- Grave’s disease
- Clinical features of thyrotoxicosis
- Types of presentation
- Differential diagnosis
- Long-term risks of hyperthyroidism
- Hyperthyroidism and pregnancy
- Other causes of hyperthyroidism
- Related Articles
- 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
- 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:
- 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 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
- Can occur at any age
- Peak onset age 40-60
- F:M 5-10 : 1
- Environment triggers include:
- High iodine intake
- 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.
- 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
- Fatigue, weakness
- Weight loss with increased appetite
- Diarrhoea, steatorrhea
- 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
- Diffuse pigmentation
- Palmar erythema
- Muscle weakness and wasting
- Eyelid retraction
- Rarely there may be psychosis
- Periodic paralysis (common in Asian males)
- Impaired consciousness
- 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.
- 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
- 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.
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.
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.
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.
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
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 autoantibodies||Thyroglobulin autoantibodies||TSH Receptor antibodies|
Adapted from a table in Evaluating and managing patient with thyrotoxicosis – afp – August 2012
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
- 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
- Surgery is rarely used – it is normally only used when there is mechanical obstruction of the trachea from an enlarged thyroid.
- 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 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.
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.
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.
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.
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
- 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
- 131I has a half-life of 8 days; so after 2 months the radiation has disappeared.
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.
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
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
- 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
- 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
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Evaluating and managing patients with thyrotoxicosis