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THYROID GLAND

DISEASE

These are common, affecting some 5% of the population, predominantly females. The thyroid axis is involved in the regulation of cellular differentiation and metabolism in virtually all nucleated cells, so that disorders of thyroid function have diverse manifestations. In addition, structural diseases in the thyroid gland, such as goitre, commonly occur without abnormal thyroid function.

T3 and T4 circulate in plasma almost entirely (> 99%) bound to transport proteins, mainly thyroxine-binding globulin (TBG). It is the unbound or free hormones which diffuse into tissues and exert diverse metabolic actions. While it is possible to measure the concentration of total or free T3 & T4 in plasma, the advantage of the free hormone measurements is that they are not influenced by changes in the concentration of binding proteins; in pregnancy, for example, TBG levels are increased and total T3 & T4 may be raised, but free thyroid hormone

levels are normal.

PRESENTING PROBLEMS IN THYROID DISEASE

The most common presentations of thyroid disease are thyrotoxicosis (i.e. hyperthyroidism), hypothyroidism and goitre (i.e. enlargement of the thyroid). In addition, ready access to accurate tests of thyroid function and an increasing tendency to screen certain populations (e.g. elderly, hospitalised) have led to the identification of patients with abnormal results who are either asymptomatic or have non-specific complaints such as tiredness and weight gain.

THYROTOXICOSIS

Management

Definitive treatment of thyrotoxicosis depends on the underlying cause, and may include antithyroid drugs, radioactive iodine or surgery. In all patients with thyrotoxicosis a non-selective β-adrenoceptor antagonist (β-blocker), such as propranolol (160 mg daily) or nadolol (40-80 mg daily), will alleviate but not abolish symptoms within 24-48 hours. Beta-blockers cannot be recommended for long-term treatment, but they are extremely useful in the short term, e.g. for patients awaiting

hospital consultation or following I131 therapy.

Atrial fibrillation in thyrotoxicosis

Thyrotoxicosis is an important cause of atrial fibrillation; in one series of patients presenting with atrial fibrillation the prevalence of thyrotoxicosis was 26%, while atrial fibrillation is present in about 10% of all patients with thyrotoxicosis. The incidence increases with age so that almost half of all males with

thyrotoxicosis over the age of 60 are affected.

Moreover, subclinical thyrotoxicosis is a risk factor for atrial fibrillation. Characteristically, the ventricular rate is little influenced by digoxin, but responds to the addition of a β-blocker. Thrombo-embolic vascular complications are particularly common in thyrotoxic atrial fibrillation so that anticoagulation with warfarin is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial fibrillation will spontaneously revert to sinus rhythm in 50% of patients∼ . In the remainder, cardioversion will restore sinus

rhythm in up to 50%.

Thyrotoxic crisis ('thyroid storm)

This is a rare and life-threatening increase in the severity of the clinical features of thyrotoxicosis. The most prominent signs are fever, agitation, confusion, tachycardia or atrial fibrillation and, in the older patient, cardiac failure. It is a medical emergency and, despite early recognition and treatment, the mortality rate is 10%.

Thyrotoxic crisis is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis. It may also develop shortly after subtotal thyroidectomy in an ill-prepared patient or within a few days of I131 therapy when acute irradiation damage may lead to a transient rise in serum thyroid hormone levels.

Patients should be rehydrated and given a broad-spectrum antibiotic. Propranolol is rapidly effective orally (80 mg 6-hourly) or intravenously (1-5 mg 6-hourly). Sodium ipodate (500 mg per day orally) will restore serum T3 levels to normal in 48-72 hours. This is a radiographic contrast medium which not only inhibits the release of thyroid hormones, but also reduces the conversion of T3 to T4 and is, therefore, more effective than potassium iodide or Lugol's solution. Dexamethasone (2 mg 6-hourly) and amiodarone have similar effects. Oral carbimazole 40-60 mg daily inhibits the synthesis of new thyroid hormone. If the patient is unconscious or uncooperative, carbimazole can be administered rectally with good effect, but no preparation is available for parenteral use. After 10-14 days the patient can usually be maintained

on carbimazole alone.

HYPOTHYROIDISM

Management most patients do not require specialist review and will

require life-long thyroxine therapy. It is customary to start slowly and a dose of 50 μg per day should be given for 3 weeks, increasing thereafter to 100 μg per day for a further 3 weeks and finally to a maintenance dose, usually 100-150 μg per day. Thyroxine has a half-life of 7 days so it should always be taken as a single daily dose and at least 6 weeks should pass before repeating thyroid function tests and adjusting the dose, usually in increments of 25 μg per day. Patients feel better within 2-3 weeks. Reduction in weight and periorbital puffiness occurs quickly, but the restoration of skin and hair texture and resolution of any effusions may take 3-6

months.

The correct dose of thyroxine in the long term is that which restores serum TSH to within the reference range. To achieve this, serum T4 will usually be in the upper part of the normal range or even slightly raised, because the T3 required for receptor activation is derived exclusively from conversion of T4 within the target tissues without the usual contribution from thyroid secretion. Some physicians advocate combined replacement with T4 & T3 but this approach remains controversial and no ideal preparation exists. Some patients remain symptomatic despite normalisation of TSH and may wish to take extra thyroxine which suppresses TSH values. However, there is evidence that suppressed TSH is a risk factor for osteoporosis and atrial fibrillation so this approach cannot be

recommended .

It is important to measure thyroid function every 1-2 years once the dose of thyroxine is stabilised. This encourages patient compliance with therapy and allows adjustment for variable underlying thyroid activity and other changes in thyroxine requirements. In some poorly compliant patients, thyroxine is taken diligently or even in excess for a few days prior to a clinic visit, resulting in the seemingly anomalous combination of a high serum T4

and high TSH .

Thyroxine replacement in ischaemic heart disease

Hypothyroidism and ischaemic heart disease are both common, so inevitably they will sometimes occur together. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are well-recognised complications of thyroxine replacement, even using doses as low as 25

μg per day.

In patients with known ischaemic heart disease, thyroxine should be introduced at low dose and increased very slowly under specialist supervision. It has been suggested that T3 has an advantage over T4 , since T3 has a shorter half-life and any adverse effect will reverse more quickly, but the more distinct peak in hormone levels after each dose of T3 is a disadvantage. Approximately 40% of patients with angina cannot tolerate full replacement therapy despite the use of β-blockers and vasodilators; coronary artery surgery or balloon angioplasty can be performed safely in such patients and, if successful, allow full replacement dosage of

thyroxine in the majority .

Hypothyroidism in pregnancy Most pregnant women with primary

hypothyroidism require an increase in the dose of thyroxine of 50 ∼ μg daily to maintain normal TSH levels. This may reflect increased metabolism of thyroxine by the placenta and increased serum thyroxine-binding globulin during pregnancy, resulting in an increase in the total thyroid hormone pool to maintain the same free T4 & T3 concentrations. Recent research suggests that inadequate maternal T4 therapy is associated with impaired cognitive development in their offspring. Serum TSH and free T4 should be measured during each trimester and the dose of

thyroxine adjusted to maintain a normal TSH .

Myxoedema coma This is a rare presentation of hypothyroidism in

which there is a depressed level of consciousness, usually in an elderly patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsions are not uncommon and cerebrospinal fluid (CSF) pressure and protein content are raised. The mortality rate is 50% and survival depends upon early recognition and treatment of hypothyroidism and other factors contributing to the altered consciousness level, e.g. drugs such as phenothiazines, cardiac failure, pneumonia,

dilutional hyponatraemia and respiratory failure.

Myxoedema coma is a medical emergency and treatment must begin before biochemical confirmation of the diagnosis. Thyroxine is not usually available for parenteral use so triiodothyronine is given as an intravenous bolus of 20 μg followed by 20 μg 8-hourly until there is sustained clinical improvement. In survivors there is a rise in body temperature within 24 hours and, after 48-72 hours, it is usually possible to substitute oral thyroxine in a dose of 50 μg per day. Unless it is apparent that the patient has primary hypothyroidism, e.g. thyroidectomy scar or goitre, the thyroid failure should be assumed to be secondary to hypothalamic or pituitary disease and treatment given with hydrocortisone 100 mg i.m. 8-hourly, pending the results of T4, TSH and cortisol concentration. Other measures include slow rewarming, cautious use of intravenous fluids, broad-spectrum antibiotics and high-flow oxygen. Occasionally,

assisted ventilation may be necessary.

ASYMPTOMATIC ABNORMAL THYROID FUNCTION

TEST RESULTS

Subclinical thyrotoxicosis: The serum TSH is undetectable and the serum

T3&T4 lie in the upper parts of their respective reference ranges. This combination is most often found in older patients with multinodular goitre. These patients are at increased risk of atrial fibrillation and osteoporosis and hence the consensus view is that such patients have mild thyrotoxicosis and require therapy, usually with I131. Otherwise, annual review is essential as the conversion rate to overt thyrotoxicosis with elevated T4 &/or T3 concentrations is 5% each

year.

Subclinical hypothyroidism

The serum TSH is raised and the serum T4&T3 concentrations are usually in the lower part of their respective reference ranges. It may persist for many years, although there is a risk of progression to overt thyroid failure, particularly if antibodies to thyroid peroxidase are present in the serum or if the TSH rises above 10 mU/l. In patients with non-specific symptoms a trial of thyroxine therapy may be appropriate. In those with positive autoantibodies or TSH > 10 mU/l it is better to treat the thyroid failure early rather than risk loss to follow-up and subsequent presentation with profound hypothyroidism. Thyroxine should be given in a dose sufficient to restore the serum TSH concentration to

normal.

Non-thyroidal illness ('sick euthyroidism)

In patients with systemic illness (e.g. myocardial infarction, pneumonia) there is decreased peripheral conversion of T4 to T3 and alterations of binding proteins and their affinity for thyroid hormones. In addition, serum TSH concentrations may be subnormal as a result of the illness itself or the use of drugs such as dopamine or corticosteroids. The most common combination is a low serum TSH, raised T4 and normal or low T3, but many patterns of thyroid function tests can be seen, dependent upon the type of assay used. During convalescence, serum TSH concentrations may increase to levels found in primary hypothyroidism. It follows that biochemical assessment of thyroid function should not be undertaken in patients with non-thyroidal illness, unless there is good evidence of concomitant thyroid disease, e.g. goitre, exophthalmos. If an abnormal result is found, treatment should only be given with specialist advice and the tests

should be repeated after recovery.

AUTOIMMUNE THYROID DISEASE

Thyroid diseases are amongst the most prevalent antibody-mediated autoimmune diseases and are associated with other organ-specific autoimmunity. Autoantibodies may produce inflammation and destruction of thyroid tissue resulting in hypothyroidism, goitre (in Hashimoto's thyroiditis) or sometimes even transient thyrotoxicosis ('Hashitoxicosis'), or they may stimulate the TSH receptor to cause thyrotoxicosis (in Graves' disease). There is overlap between these conditions, since some

patients have multiple autoantibodies.

GRAVES' DISEASE

The most common manifestation is thyrotoxicosis with or without a diffuse goitre. Graves' disease also causes ophthalmopathy and rarely pretibial myxoedema. These features usually occur in thyrotoxic patients, but can occur in the absence of thyroid dysfunction. Graves' disease can occur at any age but is unusual before puberty and most

commonly affects women aged 30-50 years.

Pathophysiology The thyrotoxicosis results from the production of

IgG antibodies directed against the TSH receptor on the thyroid follicular cell, which stimulate thyroid hormone production and, in the majority, goitre formation. These antibodies are termed thyroid-stimulating immunoglobulins or TSH receptor antibodies (TRAb) and can be detected in the serum of 80-95% of patients with Graves' disease. The concentration of TRAb in the serum is presumed to fluctuate to account for the natural history of Graves' thyrotoxicosis. The ultimate thyroid failure seen in some patients is thought to result from the presence of blocking antibodies against the TSH receptor, and from tissue destruction by cytotoxic

antibodies and cell-mediated immunity.

Management

Graves' ophthalmopathy

This condition is immunologically mediated, but the autoantigen that causes the local accumulation of lymphocytes has not been identified. Within the orbit (and the dermis) there is cytokine-mediated proliferation of fibroblasts which secrete hydrophilic glycosaminoglycans. The resulting increased interstitial fluid content, combined with a chronic inflammatory cell infiltrate, causes marked swelling and ultimately fibrosis of the extraocular muscles and a rise in retrobulbar pressure. The eye is displaced forwards (proptosis, exophthalmos) and in more

severe cases there is optic nerve compression.

The majority of patients require no treatment other than reassurance. Methylcellulose eye drops and gel counter the gritty discomfort of dry eyes, and tinted glasses or side shields attached to spectacle frames reduce the excessive lacrimation triggered by sun or wind. Severe inflammatory episodes are treated with oral glucocorticoids (e.g. prednisolone 60 mg daily) and sometimes orbital irradiation. Loss of visual acuity is an indication for urgent surgical decompression of the orbit. In 'burnt out' disease, surgery to the eyelids and/or ocular muscles may improve conjunctival exposure,

cosmetic appearance and diplopia.

HASHIMOTO'S THYROIDITIS The nomenclature of autoimmune hypothyroidism can be

confusing. Some authorities reserve the term 'Hashimoto's thyroiditis' for patients with positive thyroid peroxidase autoantibodies and a firm goitre who may or may not be hypothyroid, and use the term 'spontaneous atrophic hypothyroidism' for hypothyroid patients without a goitre in whom TSH receptor-blocking antibodies may be more important than antiperoxidase antibodies. However, these syndromes can both be considered as variants of Hashimoto's thyroiditis since both are characterised by destructive lymphoid infiltration of the thyroid, ultimately leading to a varying degree of fibrosis which accounts for the varying degree of thyroid enlargement. In association with the lymphoid thyroid infiltration there is an increased risk of thyroid lymphoma, although this is an exceedingly rare

complication.

Hashimoto's thyroiditis increases in incidence with age and affects 3.5 per 1000 women and 0.8 per 1000 men ∼each year. Many present with a small or moderately sized diffuse goitre, which is characteristically firm or rubbery in consistency. The goitre may be soft, however, and impossible to differentiate from simple goitre by palpation alone. Around 25% of patients are hypothyroid at presentation. In the remainder, serum T4 is normal and TSH normal or raised, but these patients are at risk of developing overt hypothyroidism in future years. Thyroid peroxidase antibodies are present in the serum in > 90% of patients with Hashimoto's thyroiditis. In those under the age of 20 years, antinuclear factor (ANF) may also be positive. Thyroxine therapy is indicated not only for hypothyroidism, but also sometimes for goitre shrinkage. In this context, the dose of thyroxine should be sufficient to suppress serum TSH to low but

detectable levels.

SUBACUTE (DE QUERVAIN'S) THYROIDITIS

In its classical painful form, subacute thyroiditis is a virus-induced (e.g. Coxsackie, mumps or adenovirus) transient inflammation of the thyroid gland. There is pain in the region of the thyroid that may radiate to the angle of the jaw and the ears, and is made worse by swallowing, coughing and movement of the neck. The thyroid is usually palpably enlarged and tender. Systemic upset is common. Affected patients are usually females aged 20-40 years.

Painless transient thyroiditis also occurs, sometimes after viral infection and sometimes in

patients with underlying autoimmune disease.

In both painless and painful varieties, inflammation in the thyroid gland is associated with release of colloid and stored thyroid hormones, but also with damage to follicular cells and impaired synthesis of new thyroid hormones. As a result, T4&T3 levels are raised for 4-6 weeks until the pre-formed colloid is depleted. Thereafter, there is usually a period of hypothyroidism of variable severity before the follicular cells recover and normal thyroid function is restored within 4-6 months. In the thyrotoxic phase, the iodine uptake is low because the damaged follicular cells are unable to trap iodine and because endogenous TSH secretion is suppressed. Low-titre thyroid autoantibodies appear transiently in the serum, and the erythrocyte sedimentation rate (ESR) is usually raised. High titre autoantibodies suggest an underlying autoimmune pathology and risk of recurrence and ultimate progression to

hypothyroidism .

The pain and systemic upset usually respond to simple measures such as non-steroidal anti-inflammatory drugs (NSAIDs). Occasionally, however, it may be necessary to prescribe prednisolone 40 mg daily for 3-4 weeks. The thyrotoxicosis is mild and treatment with propranolol or nadolol is usually adequate. Antithyroid drugs are of no benefit because thyroid hormone synthesis is impaired rather than enhanced. Careful monitoring of thyroid function and symptoms is required so that thyroxine can be prescribed temporarily in the hypothyroid phase. Care must be taken to identify patients presenting with hypothyroidism who are in the later stages of a transient thyroiditis, since they are unlikely to require life-

long thyroxine therapy.

POST-PARTUM THYROIDITIS

The maternal immune response, which is modified during pregnancy to allow survival of the fetus, is enhanced after delivery and may unmask previously unrecognised subclinical autoimmune thyroid disease. Surveys have shown that transient biochemical disturbances of thyroid function, i.e. thyrotoxicosis, hypothyroidism and thyrotoxicosis followed by hypothyroidism, occur in 5-10% of women within 6 months of delivery.

Those affected are likely to have antithyroid peroxidase antibodies in the serum in early pregnancy. Symptoms of thyroid dysfunction are rare and there is no association between postnatal depression and abnormal thyroid function tests. However, symptomatic thyrotoxicosis presenting for the first time within 6 months of childbirth is likely to be due to post-partum thyroiditis and the diagnosis is confirmed by a negligible radio-isotope uptake. The clinical course and treatment are similar to painless subacute thyroiditis (see above). Post-partum thyroiditis tends to recur after subsequent pregnancies and eventually patients progress over a period of years to permanent

hypothyroidism.

SIMPLE DIFFUSE GOITRE

This form of goitre usually presents between the ages of 15 and 25 years, often during pregnancy, and tends to be noticed, not by the patient, but by friends and relatives. Occasionally, there is a tight sensation in the neck, particularly when swallowing. The goitre is soft and symmetrical and the thyroid is enlarged to two or three times its normal size. There is no tenderness, lymphadenopathy or overlying bruit. Concentrations of T3&T4 and TSH are normal and no thyroid autoantibodies are detected in the serum. No treatment is necessary and in most cases the goitre regresses. In some, however, the unknown stimulus to thyroid enlargement persists and, as a result of recurrent episodes of hyperplasia and involution during the following 10-20 years, the gland becomes multinodular

with areas of autonomous function.

MULTINODULAR GOITRE

Patients with thyroid enlargement in the absence of thyroid dysfunction or positive autoantibodies (i.e. with 'simple goitre', see above) as young adults may progress to develop nodules. These nodules grow at varying rates and secrete thyroid hormone 'autonomously', thereby suppressing TSH-dependent growth and function in the rest of the gland. Ultimately, complete suppression of TSH occurs in about 25% of cases, with T3&T4 levels often within the normal range but sometimes elevated. Opinions differ as to whether the nodules represent multiple adenomas or focal hyperplasia. There are reports that the prevalence of foci of thyroid cancer is increased in multinodular goitres, but for practical purposes patients can be reassured that it is a benign condition and malignancy need only be considered in patients with a large 'dominant' nodule that is 'cold' (i.e. does not take up radioisotope).

Clinical features and investigations

Multinodular goitre is usually diagnosed in patients presenting with thyrotoxicosis, a large goitre with or without tracheal compression, or sudden painful swelling caused by haemorrhage into a nodule or cyst. The goitre is nodular or lobulated on palpation and may extend retrosternally; however, not all mutinodular goitres causing thyrotoxicosis are easily palpable. Very large goitres may cause mediastinal compression with stridor, dysphagia and obstruction of the superior vena cava. Hoarseness due to recurrent laryngeal nerve palsy can occur, but is far more suggestive of

thyroid carcinoma.

The diagnosis is confirmed by a radioisotope thyroid scan and/or ultrasonography. In patients with large goitres a flow-volume loop is a good screening test for significant tracheal compression. If intervention is contemplated, a chest X-ray may be helpful, but CT or MRI of the thoracic inlet is optimal to quantify the degree of tracheal displacement or compression and the extent of retrosternal extension. In those with a 'dominant', 'cold' nodule, fine needle aspiration is

indicated to exclude thyroid cancer .

Management

If the goitre is small, no treatment is necessary but annual review should be arranged as the natural history is progression to a toxic multinodular goitre. Partial thyroidectomy is indicated for large goitres which cause mediastinal compression or which are cosmetically unattractive. I131 can result in a significant reduction in thyroid size and may be of value in elderly patients. Unfortunately, recurrence 10-20 years later is not uncommon. Thyroxine is of no benefit in shrinking multinodular goitres and may serve only to

aggravate any associated thyrotoxicosis.

In toxic multinodular goitre treatment is usually with I131. The iodine uptake is lower than in Graves' disease so a higher dose is employed (555-1850 MBq, 15-50 mCi) and hypothyroidism is less common. In thyrotoxic patients with a large goitre, partial thyroidectomy may be indicated. Long-term treatment with antithyroid drugs is not usually appropriate as relapse is invariable after drug withdrawal . Asymptomatic patients with subclinical thyrotoxicosis are increasingly being treated with I131 on the grounds that a suppressed TSH is a risk factor for atrial fibrillation and, particularly in post-

menopausal women, osteoporosis .