Hyperthyroidism (Thyrotoxicosis)

See related articles Graves' Disease and Thyroid Eye Disease.

Hyperthyroidism is over activity of the thyroid gland, which results in a number of symptoms and signs. It can be primary or secondary:¹

• Primary hyperthyroidism is when the pathology is within the thyroid gland.
• Secondary hyperthyroidism is when the thyroid gland is stimulated by excessive thyroid stimulating hormone in the circulation.

• Prevalence - In Caucasians, 2-3% in women and 0.2-0.3% in men. 60-86% of cases are due to Graves' disease with a peak onset at 20-50 years, the remainder are largely due to nodular thyroid disease that appears later in life. It affects females more than males (ratio 9:1).
• Incidence - This has been reported at 0.8 per 1000 annually in females and less than 0.1 in males, during the same follow-up period.
• Risk Factors - Family history, high iodine intake, smoking (particularly for thyroid-associated ophthalmopathy), toxic multi-nodular goitre is especially associated with an increased iodine intake either from a change in diet or an acute dose from iodine-containing agents e.g. amiodarone, contrast agents.

Extra signs in Graves' disease

• Eye changes - exophthalmos, ophthalmoplegia, conjunctival oedema, papilloedema and keratopathy. May be severe enough to cause visual loss.
• Pretibial myxoedema - swelling above the lateral malleoli due to accumulation of glycosaminoglycans.
• Thyroid acropachy - clubbing with painful swelling of digits.
• Diffuse enlargement of thyroid gland.
• Thyroid bruit.

For management see article on Thyroid eye disease.

Presentation in certain subgroups

• The presence of symptoms and signs and their severity is dependent upon the length of the disease and the age of the patient.
• Elderly - commonly have atrial fibrillation and heart failure.
• Children - may present with excessive growth or behavioural problems.
• Patients may get paradoxical features e.g. weight gain when increasing appetite is not countered by increased metabolism.³

See related article on thyrotoxic crisis.

• Occasionally patients may present with thyrotoxic crisis or storm in either previously undiagnosed or ineffectively treated cases.⁴
• Infections, poor compliance and radioiodine therapy are all precipitants.
• It presents with fever >38.5°C, tachycardia, delirium or coma, seizures, vomiting, diarrhoea and jaundice. It is a clinical diagnosis.⁴
• Treatment involves correcting the thyroid hormones using high doses of propylthiouracil, fluid resuscitation and treating any precipitating causes.
• 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 hypothermia.

• Graves' Disease:
  • This is the commonest cause of hyperthyroidism (accounts for more than 60%) and has an autoimmune basis (IgG antibody that binds and stimulates TSH receptor).
  • Small-moderate diffuse, firm goitre with 50% of these showing ophthalmopathy.
  • There may be a personal or family history of autoimmune disease.
  • <5% have pretibial myxoedema called thyroid dermopathy (as can occur anywhere, particularly following trauma). This is usually associated with moderate-severe ophthalmopathy. 10-20% have clubbing (thyroid acropathy).Thyroid dermopathy usually appears as non-pitting plaques with pink/purple colour. There are also nodular and generalised forms.
  • There may also be lymphoid hyperplasia including splenomegaly and an enlarged thymus.
  • TSH receptor antibodies are commonly detected.
  • Associated with other autoimmune conditions e.g. pernicious anaemia, type 1 diabetes mellitus.⁵
• Toxic nodular goitre: Presence of multi-nodular goitre without the above symptoms (i.e. specific features of Graves' disease) suggests toxic nodular goitre (common in the elderly).
• Solitary thyroid nodule: palpable, toxic adenoma.
• De Quervains Thyroiditis:
  • Transient hyperthyroidism which probably results from a viral infection.
  • Presents with features of hyperthyroidism with pyrexia and pain in the neck.
• Self medication
• Follicular carcinoma of thyroid gland: associated with metastatic disease.
• Drugs: e.g. Amiodarone, lithium, exogenous iodine.
• Ovarian teratomas

Phaeochromocytoma and any cause of weight loss.

• Thyroid function tests (TFTs): Serum TSH can exclude primary thyrotoxicosis. Confirm diagnosis with free T4 levels. If TSH suppressed but free T4 levels normal then, if not previously supplied, need free T3 level (T3 toxicosis occurs in 5% of patients).
• Autoantibodies: These are most commonly seen in Graves' disease.
  • Antimicrosomal antibodies - against thyroid peroxidase.
  • Antithyroglobulin antibodies.
  • TSH-receptor antibodies are commonly present in Graves, but are not routinely measured.
• Imaging:
  • Thyroid USS.
  • Thyroid uptake scans: to locate hot (overactivity) and cold (no activity) spots.

Refer to specialist for treatment. Betablockers 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 betablockers.

There are 3 kinds of definitive treatment:^3,6

• Anti-thyroid 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 aim is to avoid drug-induced hypothyroidism which occurs in 40-60% cases.
  • 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 anti-thyroid 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-effects.⁷
  • Carbimazole is most commonly used to begin with, in a dose of 10 mg twice or three times daily initially (depending on the weight of patient), adjusting or stepping down according to response and TFT results. TFTs usually normalise in a few weeks to months.
  • TFTs are repeated every month 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. But monitoring for recurrence is needed.
  • Minor side effects include: nausea and bitter taste after taking medication.
    Warn patients to come for FBC if they develop sore throat etc. (as anti-thyroid drugs can cause bone marrow suppression). This is seen in less than 0.5% of patients.
• Radioiodine: is increasingly the first line treatment in teenagers and above. It is given as 200-600 MBq, and some may need a second treatment.
  • Radioactive iodine is given to the patient as a drink and is taken up by the thyroid gland leading to destruction of the gland.
  • Radioiodine has the advantages that it is relatively inexpensive and a definitive method of treating hyperthyroidism.
  • It can not be given to pregnant or breast feeding females and females must be advised not to get pregnant for at least four months.
  • Radioactive iodine may also worsen eye disease in Graves' thyrotoxicosis.
  • 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. It also requires for patients to sleep alone for a week.
  • Hypothyroidism is also a potential and common complication. Estimates suggest that between 50 % to 80% of patients can develop hypothyroidism.⁵ Therefore, need long-term follow up of the TFTs.
• Surgical:
  • Sub-total or near total thyroidectomy achieves 98% cure rate. Indicated if suboptimal response to antithyroid medication or radioiodine and in children occasionally. Complications 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 multi-nodular goitre is usually treated by radioiodine, anti-thyroid drugs will work but relapse always occurs when drugs are discontinued.
  • Toxic adenoma usually treated with radioiodine but in large nodule or young patient surgical excision is a better option.

Both surgery and radioiodine require the patient to be euthyroid.

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.

• This is confirmed when T4 and T3 are within the normal range but TSH is less than 0.4mU/L (check local laboratory for reference range that applies to your area).
• Look for secondary causes of low TSH with normal thyroid hormone levels e.g. concomitant illness or medications such as, glucocorticoids, dopaminergic drugs or amiodarone.
• Recheck TFTs in 2 months - if no change in levels and no development of new symptoms or signs then check every 3-6 months based on clinical judgement.
• If abnormal results persist for more than 6 months refer to endocrinologists.

See related article on Hyperthyroidism in Pregnancy.

• Rare, occurring in 1 of 25,000 pregnancies.
• Most commonly occurs in the babies of mothers who have Graves' disease. Occasionally it is seen in neonates of euthyroid mothers.
• Neonates commonly develop tachycardia and are treated with carbimazole or propylthiouracil and beta blockers once the diagnosis is confirmed.

• The incidence of hyperthyroidism in children is approximately 0.1 to 3 per 100 000 per year (the incidence varies with age, being higher in adolescents).⁹
• Many paediatric patients with hyperthyroidism may present with non-specific symptoms e.g. irritability and behavioural problems.
• The underlying cause of the thyroid dysfunction is usually autoimmune.
• Paediatric patients are treated in a similar fashion to adults: antithyroid medication, radio-iodine (for adolescents) and surgery.⁹

• 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 hypothyroidism.¹⁰
• Amiodarone induced thyrotoxicosis is divided into two types: AIT I - thyrotoxicosis in a patient who has underlying thyroid dysfunction and AIT II - which is thyrotoxicosis resulting from destructive thyroiditis.¹⁰
• In both forms of thyrotoxicosis the amiodarone should be stopped (bearing in mind potential risk of developing the original arrhythmia). Type I is treated as per Graves' hyperthyroidism i.e. antithyroid medication and radioiodine or surgery to prevent recurrence. Type 2 is treated with antithyroid medication to control symptoms and more definitively with steroids.

• Asian males will present most commonly with signs and symptoms as other patients.
• However, rarely they can present with chorea, psychosis, impaired consciousness and periodic paralysis.

• Hyperthyroidism is characterised by relapses and remittances.
• Surgical treatment and radioactive iodine can both lead to hypothyroidism and thus close follow-up with thyroid function tests is required.
• Graves ophthalmopathy is fulminant in 5% of patients. Its course does not follow that of the thyroid disease.
• In 25% patients eye signs appear after 1 or more years and frequently progress even with normal thyroid function.
• Spontaneous remission is seen in <10% and may not persist.
• There is a 3x increased risk of death from osteoporotic fracture and 1.3x increased risk of death from cardiovascular disease and stroke in untreated hyperthyroidism.
• Long-term follow-up studies have shown increased mortality from cardiovascular and cerebrovascular disease in those with a past history of treatment with radioiodine for overt hyperthyroidism.¹¹