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.
- The thyroid gland is situated in the neck and its hormones control the metabolic rate of tissues.
- It is stimulated and controlled by TSH from the anterior pituitary.
- TSH is released by thyrotropin-releasing hormone (TRH) from the hypothalamus.
- The thyroid gland, in response to TSH, produces thyroxine (T4) and triiodothyronine (T3). Greater amounts of T4 are produced than T3.
- T4 is inactive and needs to be converted to T3 - which occurs peripherally (such as in the liver and kidney).
- Most T3 and T4 in the circulation are bound to protein (mostly thyroglobulin); it is only free thyroid hormone that is active.
- Free thyroid hormones in the circulation act negatively on the hypothalamus and pituitary - thus reducing the release of TRH and TSH.
Epidemiology and aetiology
- In Europe, thyrotoxicosis affects around 1 in 2,000 people annually.
- Graves' disease is the most common cause of thyrotoxicosis, accounting for around 75% of cases. Graves' disease is a rare disease in children, accounting for 1-5% of all patients with Graves' disease.In adults, this disease affects approximately 2% of women and 0.2% of men.
- 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.
- 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 hyperthyroidism.
- 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)).
- 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 disorders.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' disease.
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 thyrotoxicosis.
Thyrotoxic crisis or storm
See also 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 hyperthyroidism.
- The typical symptoms of thyroid storm are hyperthermia and mental disturbance, along with thyrotoxic symptoms.
- Thyroid storm is associated with precipitating events, such as the withdrawal of an anti-thyroid drug, radio-iodine therapy, infection and surgery.
- Management is with intravenous fluids, beta-blockers, anti-thyroid 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 hypothermia.
Causes of thyrotoxicosis
- 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.
This includes over-the-counter iodine supplements and 'energy boosting' preparations containing thyroid hormones.
Follicular carcinoma of the thyroid gland
Associated with metastatic disease.
These include amiodarone, lithium and exogenous iodine.
These are types of germ cell tumours.
- 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 hyperthyroidism.
- 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%.However, this test is not widely available.
- 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.
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 plan.
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:
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 day.
- Propylthiouracil is known to cause severe liver failure, particularly in children. It should be reserved for use in pregnancy and thyroid storm.
- There are two potential methods of treating hyperthyroid patients: 'block and replace' - where anti-thyroid 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.
- Most patients with hyperthyroid Graves' disease are rendered euthyroid by 4-8 weeks of treatment with carbimazole (20-40 mg daily).
- 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 anti-thyroid 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 anti-thyroid drugs can cause bone marrow suppression). This is seen in less than 0.5% of patients.
Increasingly, the first-line treatment in teenagers.It is also usually the treatment of choice in relapsed Graves' disease 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.
- Anti-thyroid 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 rates.
- It cannot be given to pregnant or breast-feeding 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.
- Surgery is used infrequently in the treatment of thyrotoxicosis.
- Patients should be returned to the euthyroid state with anti-thyroid drugs before surgery to avoid thyroid storm.
- Subtotal or near total thyroidectomy achieves a 98% cure rate. It is indicated if there is suboptimal response to anti-thyroid 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. Anti-thyroid drugs are not effective and should therefore be avoided.
Summary approach to a patient suspected of having hyperthyroidism
- Make the diagnosis:
- Note presence of signs and symptoms.
- TFTs: await results before initiating therapy if possible.
- Establish whether the patient needs urgent admission or management on an outpatient basis:
- Consider referral for urgent admission if any of the following are present:
- Unwell or unable to manage at home.
- Presence of atrial fibrillation or cardiac failure.
- Dehydration - eg, from severe diarrhoea.
- If the patient can be managed in the community:
- Educate them on the nature of the illness and the management plan.
- Start carbimazole.
- Warn the patient of the importance of seeking urgent help if they develop a sore throat or a rash.
- Consider starting a beta-blocker or calcium-channel blocker to control symptoms driven by the sympathetic nervous system - eg, atenolol or verapamil.
- Monitor TFTs regularly.
- Refer immediately to a thyroid surgeon:
- Patients with symptoms of tracheal compression due to a thyroid swelling.
- Refer urgently to a thyroid surgeon:
- Hyperthyroid patients with a thyroid swelling associated with:
- A solitary enlarging nodule.
- Previous neck irradiation.
- Family history of endocrine tumour.
- Hoarseness or voice changes without other obvious cause.
- Neck glands.
- Young age (before puberty).
- Older age (65 or more).
- Refer routinely to outpatient endocrinology:
- Patients without the above features but who have thyrotoxicosis confirmed by TFTs. It is helpful to include the thyroid peroxidase result in the referral letter.
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.
- TSH-secreting pituitary adenoma.
- Thyroid hormone-resistance syndrome.
- hCG-secreting tumour.
- Gestational thyrotoxicosis.
- This is confirmed when T4 and T3 are within the normal range but TSH is less than 0.4 mIU/L (check with a local laboratory for the reference range that applies to your area).
- Subclinical hyperthyroidism occurs in around 2% of the elderly population.
- Look for secondary causes of low TSH with normal thyroid hormone levels - eg, concomitant illness or medications such as glucocorticoids, dopaminergic drugs or amiodarone.
- Recheck TFTs in two 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 six months, refer to endocrinologists.
- The most common cause of true subclinical hyperthyroidism is toxic nodular goitre, especially in the elderly.
- 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/L.
- 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/L.
- Some experts recommend that treatment should be considered for low but detectable TSH in the elderly or in people with heart disease.
- If the decision is made to treat, radio-iodine is generally the treatment of choice, especially in toxic nodular goitre. An alternative is longterm carbimazole.
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' disease.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 autoimmune.
- The onset of symptoms may be insidious and subsequently associated with a delay in diagnosis.
- Weight loss, tiredness, change in behaviour and heat intolerance are the most common symptoms.
- Paediatric patients are treated in a similar fashion to adults: anti-thyroid medication, radio-iodine (for adolescents) and surgery.
- 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.
- 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 dysfunction.
- 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 patients.
- In both forms of thyrotoxicosis the amiodarone should usually be stopped (bearing in mind the potential risk of developing the original arrhythmia).Type I is treated as per Graves' hyperthyroidism, ie anti-thyroid medication and radio-iodine or surgery to prevent recurrence. Type 2 is treated with anti-thyroid medication to control symptoms and more definitively with steroids.
- 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 persist.
- There is an increased risk of:
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.
Further reading and references
Garmendia Madariaga A, Santos Palacios S, Guillen-Grima F, et al; The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab. 2014 Mar99(3):923-31. doi: 10.1210/jc.2013-2409. Epub 2014 Jan 1.
Leger J, Carel JC; Hyperthyroidism In Childhood: Causes, When and How To Treat. J Clin Res Pediatr Endocrinol. 2012 Nov 15. doi: 10.4274/jcrpe.854.
Franklyn JA, Boelaert K; Thyrotoxicosis. Lancet. 2012 Mar 24379(9821):1155-66. doi: 10.1016/S0140-6736(11)60782-4. Epub 2012 Mar 5.
Vaidya B, Pearce SH; Diagnosis and management of thyrotoxicosis. BMJ. 2014 Aug 21349:g5128. doi: 10.1136/bmj.g5128.
Chang RY, Lang BH, Chan AC, et al; Evaluating the efficacy of primary treatment for graves' disease complicated by thyrotoxic periodic paralysis. Int J Endocrinol. 20142014:949068. doi: 10.1155/2014/949068. Epub 2014 Aug 3.
Nakashima Y, Kenzaka T, Okayama M, et al; A case of thyroid storm with cardiac arrest. Int Med Case Rep J. 2014 May 87:89-92. doi: 10.2147/IMCRJ.S63475. eCollection 2014.
Natsuda S, Nakashima Y, Horie I, et al; Thyroid storm precipitated by duodenal ulcer perforation. Case Rep Endocrinol. 20152015:750390. doi: 10.1155/2015/750390. Epub 2015 Mar 9.
Akamizu T, Satoh T, Isozaki O, et al; Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys. Thyroid. 2012 Jul22(7):661-79. doi: 10.1089/thy.2011.0334. Epub 2012 Jun 12.
Tozzoli R, Bagnasco M, Giavarina D, et al; TSH receptor autoantibody immunoassay in patients with Graves' disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis. Autoimmun Rev. 2012 Dec12(2):107-13. doi: 10.1016/j.autrev.2012.07.003. Epub 2012 Jul 7.
Akmal A, Kung J; Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity. Expert Opin Drug Saf. 2014 Oct13(10):1397-406. doi: 10.1517/14740338.2014.953796. Epub 2014 Aug 26.
Abraham P, Avenell A, McGeoch SC, et al; Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev. 2010 Jan 20(1):CD003420.
Watanabe N, Narimatsu H, Noh JY, et al; Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease. J Clin Endocrinol Metab. 2012 Jan97(1):E49-53. doi: 10.1210/jc.2011-2221. Epub 2011 Nov 2.
Turner N, Driver I, Salotti JA, et al; Increasing use of radioiodine in young people with thyrotoxicosis in Great Britain. Eur J Endocrinol. 2012 Nov167(5):715-8. doi: 10.1530/EJE-12-0542. Epub 2012 Sep 6.
Collet TH, Bauer DC, Cappola AR, et al; Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. J Clin Endocrinol Metab. 2014 Sep99(9):3353-62. doi: 10.1210/jc.2014-1250. Epub 2014 Jun 10.
Blum MR, Bauer DC, Collet TH, et al; Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015 May 26313(20):2055-65. doi: 10.1001/jama.2015.5161.
Batra CM; Fetal and neonatal thyrotoxicosis. Indian J Endocrinol Metab. 2013 Oct17(Suppl 1):S50-4. doi: 10.4103/2230-8210.119505.
Bauer AJ; Approach to the pediatric patient with Graves' disease: when is definitive therapy warranted? J Clin Endocrinol Metab. 2011 Mar96(3):580-8. doi: 10.1210/jc.2010-0898.
Bogazzi F, Tomisti L, Bartalena L, et al; Amiodarone and the thyroid: a 2012 update. J Endocrinol Invest. 2012 Mar35(3):340-8. Epub 2012 Mar 19.
Barvalia U, Amlani B, Pathak R; Amiodarone-induced thyrotoxic thyroiditis: a diagnostic and therapeutic challenge. Case Rep Med. 20142014:231651. doi: 10.1155/2014/231651. Epub 2014 Nov 12.
Hudzik B, Zubelewicz-Szkodzinska B; Amiodarone-related thyroid dysfunction. Intern Emerg Med. 2014 Dec9(8):829-39. doi: 10.1007/s11739-014-1140-1. Epub 2014 Oct 28.
Mirza F, Canalis E; Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. Eur J Endocrinol. 2015 Sep173(3):R131-51. doi: 10.1530/EJE-15-0118. Epub 2015 May 13.
Tsai MS, Chuang PY, Huang CH, et al; Better adherence to antithyroid drug is associated with decreased risk of stroke in hyperthyroidism patients. Int J Clin Pract. 2015 Aug 24. doi: 10.1111/ijcp.12724.
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