Introduction

Thyrotoxicosis is the state produced by excessive thyroid hormone. It is not strictly the same thing as hyperthyroidism, as thyrotoxicosis can exist without hyperthyroidism being present – for example – after the administration of excessive thyroxine that may be seen when hypothyroidism is treated. However, in clinical practice, the terms thyrotoxicosis and hyperthyroidism are often used interchangeably.
  • Thyrotoxicosis is a common GP presentation – with a prevalence of around 0.5%
  • Grave’s disease is the most common cause
  • Other causes include toxic multinodular goitre, toxic adenoma and thyroiditis. Hashimoto’s thyroiditis can also occasionally cause an initial hyperthyroidism, before, in the long-term, become a hypothyroid disorder
  • Thyroiditis can be safely managed in the community, but thyrotoxicosis of any other origin should be referred for specialist care
  • Presentation can be atypical in the elderly
  • Treatment depends on the cause:
    • Grave’s is usually treated with an anti-thyroid drug (usually carbimazole)
    • Toxic multinodular goitre and toxic adenoma are treated with radioactive iodine therapy
    • Thyroiditis does not usually require any treatment, but symptomatic agents may be required

Epidemiology

  • Affects 2-5% of females and 0.2-03% of men.
  • The female : male ratio is 5:1.
  • Onset usually occurs between the ages of 20 and 40 in cases of Graves disease, but later in life where the cause is nodular thyroid disease.
  • 99% of cases are caused by intrinsic thyroid disease, and less than 1% caused by a primary pituitary problem.
  • Grave’s disease accounts for 60-80% of cases of thyrotoxicosis.
  • Nodular thyroid disease accounts for most of the rest (20-40%).
  • Rarer causes include:
    • Thyroiditis
    • Exogenous thyroid hormone
    • Iodine excess
    • Thyroid carcinoma
    • Mutation of TSH receptor
  • Secondary causes:
    • TSH secreting pituitary tumour
    • Thyroid hormone resistance
    • Gonadotrophin-secreting tumours

Grave’s disease

  • Grave’s disease is and autoimmune disorder caused by the production of TSH receptor stimulating antibodies.
  • These antibodies stimulate the thyroid gland to produce more T3 and T4

Epidemiology

  • Can occur at any age
  • Peak onset age 40-60
  • F:M 5-10 : 1

Aetiology

  • Environment triggers include:
    • High iodine intake
    • Stress
    • Smoking
    • Smoking is also a major risk factor in thyroid associated Grave’s opthalmopathy.
  • Genetic factors – In monozygotic twins, concordance is 20-50% – so there is some genetic factor involved. In dizygotic twins concordance is 5%. The antibodies are detectable in the blood. The exact cause is unknown, however it is interesting to note that E. Coli and other Gram-negative bacteria contain TSH binding sites. Thus, Grave’s disease may result from some sort of initiating event caused by one of these pathogens in a genetically susceptible individual
    • No specific genes have been identified as being involved
    • Grave’s disease is also closely related to other auto-immune diseases such as myasthaenia gravis, coeliac disease and pernicious anaemia. The disease follows a relapse and remission pattern. Up to 40% of patients may have only a single episode. Many patients eventually become hypothyroid.

Pathology

  • There is thyroid hypertrophy and hyperplasia.
  • The follicles have a very small colloid, and the follicular cells are columnar.
  • There are focal and generalised lymphocytic infiltrates
  • Lymph node hyperplasia can occur in the spleen, lymph nodes and thymus.
  • The above changes are all reversed by antithyroid drugs.
 

Clinical features of thyrotoxicosis

These vary depending on the age of the patient and severity of the disease. Occasionally, the symptoms may seem paradoxical, for example:

  • 10% of patients may have weight gain
  • This is due to the increased appetite caused by the condition, and in 10% of cases the increase in appetite exceeds the effects of increased metabolism.

General features of thyrotoxicosis

  • Hyperactivity, irritability, altered mood
  • Heat intolerance, sweating
  • Palpitations
  • Fatigue, weakness
  • Weight loss with increased appetite
  • Hyper-reflexia
  • Diarrhoea, steatorrhea
  • Polyuria
  • Loss of libido
  • Oligomenorrhoea (infrequent periods)
  • Menorrhagia (very heavy periods)
  • Sinus tachycardia
  • Atrial fibrillation (particularly in elderly)
    • Up to 20% of patients
  • Fine tremor
  • Warm, moist skin
  • Goitre
  • Diffuse pigmentation
  • Palmar erythema
  • Muscle weakness and wasting
  • Eyelid retraction
  • Gynecomastia
  • Rarely there may be psychosis
  • Periodic paralysis (common in Asian males)
  • Impaired consciousness

Thyrotoxic Storm

  • Thyrotoxic storm is severe acute presentation of thyrotoxicosis (thyrotoxic crisis). In a similar way to myxedema coma, this often presents as a result of acute illness, and there may not be any previous history of thyrotoxicosis. It has a 20-30% mortality rate. With this there is:
  • Treatment should be started as soon as possible – and patients should be given propanolol, antithyroid drugs, potassium iodide (to reduce vascular flow to the gland) and corticosteroids.

Types of presentation

The “classical” presentation is that of a woman aged 40-60 with a diffuse goitre and thyrotoxicosis. 50% of patients with have thyroid eye disease.

Goitre

  • Occurs in almost all presentations of Grave’s disease – in which case it is usually diffuse and symmetrical

The eye signs – Ophthalmopathy

  • Occur in 50% of cases of Grave’s disease
  • The eye signs only occur in Grave’s disease, and not in other causes of thyrotoxicosis
  • Signs include:
    • Eye-lid retraction
    • Periorbital oedema
    • Proptosis

Other signs

  • Pretibial myxoedema is a sign appearing on the leg which usually occurs in conjunction with the eye signs.
    • It is a big lumpy fatty looking growth. It can actually occur anywhere on the body.
    • 5% of Grave’s patients will have this.
    • Patients with this sign will always have ophthalmic symptoms and 10-20% will have clubbing. A small to moderate diffuse firm goitre is also present in many Grave’s patients.
    • Other autoimmune conditions may be present in the family. Hyperplasia of lymphoid tissue (such as splenomegaly) is sometimes found accompanying Grave’s disease.

The elderly

Elderly patients typically present with atrial fibrillation and tachycardia with or without other heart signs. Other general signs are often not present. Thyroid function tests are mandatory in any patient with atrial fibrillation.

Children

May frequently present with excessive growth rate and height, along with behavioural problems such as hyperactivity. They are likely to show eight gain rather than weight loss.

Apathetic thyrotoxicosis

This is a condition found in the elderly. There may be very few signs, and what signs there are may mimic that of hypothyroidism, when in actual fact the underlying cause is thyrotoxicosis.

 

Differential diagnosis

The vague nature of symptoms can mask the true identity of the condition – and other conditions that cause weight loss and anxiety may be suspected. However, biochemical testing can easily distinguish thyrotoxicosis.
 

Investigations

Serum TSH will be low, typically <0.05mU/L. Normal levels are 0.4-5 U/L. To confirm diagnosis, you will also need increased levels of T4 / T3.

– T3 in this instance is more sensitive than T4.

TPO and thyroglobulin antibodies are likely to also be present in Grave’s disease. TSH receptor antibodies are not commonly tested but are usually present (in Grave’s disease these will be detectable in 60-90% of cases).

  • Grave’s disease may be diagnosed clinically in a patient with typical symptoms of thyrotoxicosis, a symmetrical goitre and thyroid eye disease – but in reality blood tests will usually be performed as well
  • TSH is usually the initial first test
  • In  all causes of thyrotoxicosis, TSH is suppressed and T3 and T4 are raised
  • In “subclinical hyperthyroidism” the TSH can normal or supressed, but the T3 and T4 will be normal
    • “Subclinical” is a misnomer because many patients are symptomatic during this phase of the disease. These patients may still require further work-up and management as per true thyrotoxicosis

Autoantibodies

The presence and absence fo various autoantibodies can assist with the diagnosis, but the interpretation is often not straightforward. All of the antibodies can exist in healthy individuals, in various incidences. However, certain patterns make certain diagnoses more likely.

  • TSH receptor antibodies can be used to diagnose Grave’s disease
    • The presence of TSH receptor antibodies AND thyrotoxicosis confirms the diagnosis of Grave’s Disease
    • Up to 10% of patients with Grave’s disease, TSH receptor antibodies are undetectable
    • They are present in 1-2% of the general population
  • The presence of Thyroid peroxidase (TPO) and/or thyroglobulin autoantibodies may also assist in differentiating the cause of the thyrotoxicosis. They are much less specific than TSH receptor antibodies.
    • TPO and / or thyroglobulin in the ABSENCE of TSH receptor antibodies indicated likely chronic autoimmune thyroiditis.
    • TPO and thyroglobulin negative and TSH antibody positive likely represents Grave’s disease
Thyroperoxidase autoantibodiesThyroglobulin autoantibodiesTSH Receptor antibodies
General Population8-27%5-20%1-2%
Graves Disease50-80%50-70%90-99%
Autoimmune Thyroiditis90-100%80-90%10-20%

Adapted from a table in Evaluating and managing patient with thyrotoxicosis – afp – August 2012

Imaging

If there is doubt over the cause of the thyrotoxicosis, then imaging can help to differentiate the possible causes.

  • Radionulide scan is the imaging modality of choice in differentiating the cause of thyroxtoxicosis
    • Technithium pertechnetate (Tc-99m) is the main nuclide used for the scan
    • This is associated with a dose of radiation of around 2.4mSv – about the same as a single CT scan
    • It is contraindicated in pregnancy. In breastfeeding, women should cease breastfeeding for 48 hours after the scan – they should express and discard the milk so as not to affect the supply
    • Results:
      • Grave’s disease – diffuse widespread uptake
      • Toxic multinodular goitre – Can be normal, or may show multiple nodes of uptake, with the rest of the thyroid often showing reduced uptake
      • Toxic adenoma – single area of increased uptake
      • Thyroiditis – none or minimal uptake
    • Ultrasound is often NOT useful in diagnosing the cause of thyrotoxicosis

Treatments

Anti-thyroid drugs are the first line treatment for Grave’s disease. Radioactive iodine and thyroidectomy may also be considered.
  • Surgery is rarely used – it is normally only used when there is mechanical obstruction of the trachea from an enlarged thyroid.
The treatments for hypothyroidism address the problems caused by the disease, but do not alter the underlying pathology, and are thus not a ‘cure’.
Also, treatments for hyperthyroidism do not seem to alter the course of thyroid eye disease – particularly the incidence of proptosis. However, glucocorticoids such as prednisolone,  are proven to reduce this effect.

Symptomatic Agents

e.g. Propanalol
These are often used immediately after diagnosis to control the symptoms, before the drugs that affect thyroid hormones have taken effect.
They will reduce symptoms such as:
  • Tachycardia
  • Dysrhythmias
  • Tremor
  • Agitation
Beta-blockers also decrease peripheral conversion of T4 to T3.
In cases where beta-blockers are contraindicated (e.g. in asthma), then calcium channel blockers can be considered.

Antithyroid drugs

Antithyroid drugs (Thioureylenes) e.g. Carbimazole, propylthyrouracil, thiamazole (aka methimazole)
These can take several weeks to act (usually about 3-4 weeks) due to the long half life of thyroid hormones. As a result, the beta-blockers are given during this period to reduce symptoms.
Carbimazole is usually the drug of choice
  • Has a quick onset of action, can be given once daily, less hepatotoxic
  • Carbimazole also has immunosuppressive actions
    • Thiamazole is the active metabolite of carbimazole, and can be given as such
  • Typical dosing is 10-30mg of carbimazole daily, weaned to effect – TFTs should be repeated 4 weeks after initiation of therapy
  • Usually a tapering dose is required – for example down to 2.5 – 10mg – and treatment can usually be ceased after 12-18 months
    • Remission occurs in about 50% of patients at this time
    • Poor long-term remission rates are assoacited with:
      • Male gender
      • Age <40 years at onset
      • Large goitre
      • Very high T3 or T4 levels on initial presentation
    • Up to 20% of patients eventually go on to develop hypothyroidism

Propylthiouracil is thought to act more quickly than carbimazole due to the fact that it also inhibits the conversion of T4 to T3.

  • Preferred in the first trimester of pregnancy, and in thyrotoxicosis due to its quicker onset of action
These drugs decrease the output of thyroid hormones from the thyroid gland by reducing the action of the peroxidase enzyme – thus preventing iodine from joining with tyrosine – which is what normally happens before the tyrosine is excreted from the cell and incorporated into a thyroglobulin molecule.

These drugs are given orally, and then will be converted into their active form (i.e. methimazole) before being distributed about the body. They have a half life of 6-15 hours.
The average dose of carbimazole can reduce thyroid hormone production by 90% in 12 hours. – however, the clinical response may take many weeks, due to the long half-life of T4 (NB – T4 has a half life on 7 days) and the fact that lots of T4 is stored in the thyroid itself.

Prolonged treatment is either by reducing the dose gradually (dose titration), or by a ‘block and replace’ regimen. Neither of these two methods has been shown to be superior.

Dose titration

Review after 4-6 weeks. TSH level is likely to remain suppressed and is not useful at this stage – make assessment purely on T3/T4. When clinically (i.e. symptomatically) and biochemically euthyroid, then stop beta blockers Review after 2-3 months – and if controlled, reduce carbimazole. If hyperthyroidism remains controlled, gradually reduce dose to 5mg daily over period of 6-24 months. When patient is euthyroid on 5mg carbimazole daily, Stop treatment.

The treatment regimen with propylthiouracil is similar.
 

Block and replace

An alternative to the weaned tapered dogging regimen described above. Relatively high doses of carbimazole (e.g. around 40mg daily) can used to completely stop the production of thyroid hormone in the thyroid. At the same time, give the patient about 100µg thyroxine daily to replace the thyroxine they are not producing for themselves. You should not use this treatment in pregnancy, as T4 does not cross the placenta as well as carbimazole, and thus you may alter the child’s levels of thyroid hormone.

 

Thioureylene facts

About 50% of patients will relapse within 2 years after a treatment with one of these drugs. These patients can either then go onto long-term thyroid therapy (i.e. the block and replace mechanism) or they may consider radioiodine therapy. 90% of hyperthyroid patients have a diffuse goitre. Those that have single/multinodular goitre are less likely to remit after a course of treatment with anti-thyroid drugs.

Unwanted effects

Agranulocytosis is the main side effect. It appears in 1/1000 patients, usually within 3 months of treatment. it is where the patient has an abnormally low level of circulating white blood cells (particularly neutrophils). The most common symptoms of this side effect are fever, sore throat and rashes.

  • Patients should cease anti-thyroid drugs whenever they get: mouth ulcers, fever, sore throat, or any other symptoms suggestive of infection
  • Regular FBC monitoring is not effective at prevention
  • Previous agranulocytosis is a contra-indication to the use of any other anti-thyroid medication
 

Radioiodine

  • Between 65-80% of patients will be euthyroid or hypothyroid at 12 months after treatment
  • A second dose can be given at 6 or 12 months if the patient remains hyperthyroid
  • Radiation thyroiditis occurs in up to 10% of patients – this causes a worse thyrotoxicosis and often a painful goitre
  • Anti-thyroid drugs are typically used acutely before the administration of radioactive iodine – to control the thyrotoxicosis and symptoms
  • Women should avoid pregnancy for 6 months
  • Men should avoid fathering children for 4 months
  • Patients should avoid close contact with children for several days after the procedure
  • Not recommended in cases of severe thyroid eye disease as it can exacerbate symptoms
This type of treatment tends to be favoured in the USA, whilst anti-thyroid drugs tend to be first line treatment in Europe.
The iodine will be taken up by the thyroid gland, and then destroys local cells with radiation – causing cell necrosis.
The type of iodine used is usually 131I given as a sodium salt. The iodine is absorbed by the thyroid in the normal manner and taken up into the thyroglobulin. This type of iodine emits both beta and gamma radiation. The gamma will pass out through the tissues in a pretty harmless fashion, whilst the beta radiation (which emits an electron or a positron) will be absorbed by the thyroid tissue cells, and has a powerful cytotoxic action.
  • 131I has a half-life of 8 days; so after 2 months the radiation has disappeared.
It is given as a single dose, but the cytotoxic effect is not seen for 1-2 months.
Hypothyroidism will generally occur in those treated by this method, particularly in Grave’s disease. This is then easily treated by giving T4. About 75% of patients will be euthyroid after treatment, although then many of these will progress to hypothyroidism.
If the patient remains hyperthyroid after treatment, you can give them a higher dose. This improves response, but also increases the future risk of hypothyroidism.
Monitoring of thyroid function is necessary several times in the first year after threatment, and then once a year after this.
Radioiodine should be avoided in children and those who are pregnant due to the risk to the foetus.
131I can also be used to measure thyroid function – a dose is given, and then at certain intervals, a gamma-radiation counter is placed over the gland and it counts the radiation emitted.
It can also be given to treat thyroid cancer.
 
There are very strict rules in the UK regarding radiation safety, and this may put some patients off having this treatment. Usually in the UK, patients are brought to a euthyroid state with carbimazole before commencing radioiodine therapy.

Patients with thyroid eye disease are likely to show worse eye symptoms after treatment with radioiodine, and thus they are more likely to be treated with carbimazole.

The risk of cancer after treatment with radioactive iodine has long been debated, however, evidence shows that the overall risk of any cancer is NOT affected by this treatment, but that the risk of thyroid cancer is increased. However, the absolute risk of thyroid cancer still remains very low.

Surgery – subtotal thyroidectomy

  • Rapidly controls symptoms
  • Anti-thyroid drugs used pre-surgery reduce the risk of thyrotoxic storm
  • Risks include:
    • Recurrent laryngeal nerve damage <1%
    • Hyperparathyroidism – 2%

This should only be performed in patients who are already euthyroid. Normal practice prior to surgery, is to stop the treatment 10-14 days before surgery, and give potassium iodide which reduce vascular flow to the gland. Indications for surgery are:

  • Patient choice
  • Persistent side-effects of drugs
  • Poor compliance with drug therapy
  • Recurrent hyperthyroidism after drug treatments
  • A large goitre which may be causing trouble swallowing

Long-term risks of hyperthyroidism

There is a slightly increased risk of mortality in hyperthyroidism, although death normally occurs within one year of diagnosis, so in the long-term, the increase in mortality is not noticeable. The only major long term risk is increased risk of osteoporosis.

 

Hyperthyroidism and pregnancy

Hyperthyroidism in pregnancy is quite rare and usually mild. The underlying pathology is usually that of Grave’s disease. TSI (Thyroid stimulating immunoglobulin) is able to cross the placenta and stimulate the foetal thyroid.

Carbimazole – easily crosses the placenta, but T4 does not. As a result, and block and replace regimen cannot be used, and so to treat this condition during pregnancy, the smallest possible use of carbimazole should be used, and the foetus should be monitored.

It has also been associated with birth defects, especially when given in the first trimester.

As a result, propylthiouracil is preferred in the first trimester, and patient care often switched to carbimazole in the second trimester. Up to 30% of women can cease treatment by the third trimester.

The baby should be checked straight after birth, as treatment in this way can cause a goitre.
Assessing the child during pregnancy – if the mother suffers from Grave’s disease, then even if she is made euthyroid by treatment, her foetus may still be hyperthyroid. An easy may to monitor if this is the case is to check the child’s heartbeat – a heart rate of above 160 strongly suggests hyperthyroidism. To compensate for this, the dose of carbimazole given to the mother may be increased, and she may be given T4 (as this does not easily cross the placenta).
Breast feeding whilst on carbimazole or propylthiouracil at normal levels appears to be safe.
Radioactive iodine should definitely not be used.
Surgery may be necessary if it is expected that large doses of carbimazole will be needed to get the patient under control. This is best carried out in the second trimester.
Untreated neonatal hyperthyroidism is associated with hyperactivity in later age.
Thyroid function tests are difficult to interpret fro a neonate as the levels vary greatly. It is best to assess whether the child in hyperthyroid by checking for sings and symptoms.

 
 

Other causes of hyperthyroidism

Toxic Multinodular Goitre

Responsible for about 35% of cases of hyperthyroidism. This commonly occurs in older women. It is associated with an increase in iodine intake. This can be a result of dietary increase, but it has been specifically linked with iodine containing agents, such as amiodarone and some types of contrast media. The nodules in this type of goitre are adenomatous. It develops from a simple sporadic goitre. More than 50% of these are due to a genetic mutation involving the TSH receptor, or the protein it produces. Remission can rarely be achieved, and life-long treatment may be required.

  • Caused by one or more thyroid nodules
  • F > M
  • Onset typically at >50 years of age

Pathology

  • There is a mixture of relatively normal tissue, and areas of hyperplasia with nodules filled with colloid.
  • There will be a varying degree of fibrosis, haemorrhage and calcification.

Toxic solitary adenoma / nodule

Responsible for about 5% of cases of hyperthyroidism It will not usually remit after a course of treatment, but symptoms can be controlled with continual antithyroid drugs.

  • F > M
  • Onset usually age 30 – 50

Thyroiditis

  • An autoimmune disorder whereby the thyroid tissues are destroyed, and the thyroxine contained within the tissue is released
  • This causes a brief thyrotoxicosis – often lasting only 1-2 months, and then a hypothyroid period lasting 4-6 months
  • In 20% of patients, the hypothyroidism is permanent
  • Thyroperoxidase and thyroglobulin antibodies are often present in chronic autoimmune thyroiditis
    • These are present in 90%+ of cases
    • They are also present in about 80% of Grave’s Disease patients
    • TSH receptor stimulating antibodies are usually negative

References

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