The Pharmaceutical Journal Vol 265 No 7109 p240-244
August 12, 2000 Continuing education

Endocrinology

Thyroid disease

By Ian MacFarlane, MD, FRCP

This article discusses the diagnosis and treatment of thyroid disorders

Thyroid disorders are common, particularly in women, with up to 5 per cent of the UK population affected by hypo- or hyperthyroidism. Many people also have thyroid enlargement, with or without thyroid dysfunction. The development of thyroid dysfunction may be insidious and therefore the diagnosis and correct treatment may be delayed. On the other hand, many people believe that they have a thyroid problem, particularly an "underactive" thyroid, when they do not. This review outlines the presentations of thyroid disorders and discusses their diagnosis and management.

The thyroid gland

The thyroid is situated in the lower neck overlying the trachea and secretes thyroid hormones, in particular, thyroxine (T4) and tri-iodothyronine (T3). These are under the control of thyroid stimulating hormone (TSH) secreted by the pituitary.
Disorders of the thyroid gland occur frequently and, because of easily available thyroid function testing, general practitioners and hospital doctors can expect to diagnose new cases each year. When both hypothyroidism and hyperthyroidism are first diagnosed, thyroid enlargement may or may not be present. Thyroid enlargement (goitre) can be found with normal thyroid function. Thyroid function tests may be requested because of typical symptoms and signs of hyper- or hypo-thyroidism or because thyroid enlargement has been found. However, large numbers of thyroid function tests are carried out because patients describe vague non-specific symptoms. Doctors are frequently faced with decisions on the management of patients who have little or no clinical signs of thyroid dysfunction, but have abnormal tests. Transient abnormal thyroid tests may also occur. There are many causes for this, including various forms of thyroiditis and inter-current illness (eg, infection). Drugs can also alter the circulating levels of TSH, T4 and T3.

Hypothyroidism

Primary hypothyroidism (failure of thyroid hormone production due to disease, usually autoimmune) is common, occurring in more than 2 per cent of the population. It occurs 10-20 times more frequently in women than men and usually presents in people of middle age and older.¹ Secondary hypothyroidism, which is due to failure of TSH secretion, is rarer and is usually caused by structural hypothalamic-pituitary disorders, eg, pituitary tumours. Congenital hypothyroidism, due to failure of development of the thyroid gland, is very rare and is screened for in infancy. The causes, symptoms and signs of hypothyroidism are shown in Panel 1.
Any person with symptoms or signs suggestive of hypothyroidism (eg, fatigue, cold intolerance, depression, constipation) or who has thyroid enlargement should have a blood thyroid function test carried out by the local laboratory. Also, the following people should be regularly screened, perhaps yearly, for thyroid dysfunction: patients who have had previous thyroid surgery, treatment with radio-iodine or who have hypothalamic-pituitary disorders, and patients who are treated with amiodarone (Cordarone X) or lithium. There is also a national programme of screening for congenital hypothyroidism.
The diagnosis of hypothyroidism must be confirmed biochemically by a blood test in all patients. Once diagnosed, hypothyroidism requires life-long thyroxine replacement therapy and, for many, a monitoring programme for compliance.²
Figure 1 outlines the management strategy for the diagnosis and treatment of hypothyroidism. Patients with obvious signs and symptoms of hypothyroidism, and diagnostic thyroid function tests (an elevated serum TSH level [>10mIU/L] with a low free T4 level [<10 pmol/L]), should be treated with thyroxine. If the patient does not have obvious symptoms or signs of hypothyroidism then a further test for TSH and free T4 should be carried out to confirm a diagnosis. This avoids prescribing unnecessary life-long thyroxine to patients with self limiting, transient thyroiditis or the occasional person who is a victim of laboratory error.

Many people in the general population seek explanations for weight gain, fatigue and mood problems. Thyroid function tests are therefore frequently performed and most are within the normal range. The use of thyroxine treatment in the hope of alleviating symptoms in people with normal thyroid function tests is of no value and is potentially dangerous.

Treatment of hypothyroidism

Thyroxine (levothyroxine sodium, Eltroxin) is the treatment of choice for both primary and secondary hypothyroidism. Initially, thyroxine 50-100µg should be started. A serum TSH level measured after six to eight weeks will indicate whether the dose needs increasing (by a 25-50µg increment).
Caution must be exercised, however, in patients with evidence of ischaemic heart disease and in elderly patients. The initial dose of thyroxine in such patients should be 25µg daily (or even 25µg on alternate days). This can be increased every four to six weeks by 25µg increments as long as there are no untoward cardiac effects, eg, worsening angina. The usual maintenance dose which relieves symptoms and brings the serum TSH level to the normal range is 100-150µg daily, which can be administered as a single dose, usually in the morning.
Many patients taking a sufficient dose of thyroxine replacement to reduce TSH levels to the normal range will have serum free T4 levels in the upper half of the normal range for the general population (or even slightly raised). However, serum free T3 concentrations should be within the normal range in patients taking thyroxine. Some patients will have undetectable serum TSH levels while taking thyroxine. However, the dose need not be reduced if levels of serum free T4 and T3 are normal. In the majority of patients, once the appropriate dose of thyroxine has been established it remains constant. During pregnancy, an increase in the dose of thyroxine, often by 50µg daily, is needed to maintain normal TSH levels.
Most newly diagnosed hypothyroid patients can be managed in general practice although if there are management problems, such as angina, heart failure, amiodarone or lithium treatment, then referral to a hospital specialist is recommended. Hospital referral is also appropriate for patients diagnosed with hypothyroidism in the post-partum period as the condition can be transient. If tests reveal a low free T4 level with a normal TSH level, this may indicate hypothalamic/pituitary disease and further investigations will be necessary.
Annual testing of serum TSH levels in patients taking thyroxine replacement is usually not necessary. However, patients who are unlikely to comply with treatment regimes should have regular measurements of serum TSH which will detect non-compliance. Testing also encourages tablet-taking. A raised TSH level with a normal free T4 level usually indicates intermittent compliance with thyroxine therapy. It is worthwhile repeating tests for TSH and T4 levels after encouraging regular tablet-taking, before increasing the dose of thyroxine.
Patients with severe hypothyroidism and coma thought to be due to hypothyroidism are treated with tri-iodothyronine (liothyronine sodium, Tertroxin). This has a similar action to thyroxine, but is more rapidly metabolised (20µg is equivalent to 100µg of thyroxine). It is used only rarely, when a rapid response is required, at a dose of 5-20µg given by the IV or oral route every 12 hours.

Panel 1: Hypothyroidism

Causes

Primary: Auto-immune and thyroiditis
Post 131I and thyroid surgery
Antithyroid drugs
Iodine deficiency
Congenital absence of thyroid
Secondary: Hypothalamic pituitary disease (thyroid stimulating hormone deficiency)

Symptoms

Tiredness
Constipation
Cold intolerance
Dry skin
Hair loss
Mild weight gain
Depression
Excessive snoring
Hoarseness
Menorrhagia
Carpal tunnel syndrome
Deafness
Psychosis

Signs

Pale, puffy face
Diffuse hair loss
Dry, flaky skin
Peri-orbital oedema
Slow pulse
Croaky voice
Delayed relaxation of reflexes
Occasional goitre
Rarely, stupor and hypothermia

Sub-clinical hypothyroidism Doctors are often faced with the dilemma of a patient with a normal serum free T4 and a raised TSH level but who does not have symptoms or signs of hypothyroidism.² Such patients have sub-clinical hypothyroidism and they require follow-up.
When an isolated raised TSH level is found, TSH testing should be repeated, along with a serum free T4 measurement. Measurement of microsomal (thyroid peroxidase) antibodies should also be carried out. Occasionally, repeat serum TSH measurements are normal, which may indicate an episode of transient thyroiditis or a laboratory error. If the TSH level remains raised (above 5-6 mIU/L), and microsomal antibodies are positive, then treatment with thyroxine should be given. Some patients with sub-clinical hypothyroidism do derive clinical benefit from thyroxine replacement. In addition, replacement therapy will avoid the development of overt hypothyroidism if the patient is lost to follow-up. If the TSH level is only mildly raised (<10mIU/L) without microsomal antibodies, thyroxine replacement may be withheld, but serum TSH and microsomal antibodies should be measured again after three months.

Thyrotoxicosis

Thyrotoxicosis (hyperthyroidism) is usually diagnosed in people between the ages of 20 and 50 years, and affects approximately 2 per cent of women and 0.2 per cent of men. Most cases occur as a result of Grave's disease (which is caused by thyroid stimulating auto-antibodies). Another cause, in 15-20 per cent of cases, is toxic nodular goitre (which usually occurs in older women). A rarer cause is thyroiditis, a usually painless condition in which patients may be transiently thyrotoxic due to an excessive release of stored thyroid hormones.
Other causes of thyrotoxicosis include exogenous iodide administration from the use of radiographic contrast agents, and amiodarone. Amiodarone-induced thyrotoxicosis can be difficult to identify clinically because the drug causes a slow pulse.
A patient presenting with the classical symptoms of thyrotoxicosis, eg, weight loss, palpitations, tremor and heat intolerance, should be a given thyroid function test. Other signs and symptoms of hyperthyroidism are shown in Panel 2. In older patients, the development of atrial fibrillation or unexplained depression, apathy and weight loss, with or without thyroid enlargement, should prompt testing.
Blood thyroid function tests are required in all cases to confirm the diagnosis. A normal serum TSH level will exclude thyrotoxicosis in almost all patients except in very rare cases in patients with thyroid hormone resistance or a TSH-producing pituitary tumour. A low or undetectable serum TSH concentration suggests thyrotoxicosis, but this must be confirmed with free T4 and T3 measurements. In the majority of patients, both free T4 and free T3 levels are raised, but occasionally patients may have T3 toxicosis while their free T4 levels are still within the normal range. In most patients, further tests are unnecessary when planning management.
It is usually easy to differentiate between Grave's disease (which occurs in younger patients with diffuse goitre and ophthalmopathy) from toxic nodular hyperthyroidism (which occurs in older patients with palpable nodular thyroid).
Thyroid antibody measurements and thyroid isotope scanning may help differentiate these two conditions in difficult cases, but only occasionally will they help the management plan. If thyroiditis is suspected, a radio-iodine thyroid uptake test will show low values, but again this is rarely required.

Treatment of hyperthyroidism

Most patients with hyperthyroidism are diagnosed by general practitioners but it is then sensible for a management plan to be agreed with a local endocrinologist. Treatment options include the anti-thyroid drugs carbimazole (Neomercazole) and propylthiouracil, beta-blockers, radio-active iodine (131I) and surgery.^2,3 The management of thyrotoxicosis is summarised in Figure 2.

Beta-blocking agents Beta-blockers are given at diagnosis to relieve many of the symptoms of thyrotoxicosis (particularly palpitations, tremor and anxiety). They should not be given to patients with asthma and should be used cautiously in patients with heart failure. Long-acting agents such as atenolol 50mg or nadolol (Corgard) 80mg are probably preferable as a once daily regime may improve compliance. They can be discontinued after two to six weeks once the symptoms of thyrotoxicosis have subsided.
Carbimazole Carbimazole is the treatment of choice for hyperthyroidism. It is given once daily.
Carbimazole is rapidly metabolised to methimazole, which inhibits the synthesis of thyroid hormones. The aim of treatment is to restore the euthyroid state as soon as possible, with the intention of either achieving a lasting remission in patients with Grave's disease or to prepare patients for surgery or treatment with radio-iodine.
The duration of treatment with carbimazole remains controversial. Some endocrinologists believe that prolonged courses (up to 24 months) will increase the likelihood of achieving lasting remission of Grave's thyrotoxicosis when carbimazole is discontinued. However, this was not supported by a recent study.⁵ Patients with markedly elevated free T4 and free T3 levels at diagnosis, and those who have large goitres, are more likely to relapse when carbimazole is stopped. Therefore, these individuals should receive 12 months or more of treatment.
However, patients with small or impalpable thyroid glands at diagnosis often become quickly euthyroid (within weeks of starting carbimazole) and, if free T4 levels are only mildly raised, then a short course of carbimazole (between four and six months) is often all that is necessary to achieve a prolonged remission.⁴ Clearly a short course of carbimazole is preferable to the patient.

Panel 2: Hyperthyroidism

Causes

Autoimmine Grave's disease
Thyroiditis (often post-partum)
Toxic adenoma or multi-nodular goitre
Amiodarone-induced
Iodine-induced
TSH-secreting pituitary adenoma (very rare)

Symptoms

Weight loss
Exhaustion
Anxiety
Heat intolerance
Sweating
Hunger
Palpitations
Itching
Diarrhoea
Thirst
Occasionally weight gain
Anorexia

Signs

Fine tremor
Tachycardia
Warm skin
Agitation
Goitre common
Thyroid bruits
Onycholysis
Systolic hypertension
Eye signs - lid lag, lid retraction
Exophthalmos
Ankle oedema
Atrial fibrillation
Pretibial myxoedema

The initial dose of carbimazole is 10-40mg a day (depending on the clinical severity of thyrotoxicosis). A clinical and biochemical assessment should be made after four to six weeks. If the symptoms, signs and thyroid hormone levels are settling then a decision can be made to reduce the dose of carbimazole to 5-15mg. Figure 3 shows the typical improvements to be expected in thyroid hormone levels and clinical symptom score in thyrotoxic Grave's disease. It should be noted that patients continue to have symptoms and signs of thyrotoxicosis for some weeks, even after the thyroid hormone levels have reached the normal range.⁴
Some endocrinologists use a "block replacement regime" in which high doses of carbimazole (40mg or more) are given for one to two years combined with thyroxine (100-150µg daily) to avoid the development of hypothyroidism. This regime is given in the hope that high doses may achieve lasting remission. Good evidence for this is lacking and the majority of patients can be satisfactorily treated with a reducing course of carbimazole alone. In pregnancy, a "block-replacement" regime should not be used because thyroxine does not cross the placenta and foetal hypothyroidism can occur.
Permanent remission of Grave's disease after discontinuing carbimazole is achieved in less than 40 per cent of patients. If a patient relapses, a further course of carbimazole or a more definitive treatment (surgery or radio-iodine) can be considered.

Propylthiouracil Propylthiouracil is given to control thyrotoxicosis (in divided doses; starting dose 150-400mg daily, maintenance dose 50-100mg daily) instead of carbimazole.
The two main reasons for using propyl-thiouracil instead of carbimazole are if a patient develops a rash or pruritus with carbimazole (which occurs in 5 per cent of patients) or if a patient is contemplating a pregnancy. There is a suggested association between carbimazole and the development of neonatal aplasia cutis (a nail abnormality) so propylthiouracil is preferred before and during pregnancy.

Serious adverse effects Both carbimazole and propylthiouracil may cause agranulocytosis and, less commonly, hepatitis, aplastic anaemia and lupus-like syndromes. These serious adverse affects occur in approximately 0.3 per cent of patients treated.
Agranulocytosis usually occurs in the first few weeks of treatment although it may develop at any time. Patients should therefore be instructed verbally, and in writing, when starting the drugs, to report symptoms suggestive of infection, especially sore throat. The drug should be stopped promptly if there is clinical or laboratory evidence of neutropenia.
Routine monitoring of blood counts is not indicated, although a full blood count should be performed if there is clinical evidence of infection.⁶ A mild neutropenia is also a well-recognised consequence of thyrotoxicosis.

Radio-active iodine (131I) 131I is the treatment of choice in patients with toxic nodular goitre and is considered for most patients with relapsed Grave's disease. It is increasingly being used as first-line therapy for adults with thyrotoxicosis. 131I is contraindicated in children, during pregnancy and breast feeding.
Doses of 131I are variable and it is difficult to predict the dose an individual patient would require to restore the euthyroid state without causing hypothyroidism. Hypothyroidism does develop in many patients after 131I therapy and life-long follow-up of thyroid function is required.
Carbimazole and propylthiouracil should be withdrawn at least four days before a dose of 131I is given and should not be re-started for at least three days. The use of 131I is not associated with an increase in malignancy apart from with the thyroid itself. There is a slight increase in the apparent risk of thyroid cancer in patients with thyrotoxicosis treated with 131I although this may be due to the underlying disease rather than the radio-iodine.⁷
Finally, patients with significant dysthyroid eye disease should not receive 131I because it may result in a worsening of ophthalmopathy.

Surgery Thyroid surgery is indicated for only a minority of patients with thyrotoxicosis. These include patients with large goitres in whom carbimazole is ineffective, patients who have refused 131I therapy and patients with thyroid ophthalmopathy. Younger women wishing to achieve a pregnancy in the near future may also opt for surgery. All patients must be treated with carbimazole and made euthyroid before surgery to avoid the risk of thyrotoxic crisis (thyroid storm) post-operatively. Thyroid surgery should only be undertaken by experienced specialised thyroid surgeons.

Thyroid storm (thyrotoxic crisis)

This is a rare, severe form of thyrotoxicosis in which patients have a fever, marked tachycardia and often vomiting and marked weakness. It usually occurs in older patients with unsuspected thyrotoxicosis. Apart from intensive care support and intravenous fluids, treatment includes propylthiouracil, Lugol's iodine, high-dose beta-blockers and glucocorticoids. Because of the rarity of this condition there are no controlled trials of therapy.

The enlarged thyroid gland

The normal thyroid is soft, weighing 15-20g, and has two lobes (like a butterfly's wings) measuring up to 4cm in length. It can often be felt in normal people, unless the neck is thick and short, or the sterno-mastoid muscles are heavily developed.
An enlarged thyroid gland is called a goitre - a generalised enlargement is called diffuse goitre and an irregular or lumpy enlargement is called nodular goitre. All patients with thyroid enlargement should have thyroid function blood tests. Many patients with hypothyroidism have easily palpable, firm thyroid glands, which have been enlarging, diffusely over months or years (Hashimoto's thyroiditis). Thyroxine treatment in these patients usually results in the thyroid shrinking and becoming softer. Iodine deficiency in underdeveloped countries can be a common cause of goitre. Most thyrotoxic Grave's disease patients, usually young adults, have diffuse thyroid enlargement, often with bruits (abnormal sounds caused by increased blood flow) which can be heard by the doctor. Anti-thyroid drug treatment or radio-iodine commonly lead to reduction in thyroid size.
Nodular enlargement is common and is clinically present in 4 per cent of all adults. Multiple nodules may be present or, in some, a single lump. The vast majority of thyroid nodules are benign and are caused by adenomas (some thyrotoxic), cysts and prominent areas of thyroiditis. However, a small proportion are malignant and therefore all patients presenting with a thyroid nodule must be evaluated by a specialist endocrine service.
The investigation of choice is a fine-needle aspiration biopsy of the nodule by a doctor experienced in the technique. Surgical excision by a specialist endocrine surgeon is carried out if malignant or suspicious cytology is found.
In addition, surgery is occasionally indicated for patients with benign nodules for cosmetic reasons or pressure symptoms.

Conclusion

Thyroid disorders (hypo- and hyper-thyroidism, with or without thyroid enlargement) are common, particularly in women. Thyroid dysfunction is often clinically obvious and can usually be easily diagnosed with thyroid function tests. Nodular thyroid enlargement, because of the possibility of cancer, needs assessment by a specialist endocrine service. Both hypo- and hyperthyoidism can sometimes be present for months or years with long histories of multiple, vague symptoms. Therefore, a high index of suspicion for thyroid dysfunction should be maintained. It is good practice for new cases of hyperthyroidsim to be referred to a local hospital endocrinologist so that the various treatment options can be discussed. Future relapses should also be treated by the hospital. The majority of patients with hypothyroidism, however, can be managed in general practice. Encouraging compliance with thyroxine replacement therapy is very important.

Dr MacFarlane is consultant physician/honorary senior lecturer in diabetes and endocrinology, University hospital, Aintree, Liverpool

References

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2. Vanderpump MPJ, Ahlquist JAO, Franklyn JA, Clayton RN. Consensus statement for good practice and audit measures in the management of hypothyroidism and hyperthyroidism. BMJ 1996;313:539-44.

3. Franklyn JA. The management of hyperthyroidism. N Engl J Med 1994;330: 731-8.

4. MacFarlane IA, Davies D, Longson D, Shalet SM, Beardwell CG. Single daily dose short-term carbimazole therapy for hyperthyroid Grave's disease. Clin Endocrinol 1983;18:557-61.

5. Mangendre D, Gatel A, Campion L, Massart C, Guilhem I, Lorcy Y, Lescouarch J, et al. Antithyroid drugs and Grave's disease - prospective randomised assessment of long-term treatment. Clin Endocrinol 1999;50:127-32.

6. Reminder: agranulocytosis with anti-thyroid drugs. CSM/MCA Current Problems in Pharmacovigilance 1999;25:3.

7. Franklyn JA. Thyroid disease and its treatment: short and long-term consequences. J R Coll Physicians 1999,33:564-7.

The Pharmaceutical Journal Vol 265 No 7109 p240-244August 12, 2000 Continuing education