Hyperthyroidism

Synonym: thyrotoxicosis

See also the separate Hyperthyroidism in Pregnancy and Thyroid Eye Disease articles.

Hyperthyroidism is overactivity of the thyroid gland, which results in a number of symptoms and signs. It can be primary or secondary:

• Primary hyperthyroidism is the term used when the pathology is within the thyroid gland.

• Secondary hyperthyroidism is the term used when the thyroid gland is stimulated by excessive thyroid-stimulating hormone (TSH) in the circulation.

Epidemiology

• In Europe, thyrotoxicosis affects around 1 in 2,000 people annually¹.

• Thyrotoxicosis is still under-diagnosed however - it has been shown that in people older than 65 years, undiagnosed hyperthyroidism occurs in 0.3% of people and around 2% of people aged over 65 years have subclinical hyperthyroidism².

• Graves' disease In adults affects approximately 2% of women and 0.2% of men². Graves' disease accounts for around 75% of cases. Graves' disease is a rare disease in children, accounting for 1-5% of all patients with Graves' disease³.

Aetiology⁴

• Graves' disease is the most common cause of thyrotoxicosis.

• Thyrotoxicosis due to toxic nodular goitre is more common in people aged over 60 years.

• Thyroiditis, in which destruction of thyroid cells causes release of thyroid hormones into the circulation, is implicated in about 10% of thyrotoxicosis cases.

• Other causes include exogenous thyroid hormone excess, drug-induced hyperthyroidism, TSH-secreting pituitary adenomas and pituitary resistance to thyroid hormones.

Risk factors

These include:

• Family history.

• High iodine intake.

• Smoking (particularly for thyroid-associated ophthalmopathy).

• Trauma to the thyroid gland (including surgery).

• Toxic multinodular goitre (which is especially associated with an increased iodine intake, either from a change in diet or an acute dose from iodine-containing agents (eg, amiodarone, contrast agents)).

• Childbirth.

• Highly active antiretroviral therapy (HAART).

Three gene regions consistently linked to Graves' hyperthyroidism are the human leukocyte antigen region, CTLA4 and PTPN22, all of which encode proteins that are involved in immune function and linked to the cause of other autoimmune disorders². People with a history of other autoimmune disorders, those with a family history of thyroid or other autoimmune disorders and smokers are at an increased risk of developing Graves' disease⁵.

Presentation

NB: although these symptoms may be present, the symptoms and signs can be variable and in some patients they are very mild.

Thyrotoxic periodic paralysis is a serious complication characterised by muscle paralysis and hypokalaemia due to a massive intracellular shift of potassium. An annual incidence of up to 2% has been reported in Asian people with thyrotoxicosis⁶.

Thyrotoxic crisis or storm

See also the separate Hyperthyroid Crisis (Thyrotoxic Storm) article.

• Patients may rarely present with thyrotoxic crisis or storm in either previously undiagnosed or ineffectively treated cases.

• A thyroid storm is a rare condition affecting 1-2% of patients with hyperthyroidism⁷.

• The typical symptoms of thyroid storm are hyperthermia and mental disturbance, along with thyrotoxic symptoms⁸.

• Thyroid storm is associated with precipitating events, such as the withdrawal of an antithyroid drug, radio-iodine therapy, infection and surgery.

• Management is with intravenous fluids, beta-blockers, antithyroid drugs and steroids.

• It is also important to look for the presence of Addison's disease in these patients.

• It has 20-30% mortality due to arrhythmias and hypothermia⁹.

Causes of thyrotoxicosis

Graves' disease

• This is the most common cause of hyperthyroidism and has an autoimmune basis.

• It is an autoimmune disease mediated by antibodies that stimulate the TSH receptor, leading to excess secretion of thyroid hormones and hyperplasia of thyroid follicular cells, resulting in hyperthyroidism and diffuse goitre.

• Eye changes - exophthalmos, ophthalmoplegia, conjunctival oedema, papilloedema and keratopathy.

• Diffuse moderate enlargement of the thyroid gland which feels firm on palpation.

• Some patients have pretibial myxoedema called thyroid dermopathy (as can occur anywhere, particularly following trauma). This is usually associated with moderate-to-severe ophthalmopathy. 10-20% have clubbing (thyroid acropathy).

• There may also be lymphoid hyperplasia including splenomegaly and an enlarged thymus.

• The pathophysiology of Graves' disease can have a variable effect on thyroid function and patients may remain euthyroid or become hypothyroid.

• There may be a personal or family history of autoimmune disease.

Toxic nodular goitre
The presence of a multinodular goitre without the above symptoms (ie specific features of Graves' disease) suggests toxic nodular goitre (common in the elderly).

Solitary thyroid nodule
Palpable, toxic adenoma.

De Quervain's thyroiditis
Transient hyperthyroidism which probably results from a viral infection. Presents with features of hyperthyroidism with pyrexia and pain in the neck.

Self-medication
This includes over-the-counter iodine supplements and 'energy-boosting' preparations containing thyroid hormones.

Follicular carcinoma of the thyroid gland
Associated with metastatic disease.

Drugs
These include amiodarone, lithium and exogenous iodine.

Ovarian teratomas
These are types of germ cell tumours.

Differential diagnosis

Phaeochromocytoma and any cause of weight loss.

Investigations

• TFTs: serum TSH can exclude primary thyrotoxicosis. Confirm the diagnosis with free T4 levels. If TSH is suppressed but free T4 levels are normal then, if not previously supplied, free T3 level is needed (T3 toxicosis occurs in 5% of patients).

• Autoantibodies - these are most commonly seen in Graves' disease:
  

  • Antimicrosomal antibodies - against thyroid peroxidase. Thyroid peroxidase antibodies are present in about 75% of cases of Graves' hyperthyroidism and can help to differentiate autoimmune disease from toxic nodular hyperthyroidism².

  • Antithyroglobulin antibodies.

  • TSH-receptor antibodies which are commonly present in Graves' disease. They have been shown to have a sensitivity of 98% and a specificity of 99%¹⁰. However, this test is not widely available.

• Imaging:
  

  • Thyroid ultrasound scan.

  • Thyroid uptake scans: to locate hot (overactivity) and cold (no activity) spots.

• Inflammatory markers:

  • In patients with subacute thyroiditis, CRP and ESR are often raised.

Management

Refer to a specialist for treatment

All patients with new-onset thyrotoxicosis should be referred for assessment in secondary care, to establish the cause and to agree on a management plan⁵¹¹.

Beta-blockers can be used for rapid symptom control whilst waiting for thyroid function to normalise. Calcium-channel blockers may be used if patients are intolerant of beta-blockers.

There are three kinds of definitive treatment:

Antithyroid drugs

Carbimazole (methimazole) or propylthiouracil (Class: thionamides):

• These drugs act very quickly and inhibit the production of thyroid hormones. Full benefit may take 2-3 weeks to become apparent.

• The recommended starting dose of carbimazole or methimazole is 10-20 mg per day².

• Propylthiouracil is known to cause severe liver failure, particularly in children. It should be reserved for use in pregnancy and thyroid storm¹².

• There are two potential methods of treating hyperthyroid patients: 'block and replace' - where antithyroid drugs are given with thyroxine replacement, and 'dose titration' - where only antithyroid drugs are used and doses are adjusted to achieve normalisation of thyroid hormone production.

• A systematic review and meta-analysis suggest that both types of methods are equally effective. Furthermore, the dose titration method was associated with a lower rate of side-effects¹³.

• Most patients with hyperthyroid Graves' disease are rendered euthyroid by 4-8 weeks of treatment with carbimazole (20-40 mg daily)⁵.

• TFTs are repeated every six weeks and the dose altered according to the T4 level. TSH may remain suppressed for months despite the T4 coming into the normal range and is, thus, unreliable.

• Once the patient is euthyroid, the dose of carbimazole is reduced until the patient is on the lowest amount necessary to maintain the T4 and T3 within the normal range.

• Remission is usually achieved at 18-24 months, after which attempts may be made to stop antithyroid drugs.

• Minor side-effects include: nausea and a bitter taste after taking medication. Warn patients to come for FBC if they develop a sore throat, etc (as antithyroid drugs can cause bone marrow suppression). This is seen in less than 0.5% of patients¹⁴.

Radio-iodine

This is usually the treatment of choice in relapsed Graves' disease, in poor medication compliance and in those patients with toxic nodular hyperthyroidism:

• Radioactive iodine is given to the patient as a drink and is taken up by the thyroid gland, leading to destruction of the gland. It can take 3-4 months to take effect.

• Radio-iodine has the advantages that it is relatively inexpensive and a definitive method of treating hyperthyroidism.

• Antithyroid drugs should be stopped 5-7 days before treatment with radio-iodine because continuous use reduces thyroid iodide uptake and retention, which in turn reduces cure rates².

• It cannot be given to pregnant or breastfeeding females and females must be advised not to get pregnant for at least six months.

• Radioactive iodine may also worsen eye disease in Graves' thyrotoxicosis; this is more marked in smokers.

• The patient does have to be informed that the radioactive iodine is cleared via the urine and thus can be passed on. They are usually advised to avoid close contact with children and pregnant women for about three weeks.

• Hypothyroidism is also a potential and common complication.

Surgical

• Surgery is used infrequently in the treatment of thyrotoxicosis².

• Patients should be returned to the euthyroid state with antithyroid drugs before surgery to avoid thyroid storm.

• Measure TSH and FT4 at two and six months after surgery, and then TSH once a year for adults, children and young people who have had a hemithyroidectomy.

• Subtotal or near total thyroidectomy achieves a 98% cure rate. It is indicated if there is suboptimal response to antithyroid medication or radio-iodine, especially in patients who are pregnant or who have Graves' orbitopathy.

• Complications are rare but include haemorrhage, hypoparathyroidism and vocal cord paralysis.

• Patients who undergo surgery will need to be followed up over a number of years, as they may develop hypothyroidism.

• Toxic adenoma or toxic multinodular goitre which is resistant to conservative treatment or causing compression symptoms is best treated with surgical excision.

NB: thyrotoxicosis associated with thyroiditis is transient and resolves spontaneously. Antithyroid drugs are not effective and should therefore be avoided.

Summary approach to a patient suspected of having hyperthyroidism

Secondary hyperthyroidism

Secondary hyperthyroidism is rare. The pathology is at the level of the pituitary. TSH, T3 and T4 are all very high. TRH stimulation tests are used in the diagnosis and result in a flat response curve.

Causes include:

• TSH-secreting pituitary adenoma.

• Thyroid hormone-resistance syndrome.

• hCG-secreting tumour.

• Gestational thyrotoxicosis.

Subclinical hyperthyroidism

• Subclinical hyperthyroidism occurs in around 2% of the elderly population².

• Look for secondary causes of low TSH with normal thyroid hormone levels - eg, concomitant illness or medications such as glucocorticoids, dopaminergic drugs or amiodarone.

• The most common cause of true subclinical hyperthyroidism is toxic nodular goitre, especially in the elderly.

• Refer for specialist advice on managing subclinical hyperthyroidism if they have two TSH readings lower than 0.1 mIU/L at least three months apart and evidence of thyroid disease or symptoms of thyrotoxicosis¹¹. Refer all those less than 18 years old.

• Subclinical hyperthyroidism is associated with increased risks of coronary heart disease (CHD) mortality and incident atrial fibrillation, with highest risks of CHD mortality and atrial fibrillation when thyrotropin level is lower than 0.10 mIU/L¹⁵.

• Subclinical hyperthyroidism is also associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L¹⁶.

• If the decision is made to treat, radio-iodine is generally the treatment of choice, especially in toxic nodular goitre. An alternative is long-term carbimazole.

• If untreated, check TSH every six months.

Hyperthyroidism in neonates

This condition occurs rarely and is principally seen in newborn babies of mothers who have Graves' disease. It occurs in around one out of 70 pregnancies with Graves' disease¹⁷. Occasionally it is seen in neonates of euthyroid mothers. Maternal TSH-receptor antibody levels may be high. Clinical features vary but may include tachycardia, pulmonary hypertension and cardiopulmonary failure. Neonates commonly develop tachycardia and are treated with carbimazole and beta-blockers once the diagnosis is confirmed.

Hyperthyroidism in children

• Girls have a higher incidence than boys.

• Thyrotoxicosis is less common in children than in adults, with an incidence in the UK and Ireland of 0.9 per 100,000 per year, of which 96% of cases are autoimmune².

• The onset of symptoms may be insidious and subsequently associated with a delay in diagnosis¹⁸.

• Weight loss, tiredness, change in behaviour and heat intolerance are the most common symptoms.

• Paediatric patients are treated in a similar fashion to adults: antithyroid medication, radio-iodine (in patients who are non-compliant with medication) and surgery¹⁹.

Amiodarone-induced thyrotoxicosis

• Amiodarone is a heavily iodinated drug used commonly in several forms of arrhythmias.

• Patients should have their thyroid function tested prior to starting amiodarone.

• Amiodarone can cause hyperthyroidism and hypothyroidism²⁰.

• Amiodarone-associated thyrotoxicosis occurs in 6-10% of people given the drug and is more common in iodine-deficient areas. This complication is serious and is associated with more than doubling of adverse cardiac events and worse outcomes than in Graves' or toxic nodular hyperthyroidism, especially in patients with left ventricular dysfunction².

• Amiodarone-induced thyrotoxicosis (AIT) is divided into two types:

  • Type 1 - thyrotoxicosis in a patient who has underlying thyroid dysfunction.

  • Type 2 - thyrotoxicosis resulting from destructive thyroiditis in which there is excess release of pre-formed T4 and T3 into the circulation. It typically occurs in patients without underlying thyroid disease and is caused by a direct toxic effect of amiodarone on thyroid follicular cells. The thyrotoxic phase may last several weeks to several months and it is often followed by a hypothyroid phase with eventual recovery in most patients²¹.

• In both forms of thyrotoxicosis the amiodarone should usually be stopped (bearing in mind the potential risk of developing the original arrhythmia)²². Type I is treated as per Graves' hyperthyroidism, ie antithyroid medication and radio-iodine or surgery to prevent recurrence. Type 2 is treated with antithyroid medication to control symptoms and more definitively with steroids²⁰.

Prognosis

• Hyperthyroidism is characterised by relapses and remittances.

• Surgical treatment and radioactive iodine can both lead to hypothyroidism and thus close follow-up with TFTs is required.

• Spontaneous remission is seen in <10% and may not persist⁵.

• There is an increased risk of:

  • Death from osteoporotic fracture²³.

  • Death from CVD and stroke (independent of atrial fibrillation) in untreated hyperthyroidism²⁴.

History

Robert James Graves (1796-1853) was an outstanding Irish physician and teacher. He was a prolific medical author and his paper 'Newly observed affection of the thyroid gland in females' was published in the London Medical and Surgical Journal in 1853.