropriate. An incision is made in the midline down to the periosteum, with cutting diathermy from the suprasternal notch to the xiphisternum (Fig. 33) 771. The parietal pleura is freed in the midline and deviated laterally; the retrosternal goitre is then removed along routine lines and the chest closed by accurately reapproximating the sternum using wire sutures. A retrosternal drain is brought out superiorly and attached to an underwater seal to control any small pneumothorax which might be present.

Thyroid lobectomy should always be for the treatment of a non-toxic solitary nodule which may prove to be malignant. If malignancy is confirmed on histological examination of frozen section total thyroidectomy may be appropriate, depending on cell type. The approach to the thyroid is standard but the subtotal excision technique described earlier differs in several important ways. At no stage is the gland grasped with tissue forceps for traction: this may rupture a malignant focus, with spillage of tumour cells. Multicentric tumour deposits or capsular invasion must be assumed to be present. The entire lobe, isthmus, and the midline portion of the contralateral lobe should therefore be removed, although if the recurrent laryngeal nerve or parathyroids may be compromised it is better to leave a small amount of thyroid tissue and ablate this later with radio-iodine. Blood is supplied to each parathyroid via an end artery arising from the inferior thyroid artery, but collaterals to this artery are probably picked up on the thyroid capsule from the oesophageal and tracheal vessels. It is better, therefore, not to ligate the inferior thyroid artery in continuity but to trace out each of its terminal branches and individually clip and divide these between mosquito forceps as they enter the false capsule. Concurrently, the recurrent laryngeal nerve is traced out along its course. As it traverses Berry's ligament to gain access to the larynx damage will be avoided by dissecting the nerve free under direct vision. Local invasion may prevent complete removal of thyroid malignancy, notably on the side of the larynx and oesophagus. In these circumstances the extent of the residual tumour should be marked with small clips to assist the radiotherapist in planning subsequent treatment fields.

The standard Kocher incision is extended on one or both sides (Figs. 34, 35) 772,773 to allow routine exposure of the thyroid gland. If the malignancy involves the strap muscles or sternomastoid on one side these are resected en bloc with the thyroid, as described previously. The plane between the sternomastoid and strap muscles is opened up and the carotid sheath exposed. Involvement of lymph nodes of the internal jugular chain, extending to the posterior cervical and supraclavicular groups, can be detected if the sternal and clavicular heads of the sternomastoid are detached, and the muscle rotated upwards. This provides excellent exposure yet preserves the blood supply (occipital artery) and nerve supply (accessory). The muscle can be reattached on completion of the nodal dissection. Great care is needed when removing the upper and lower deep cervical nodes and their surrounding fat from the surface of the internal jugular vein. However, if the latter is heavily affected it too will require excision. The vagus and phrenic nerves are easily identified and preserved; however, the thoracic duct on the left and the main lymphatic duct on the right are easily damaged and if this occurs the affected duct should be tied off rather than repaired.

In competent hands thyroid surgery is associated with a low morbidity rate and no mortality. There are, however, local and specific complications which can severely compromise the outcome and be life threatening. The majority are avoidable with sound surgical technique and good preparation, particularly in thyrotoxic patients.

This is typically reactionary and is a potential problem in the first 24 h after surgery. Failure to secure the superior thyroid vessels efficiently, preferably with a transfixion suture, is associated with the risk of serious blood loss. Inadequate control of the inferior and middle thyroid vein may also have serious consequences. Major haemorrhage deep to the strap muscles must be recognized quickly: this may cause pressure on the airway within a confined space and rapid laryngeal and subglottic oedema. Medical and nursing staff need to be aware of the significance of pallor, respiratory difficulty, stridor, and swelling of the wound. The absence of blood loss from drains is not a reliable indicator of haemostasis since these can block easily. Any haematoma should be evacuated immediately, and intubation or tracheostomy may be necessary to avert a potentially life-threatening situation. Clip removers and a pair of artery forceps should be readily available at the bedside of all patients following thyroidectomy. These will allow the incision and the strap muscles to be opened. If stridor persists, skilled anaesthetic help is needed to perform intubation, which may be difficult in the presence of oedema. In the absence of such help a mini-tracheostomy or large medicut needle and cannula (No.12 blue) inserted percutaneously through the cricothyroid membrane or between the tracheal rings should stabilize the patient until haemorrhage can be arrested.

The incidence of permanent and transient damage to the nerve is low (less than 0.1 per cent and 2–4 per cent, respectively). It is largely avoidable if the surgeon routinely seeks to identify the nerve on each side during all operations on the gland. Loss of vocal power and huskiness is often evident for 2 or 3 days after surgery; this is most likely to be due to oedema and is relieved by local anaesthetic lozenges and/or humidified air. Persistence of symptoms may indicate neuropraxia, caused by stretching or crushing of the nerve; this is reversible and recovers over several weeks or months. Permanent damage will result if the nerve is divided or ligated and is more likely to occur when the anatomy is distorted, for example with recurrent or malignant goitres. Unilateral injury may be asymptomatic and will undetected due to compensatory hyperadduction of the unaffected cord unless routine postoperative laryngoscopy is performed. Symptomatic unilateral cord paralysis improves if the affected cord is stabilized in adduction by the submucous injection of Teflon under direct laryngoscopy. The effects of bilateral nerve injury are likely to be temporary but pose an immediate problem when the patient is extubated at the end of surgery since the unopposed adductor action of the cricothyroid muscles closes the glottis to such an extent that the least exertion results in airway obstruction. The patient must be promptly reintubated, paralysed, and ventilated whilst hydrocortisone is given 100 mg three times daily to combat the oedema and inflammatory response. The patient can usually be successfully extubated within 48 h; if this extubation fails tracheostomy is required. The permanent nature of laryngeal damage should not be accepted unless it lasts for more than 9 months. Exploration and resuture of the nerve, with grafting when necessary, is now feasible, as is the anastomosis of the hypoglossal and recurrent nerves.

The true incidence of this injury is unknown due to the lack of any objective test of function until recently. A change in the voice, such as loss of pitch and inability to make explosive sounds, makes damage likely. Voice analysis using a Visipitch oscilloscope will help to confirm this damage, which may occur in up to 25 per cent of patients. The majority of patients will recover since the nerve has only been stretched. If no improvement is evident after 3 months, it is unlikely to occur. Bilateral damage results in a very flat, hoarse voice that tires easily.

The serum calcium level should be monitored postoperatively since patients without overt hypoparathyroidism may develop vague lethargy and depression, insidious cataracts, mental deterioration, and psychosis. Hypocalcaemia due to parathyroid deficiency will usually be evident within 1 week of operation and should be suspected if the patient appears unduly agitated or depressed or hyperventilates. Circumoral tingling is generally the first and most sensitive indicator of a low serum calcium; paraesthesia in the fingers and toes preceding frank tetany is seen when hypocalcaemia is profound. Tapping over the facial nerve will cause contraction of the facial muscles (Chvostek–Weiss sign); however, this phenomenon may also be observed in 10 to 15 per cent of normal individuals. Carpopedal spasm, provoked by occlusion of the circulation to the arm (Trousseau's sign), indicates severe hypocalcaemia: intravenous infusion of 10 ml of 10 per cent calcium gluconate (given slowly to avoid cardiac arrest in systole) is required. This infusion may need to be repeated every 4 to 6 h. Oral effervescent calcium should also be administered 4 to 6 g daily, depending on response. If hypocalcaemia persists, vitamin D (calciferol 25 000–100 000 units) and 2 to 3 g oral calcium per day are given until a normocalcaemic state is achieved. Signs and symptoms of hypocalcaemia will recur in these patients at times of metabolic stress, such as pregnancy or the menopause.

The ability of the thyroid to produce sufficient thyroxine after thyroidectomy reflects not only the size of the remnant but also the pre-existing pathological processes within the gland. Hypothyroidism is inevitable after total thyroidectomy or malignancy, but is less predictable after, for example, a thyroid lobectomy to remove a benign solitary nodule. Avoiding hypothyroidism is one of the main challenges when operating for thyrotoxicosis. Factors affecting postoperative thyroid function include the severity of disease prior to surgery; the age of the patient; the presence of high levels of antithyroid autoantibodies before surgery; the size of the gland and evidence of lymphoid infiltration on histology; and how much of the gland is removed. An experienced surgeon can treat patients with resultant hypothyroidism rates of 10 to 15 per cent and persistent hyperthyroidism rates below 5 per cent. Hypothyroidism with rising TSH levels should be allowed to develop over 6 weeks after total thyroidectomy for malignancy (notably follicular lesions). A radio-iodine scan will then identify possible distant metastases, which can be ablated. Thereafter, T&sub3; (50–100 &mgr;g/day) is then administered in preference to T&sub4; by virtue of its shorter biological half-life (1 week), which enables repeat scans to be performed with minimal delay. Once isotope ablation of residual disease has been achieved conversion to T&sub4; is appropriate. The dose required shows great inter-individual variation, the majority only requiring 0.2 to 0.3 mg/day. Nearly all patients undergoing surgery for thyrotoxicosis become biochemically hypothyroid for 2 to 3 months after surgery; no correction is necessary as the majority will then stabilize in a euthyroid state. Clinical assessment should be maintained for at least 2 years, during which serum thyroxine and TSH levels should be monitored: a small percentage of patients will become clinically hypothyroid and require T&sub4; supplementation (0.1 to 0.2 mg daily). Routine administration of T&sub4; (0.1 mg daily) is recommended for all patients undergoing surgery for non-toxic, diffuse, or multinodular goitres since failure to suppress TSH drive can result in recurrent goitre, even if hypothyroidism is subclinical.

Collapse of the trachea, the wall of which has become softened due to chondromalacia, occasionally occurs following removal of a long-standing goitre, especially if retrosternal. Such patients usually also suffer laryngeal oedema and reduced movement of the vocal cords, following difficult intubation and delivery of the lobes. Whenever the trachea is markedly soft and narrow, an elective tracheostomy should be performed.

This is now very rare, with the improved methods of control of thyrotoxicosis, but when fully expressed, is characterized by high fever, tachycardia (atrial fibrillation), extreme restlessness, and delirium. High doses of antithyroid drugs (Neo Mercazole (carbimazole) 30 mg immediately and then 15 mg 8-hourly), plus 1 g of sodium iodide IV should be given promptly. Propranolol (2 mg) is slowly infused IV, with electrocardiographic control. Fluid replacement, ice pack cooling, and sedation may help to abort the crisis.

This rare complication results from deep, forceful retraction on the carotid sheath, producing Horner's syndrome. This is notable by the absence of the vascular dilatation component. The resulting myosis and ptosis are frequently permanent.

The deposition of excessive collagen in the scar to form a keloid is an unpredictable complication, but is said to be more prevalent in negroes, redheads, and in those undergoing surgery during pregnancy. Unless the scar can be excised and adapted to conform more readily to Langer's lines reoperation is unlikely to confer any improvement, but topical steroids and low dose irradiation may prevent recurrence. Infection is an uncommon complication and when it occurs a foreign body should be suspected; the most common offender is non-absorbable suture material. Rarely, sensitivity to the nickel clips used for skin closure results in blistering and breakdown.

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