Clinical Review: Hyperthyroidism

Contributed by Dr Sudesna Chatterjee, consultant physician and specialist in diabetes and endocrinology, Stoke Mandeville Hospital, Buckinghamshire

Section 1: Epidemiology and aetiology
Hyperthyroidism is one of the most common endocrine conditions worldwide.

It occurs in 1-2 per cent of the population with greater incidence in iodine-deficient regions and is 10 times more common in women than men between the ages of 20 and 40 years. In the UK Whickham survey, the prevalence of hyperthyroidism was estimated at 0.8 per 1,000 per year in women and less than 0.1 per 1,000 per year in men.1

Aetiology
Hyperthyroidism, or thyrotoxicosis, is defined by excess circulating thyroid hormones. It is caused mainly by stimulation of thyroid tissue by thyroid-stimulating hormone (TSH) receptor stimulating antibodies (TRAb) as in Graves' disease, or by autonomous production by groups of benign cells, for example with multinodular goitre or toxic adenoma.

Very rarely, secondary hyperthyroidism is due to TSH overproduction by a benign tumour in the anterior pituitary gland.

Graves' disease is the most common cause of thyrotoxicosis in young people, whereas multinodular goitre accounts for 50 per cent of cases in patients over 60 years.

Rarer causes include drugs such as amiodarone, lithium or thyroxine, solitary adenoma or thyroiditis, especially in the postpartum period.

Hyperthyroidism associated with amiodarone therapy is more prevalent in iodine-deficient areas and in patients with underlying thyroid disease.

Risk factors
Around 60 per cent of patients with hyperthyroidism have a family history of autoimmune thyroid disease and are at increased risk of other autoimmune disorders such as type-1 diabetes and Addison's disease.

Smoking is a risk factor for Graves' disease whereas obesity appears to confer protection.2

Section 2: Diagnosis

Presentation
Hyperthyroid patients may present with classical features associated with excess thyroid hormone, resulting in increased metabolic rate.

These include agitation, frequent bowel habit, fine resting tremor, sweating, heat intolerance and palpitations.

Goitre caused by overstimulation of the thyroid gland may be present and can cause dysphagia or even dyspnoea.

Specifically with Graves' disease, pretibial myxoedema and signs of eye disease ranging from corneal grittiness to severe lid retraction, proptosis and ophthalmoplegia can be evident.

Occasionally, Graves' ophthalmopathy occurs in the presence of normal thyroid function.

The diagnosis is sometimes delayed as patients suffer from non-specific constitutional symptoms of gradual malaise, insomnia, mood disorders and weight loss over several months.

Women may present with irregular menstrual cycles and subfertility. Children with hyperthyroidism may demonstrate short attention spans, hyperactivity and failure to thrive. If left untreated, patients can develop serious cardiac manifestations such as AF and heart failure.

Investigations
The diagnosis should be confirmed with measurement of TFTs, which demonstrate a fully suppressed TSH concentration associated with high free thyroxine (fT4) and triiodothyronine (fT3) concentrations.

In some cases, T3 toxicosis dominates the biochemical picture. Positive thyroid peroxidase autoantibodies (TPO) only suggests Graves' disease, whereas TRAb are a more specific indicator of autoimmune aetiology.

In the presence of negative antibodies combined with atypical clinical features, a thyroid iodine-131 or technetium-99m radioisotope scan should be arranged to rule out alternative diagnoses such as thyroid adenoma or thyroiditis.

In pregnancy, positive TRAb concentrations at 30 weeks' gestation necessitate careful monitoring for neonatal thyrotoxicosis as these antibodies cross the placenta.

Baseline blood tests before starting antithyroid treatment should include an FBC and LFTs.

Amiodarone therapy can make it difficult to interpret thyroid function as it decreases conversion of T4 to T3. Approximately 50 per cent of patients have abnormal tests on amiodarone and thyroid function should be checked prior to treatment.

Thyroid function should also be checked prior to starting treatment, at three-monthly intervals thereafter and up to one year on discontinuation.

Section 3: Management
Initial treatment of hyperthyroidism is usually with antithyroid drugs (ATD). More definitive options are radioactive iodine and thyroidectomy.

Troublesome adrenergic symptoms can be controlled with beta-blockers such as propranolol or atenolol until the patient is rendered euthyroid.

Large goitre may be a reason to consider total thyroidectomy

Pharmacotherapy
The commonly used ATDs in the UK are carbimazole and propylthiouracil (PTU).

Common side-effects include rashes and musculoskeletal pains. Agranulocytosis is the most serious side-effect, and patients must be advised to consult a doctor if they develop sore throat, mouth ulcers or pyrexia and this should be documented in the notes.

FBC with differential should be urgently requested and the drug may need to be discon- tinued if any side-effects occur.

The two main methods of oral antithyroid treatment are dosage titration and block- and-replace.

Dosage titration involves initiating therapy with a high dosage of ATD e.g. carbimazole 30-40mg daily or PTU 300-400mg in divided doses due to the drug's shorter half-life.

Once the patient is rendered clinically and biochemically euthyroid, the maintenance dosages are carbimazole 5-15mg daily or PTU 50-150mg daily.

In block-and-replace regimens, the patient is rendered hypothyroid and then thyroxine replacement is commenced.

Treatment duration of 12-18 months is often advocated, with at least six months' treatment necessary to reduce goitre size and lessen subsequent relapse.

TFTs should be measured every four to six weeks until maintenance dosages are reached when the testing frequency can be reduced to every three months.

As TSH can remain suppressed for several months due to prolonged thyroid hormone excess, fT4 should be used to guide dosage adjustments.

A review of 12 studies using these two different regimens showed that relapse rate was the same for both, at 50 per cent.3

There was a higher rate of skin rashes and greater treatment discontinuation in the block-and-replace group, with similar incidence of agranulocytosis.

Relapse
Once relapse occurs, radioactive iodine therapy (RAI) or surgery may be considered after stabilisation of thyroid function with ATD. RAI is a non-invasive, convenient procedure involving administration of an iodine-131 isotope in capsule form by a licensed radiotherapist.

The effect of RAI often takes up to six months. Patients are usually rendered hypothyroid and require lifelong thyroxine replacement, although some may be completely cured or require further doses. Patients are advised to avoid close contact with others, particularly pregnant women and young children, due to the small risk of radiation exposure for two to three weeks after the treatment.

Fears of increased cancer risk have diminished following safe usage for more than 50 years.

RAI should be preceded by steroid therapy in patients with severe Graves' ophthalmopathy.

Surgery
Thyroidectomy is useful for management of large goitres or patients with severe ophthalmopathy.

Rendering patients euthyroid prior to surgery is essential to avoid a hyperthyroid crisis or 'thyroid storm'. Total thyroidectomy is now the operation of choice, as even a small thyroid remnant has the potential to become overactive or cancerous. Lifelong thyroxine is subsequently necessary.

Minimal access surgery results in shorter hospital admissions and post-operative morbidity. There is a risk of vocal cord paralysis and hypoparathyroidism due to inadvertent ischaemia or removal of parathyroid glands, but this is reduced with experienced endocrine surgeons.

Section 4: Prognosis
Hyperthyroidism due to Graves' disease or multinodular goitre can lead to serious complications if left untreated.

Conversely, viral thyroiditis is a self-limiting condition characterised by a period of hyperthyroidism followed by hypothyroidism with eventual restoration of normal thyroid function after several months. Monitoring of TFTs is often all that is required.

Pregnancy
It is important to normalise thyroid function during pregnancy to ensure good maternal and fetal outcomes.

Ideally, these women should be managed in a dedicated antenatal endocrine clinic.

With Graves' disease, the immune status of pregnancy can sometimes lead to spontaneous remission without the need for ATD.

PTU is usually the drug of choice as there is a very small risk of aplasia cutis with carbimazole.

RAI is contraindicated in pregnancy. Positive titres of TRAb at 30 weeks' gestation predict the development of neonatal hyperthyroidism.

Concurrent therapy
Patients taking amiodarone may need to discontinue the drug, and close liaison with their cardiologist is essential.

Smoking cessation advice is valuable in hyperthyroid patients, especially because they are at greater risk of treatment failure.

A recent study showed that smokers required higher dosages of carbimazole to achieve a decline in TSH receptor antibodies.4

Subclinical disease
The management of subclinical hyperthyroidism, when TSH is suppressed with normal fT4 and fT3 concentrations, remains controversial. There is an increased risk of cardiac arrhythmias and osteoporosis, and treatment options include low-dose ATD or RAI.

The morbidity associated with undiagnosed hyperthyroidism can be considerable. A high index of suspicion, especially in patients with generalised multisystemic symptoms, is required to make the diagnosis and ensure prompt treatment.

Resources

References

1. Tunbridge W M, Evered D C, Hall R et al. The spectrum of thyroid disease in the community: the Whickham Survey. Clin Endo 1977; 7: 481-93.

2. Holm I, Manson J E, Michels K B et al. Smoking and other lifestyle factors and the risk of Graves' hyperthyroidism. Arch Intern Med 2005; 165(14): 1,606-11.

3. Abraham P, Avenell A, Watson W A et al. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev 2005 Apr 18; (2): CD003420.

4. Nyirendra M J, Taylor P N, Stoddart M et al. Thyroid-stimulating hormone-receptor antibody and thyroid hormone concentrations in smokers vs nonsmokers with Graves disease treated with carbimazole. JAMA 2009; 301(2): 162-4.

Further Resources

For an archive of all GP clinical reviews visit www.healthcarerepublic.com/clinical/GP

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