- Grave’s disease
- Clinical features of thyrotoxicosis
- Types of presentation
- Differential diagnosis
- Long-term risks of hyperthyroidism
- Hyperthyroidism and pregnancy
- Other causes of hyperthyroidism
- 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 in cases of nodular thyroid disease.
- 99% of cases are caused by intrinsic thyroid disease, and less than 1% caused by pituitary problems.
- 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:
- Iodine excess
- Thyroid carcinoma
- Mutation of TSH receptor
- TSH secreting pituitary tumour
- Thyroid hormone resistance
- Gonadotrophin-secreting tumours
This is caused by TSH receptor stimulating antibodies. 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.
Environment triggers include:
- High iodine intake
Smoking is also a major risk factor in thyroid associated opthalmopathy. Grave’s disease is also closely related to other auto-immune diseases such as myasthaenia gravis 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 is focal and generalised lymphocytic infiltrate
- 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
10% of patients may have weight gain
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)
- fine tremor
- warm, moist skin
- diffuse pigmentation
- palmar erythema
- muscle weakness and wasting
- eyelid retraction
- rarely there may be
- periodic paralysis (common in Asian males)
- impaired consciousness
Types of presentation
The eye signs
This is the typical presentation of Grave’s disease. The eye signs infact only occur in Grave’s disease Pretibial myxedema 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. 50% of Grave’s patients will have the ophthalmic sing. 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 sinus 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).
- 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.
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
Relatively high doses of carbimazole (e.g. around 40mg daily) are 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. If side effects appear with carbimazole, then patient should be changed to propylthiouracil, and vice-versa. It is rare for side-effects to occur on both drugs.
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: o Patient choice o Persistent side-effects of drugs o Poor compliance with drug therapy o Recurrent hyperthyroidism after drug treatments o 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. 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 old women This is very closely linked 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.
- 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.