July 2007: Tailor treatment to the patient in thyrotoxicosis
What are the causes of hyperthyroidism?
What are the treatment options?
Which patients are suitable for surgery?
What are the causes of hyperthyroidism?
What are the treatment options?
Which patients are suitable for surgery?
Thyrotoxicosis is caused by an excess circulation of free thyroxine (t4) and/or free triiodothyronine (T3). There is an associated suppression of thyroid stimulating hormone (TSH).
The prevalence of hyperthyroidism in the UK is widely reported to be approximately 2%. It is ten times more common in women than men and is self-limiting in 40% of cases.
The typical presentation of thyrotoxicosis is a young woman with weight loss despite increased appetite, heat intolerance and mood changes. The clinical features of thyrotoxicosis are listed in table 1, attached.
Causes of Hyperthyroidism
There are four major causes:
• A generalised enlargement of the thyroid (Graves' disease)
• An overactive solitary lump in the thyroid (Plummer's disease)
• Overactivity in a multinodular goitre (toxic multinodular goitre)
• Inflammation of the thyroid resulting in release of excess thyroid hormone (thyroiditis).
Rarer causes of thyrotoxicosis include:
• Drugs such as amiodarone or lithium
• Iodine excess
• TSH-secreting tumour
• Factitious causes
Graves' disease is responsible for 75% of cases of hyperthyroidism in the UK.1 It affects approximately 1 in 100 of the adult population. Autoantibodies (IgG to the TSH receptor) stimulate the thyroid leading to increased production of T4 and growth of the thyroid gland.
Graves' disease is associated with an organ-specific autoimmune disease and eye disease: thyroid associated ophthalmopathy (TAO). Up to 50% of patients with Graves' disease will have ocular manifestations.
Unlike other causes of thyrotoxicosis, Graves' disease may be associated with a strong family history of autoimmune disease. It may also be associated with vitiligo, pernicious anaemia and type 1 diabetes.
Thyroid associated ophthalmopathy in Graves' disease
TAO may consist of:
• Lid lag
Complications of TAO include grittiness and increased tear production, periorbital oedema, conjunctival oedema and proptosis, which may be unilateral in 5-10% of patients. Double vision may occur, caused by extraocular muscle dysfunction. Traction and swelling on the optic nerve may lead to blindness.
Smoking is an important aetiological factor in the progression of TAO. Patients diagnosed with the disease should be advised to stop smoking immediately.2 Thyroid associated ophthalmopathy is treated with steroids and immunosuppresive drugs, such as azathioprine.
Toxic multinodular goitre
Toxic multinodular goitre is responsible for only 15% of cases of hyperthyroidism in the UK.
Thyrotoxicosis developing in a multinodular goitre tends to relapse after medical treatment and usually requires definitive surgical treatment.
Occasionally, radioactive iodine can be used if there is no suggestion of pressure effects on the trachea, superior vena cava or oesophagus. There is an approximate 50% reduction in the size of the goitre with this treatment.
One in 20 cases of hyperthyroidism are caused by a single adenoma. In Plummer's disease an autonomous hyperfunctioning adenoma produces excessive T4 and suppresses TSH, leading to clinical hyperthyroidism.
The nodule may not be clinically palpable, but can be clearly seen on a technetium scan.
Thyroiditis is inflammation of the thyroid gland, which may precipitate thyrotoxicosis.
Common examples of thyroiditis are Hashimoto's thyroiditis, postpartum thyroiditis and de Quervain's thyroiditis.
Hashimoto's thyroiditis typically affects women aged 55 to 75 years. It is an autoimmune disorder associated with positive thyroid antibodies.
It is a common cause of hypothyroidism. However, the disease may have an initial toxic phase. In this phase toxicity is mild and it is usually not a problem to differentiate Hashimoto's disease from other causes of thyrotoxicosis.
Patients with Hashimoto's thyroiditis are predisposed to lymphoma of the thyroid, which usually presents as a rapidly growing mass within one of the thyroid lobes.
Subacute (de Quervain's) thyroiditis
Pain in the thyroid is characteristic of subacute thyroiditis due to de Quervain's disease and can present either suddenly or over a longer period of time. Patients usually present with a small, tender thyroid, high fever and a grossly elevated erythrocyte sedimentation rate. In the early stages there may be a mild form of thyrotoxicosis, with raised T3 and T4 and a suppressed TSH.
There is usually a previous history of a flu-like illness and a variety of viruses have been implicated, including mumps, coxsackievirus and adenoviruses.
It is important to separate subacute thyroiditis from true Graves' disease, as most cases of subacute thyroiditis are self-limiting.
The disease is mild and can be treated with NSAIDs, but occasionally it may be necessary to use high doses of steroids, starting with prednisolone 40mg per day and gradually tailing off the dose over a period of six to eight weeks. Beta-blockers may be used, for example propanolol 20mg tds for four to six weeks.
In the natural history of the disease there is a phase of hypothyroidism at six weeks, followed by spontaneous recovery of normal thyroid function within six months. However, the disease may relapse, requiring further treatment.
In cases where diagnosis is uncertain, performing a technetium scan may clinch the diagnosis. This will show low or absent uptake of the radioisotope by the thyroid in patients with the disease.
Postpartum thyroiditis is a transient form of thyrotoxicosis. It is very similar to subacute thyroiditis, but is totally painless. It may occur at any time from three to six months after delivery. The thyroid swelling is usually insignificant and the thyrotoxic symptoms mild.
A technetium scan will show low or absent radioisotope uptake by the thyroid, similar to de Quervain's thyroiditis.
The standard treatment of thyrotoxicosis (with antithyroid drugs) is completely contraindicated. However, symptomatic patients can be treated with a ß-blocker.
In postpartum thyroiditis there is never any evidence of TAO and the duration of the thyrotoxicosis is short.
Amiodarone-induced thyrotoxicosis occurs in 10-20% of patients on amiodarone. It is more common in patients with a high intake of iodine.
Thyrotoxicosis is a biochemical diagnosis. With the exception of patients with a TSH-secreting pituitary tumour, all patients with thyrotoxicosis will have a suppressed TSH. In addition, T4 will be raised in the majority of cases and there should be an increase in T3.
In the early stages of hyperthyroidism, T4 may be normal and there will be a suppressed TSH. It is therefore important always to measure the T3 level in patients with a suppressed TSH and a normal T4 so that a diagnosis of T3 toxicosis may be excluded.
Pure T4 toxicosis is very uncommon, but can occur in patients who have a high iodine intake.
There has been considerable discussion about the reference range for TSH. Recent studies from the United States suggest that it should be narrowed. In the UK, the upper range of TSH is 4.5mU/l while the lower range is 0.1mU/l. Any patients with a level below 0.1mU/l will be considered thyrotoxic.
TSH-secreting pituitary adenomas
Thyrotoxicosis caused by a pituitary tumour is very uncommon. The diagnosis is made by elevated free T4 and T3 levels associated with grossly elevated TSH levels. The diagnosis can be confirmed by CT or MRI scan.
Factitious or iatrogenic thyrotoxicosis is common. It can occur in patients treated for thyroid cancer, as their TSH is suppressed to reduce the risk of tumour recurrence, and it is commonly seen in women who are trying to lose weight.
Diagnosis is made by detection of grossly elevated thyroid hormone levels associated with a suppressed TSH. Long-term administration of thyroxine results in atrophy of the gland and serum thyroglobulin will be almost undetectable.
Biochemical findings in factitious thyrotoxicosis depend on the thyroid preparation being taken by the patient. Patients taking T3 alone may develop T3 thyrotoxicosis, and their T4 may be low with an associated suppressed TSH.
Usually patients with factitious thyrotoxicosis have high T3 and T4 levels with suppressed TSH, as the most common causative drug is levothyroxine.
Management of thyrotoxicosis3,4
There are three ways to treat thyrotoxicosis:
• Drug treatment
• Radioactive iodine
In the UK it is usual to start patients on antithyroid medication and, if treatment fails, to consider radioactive iodine or surgery.5
Long-term antithyroid drugs can be used, but their use has never been popular with patients or doctors. Radioactive iodine cannot be used in patients who are breast feeding and is totally contraindicated in pregnancy.
Management with antithyroid drugs
Carbimazole and propylthiouracil act by inhibiting iodine organification by thyroid peroxidase: they reduce T3 and T4 production.
Propylthiouracil has the added advantage that it inhibits the peripheral conversion of T4 to T3. This may be particularly useful in severe thyrotoxicosis. It also has less tendency to cross the placenta and is therefore useful in thyrotoxicosis in pregnancy.
However, currently there is no way to predict how well patients will respond to drug treatment.
Two very definite regimens of drug treatment exist.
Block and replace regimen
Currently the most popular regimen is block and replace.6-8
Patients are given carbimazole 40mg per day or propylthiouracil 300mg per day, and this is continued throughout the course of treatment. Levothyroxine 100µg per day is added to the regimen at four weeks. Treatment is continued for six to 12 months, and therapy is adjusted by modifying the thyroxine dose, based on the free T4 level.
On stopping the regimen, around 40% of patients will have a recurrence of their symptoms and therefore will need either surgery or radioactive iodine.9
Seventy per cent of patients who relapse do so within the first 12 months. In most patients who relapse, further drug treatment is unsatisfactory and either radioactive iodine or surgery is considered.
Late relapses do occur and patients should have their thyroid levels checked at yearly intervals for life.
Carbimazole 40-60 mg per day or propylthiouracil 300-450 mg per day is given, initially in divided doses three or four times a day, over a period of weeks. Doses are adjusted based on free T4 levels. Treatment is usually continued for 12 to 18 months. This is an arbitrary time, which varies from unit to unit.
As in the block and replace regimen, relapse may occur, usually within the first year of stopping treatment. If relapse does occur radioactive iodine or surgery should be considered.
Patients who have been treated by titration, as with the block and replace regimen, should be followed up for life with yearly TSH level checks, since there is always a chance of late recurrence.
One of the side-effects of medical treatment is a transient rash. This occurs in fewer than 5% of patients and may mean changing the antithyroid drug. Rashes are not an indication to stop treatment.
Other complications are few and far between. These include fever, cholestatic jaundice and a general aching of the muscles.
Agranulocytosis occurs in fewer than 0.1% of patients,10 usually within the first three months of treatment. Patients should stop taking their antithyroid medication and contact their doctor immediately if they develop a sore throat or mouth ulcers. Patients should be monitored for clinical signs.
Once the antithyroid drug has been stopped the agranulocytosis is usually reversed. Very rarely, it will be necessary to admit the patient to hospital for antibiotic treatment with/without granulocyte-stimulating factor.
In both forms of treatment, either block and replace or the titration regimen, ß-blockers such as propranolol can be used. Propranolol 20-40mg tds will deal with the cardiac effects of thyrotoxicosis and may be used early in the treatment with antithyroid drugs.
Beta-blockers can usually can be tailed off as the antithyroid drugs become effective.
Radioactive iodine therapy for thyrotoxicosis
Radioactive iodine is in many ways the ideal form of treatment for thyrotoxicosis.
Radioactive iodine is concentrated in the thyroid and causes cell damage and cell death. It is therefore almost inevitable that all patients treated with radioactive iodine will, after a period of years, develop hypothyroidism.
Some centres use a large fixed dose (555MBq) to ablate the thyroid, while other centres use a variety of doses, from 200 to 400MBq, to attempt to preserve some thyroid function and allow the patient to be free of the need for thyroid replacement.
Radioactive iodine, unlike surgery or drugs, does not work rapidly and may take three to four months to be effective. It is important to wait at least six months before repeating treatment for persistent thyrotoxicosis.
It is essential that patients treated with radioactive iodine are followed up regularly at yearly intervals, since permanent hypothyroidism occurs in at least 10% of patients in the first 12 months, and at a rate of 3% per year thereafter.
Radioactive iodine has some disadvantages. Some patients are unhappy about the idea of having radioactive iodine and will opt for surgery, and there are social circumstances when it can be difficult to give radioactive iodine. It is necessary for the patient to stay well away from close relatives, particularly children, and therefore patients may not find radioactive iodine an attractive treatment option. The physics department of the hospital will issue a form indicating the length of time relatives can be near to the patient and how near they can come. In addition, the patient will be warned that if they do not comply with the recommended regulations it is possible for them to set off radiation detectors at airports.
Pregnancy is an absolute contraindication and should be avoided for at least six months after treatment. It is essential that women who have had treatment with radioactive iodine are shown to be euthyroid before trying to conceive.
It is also prudent for men treated with radioactive iodine to abstain from unprotected sex for six months after treatment.
Many young women who wish to conceive and for whom drug treatment has failed may be concerned about having radioactive iodine since, unlike surgery, it cannot be guaranteed to work immediately and they may need a second or a third dose, delaying their attempts to conceive for as long as 18 months.
Radioactive iodine is a satisfactory form of treatment for mild TAO but may need to be covered with steroid treatment for seven days. There is still a generally held view that radioactive iodine should not be used to treat severe TAO, although this view has not been substantiated in clinical trials.
Surgical management of thyrotoxicosis
A more radical approach is now used, which involves removing all the thyroid and starting the patient on thyroxine as a replacement therapy.
Surgery is effective within several weeks and has the advantage that the episode of thyrotoxicosis is resolved quite quickly. However, it has complications. A thyroid storm, an acute form of severe thyrotoxicosis precipitated by surgery in a patient who has been inadequately prepared, is now virtually unheard of. Recurrent laryngeal nerve palsy is still a problem and probably occurs in a higher percentage of patients than the 1% quoted. However, damage to the parathyroids is a very important and difficult problem in thyroid surgery for thyrotoxicosis. In our view it occurs in the short-term in up to 20% of patients and in the long-term in up to 3-4% of patients.
Hypoparathyroidism is quite easy to treat using calcium and vitamin D supplements. It is, however, a nuisance for the patient.
Treatment of amiodarone-induced thyrotoxicosis
Treatment of amiodarone-induced thyrotoxicosis is extremely difficult. The amiodarone must be stopped and large doses of antithyroid drugs are needed.
If the use of carbimazole or propylthiouracil fails, potassium perchlorate 250mg tds should be added to the standard antithyroid regimen.
Most patients will need long-term thyroid replacement for hypothyroidism. If the acute phase of thyrotoxicosis is not manageable by radioactive iodine therapy, total thyroidectomy may be necessary.
All the management options for thyrotoxicosis have advantages and disadvantages.
It is important to have a full discussion with the patient to ensure that a treatment option is selected that is tailored to the individual.authors thyrotoxicosis Authors
Dr William RD Lynn
BSc MB BS
foundation year 2 house officer, St Mary's NHS Trust, London
Mr John A Lynn
consultant endocrine surgeon, Cromwell Hospital, London
key pointsTable 1: Clinical features of thyrotoxicosis thyrotoxicosis tab2