Grave's disease

Grave's disease is an auto-immune syndrome consisting of

• Overactive, enlarged thyroid gland (overactive goitre, or hyperthyroidism) due to stimulatory antibodies increasing the production of thyroid hormones;
• Exophthalmos (protruding eyeballs); and
• Sometimes a skin condition pretibial myxoedema.

Cause and associated factors

Auto-antibodies

Chronic inflammation of the thyroid gland can result in the production of antibodies directed against its own receptors (TSH receptors) which regulate the secretion of thyroid hormones. In Grave's disease, these auto-antibodies are stimulatory, causing the gland to overproduce its hormones T3 and T4. The gland increases in size as it becomes hyperactive, and is visible as a swelling in the front of the neck. These stimulatory auto-antibodies are specific to Grave's disease. Higher levels of these antibodies are associated with recurrent disease if treatment is stopped.

These antibodies also cause swelling of the fat and connective tissues behind the eyeball, and the muscles around the eye, with deposition of substances like hyaluronic acid and fluid accumulation. All of this causes the eyeball to be pushed forward, and can lead to serious eye problems if not dealt with.

Gender and genetics

Graves 's disease occurs seven times more often in females than in males. There is a strong family tendency, with siblings often affected, and twins even more so (20-40 percent).

Stress

This may be a triggering factor: high stress states suppress immunity, followed by a rebound hyper-immune state when the stress is relieved. This may lead to antibody production. Conditions of immune suppression, such as pregnancy, have a lower incidence of Grave's disease.

Drugs

Iodine and iodine-containing drugs, such as amiodarone used for heart rhythm disorders, may interact with, or directly damage, thyroid cells. Either process can result in antibody formation: if the antibodies are stimulatory, increased thyroid activity will result.

Smoking

There is a strong association between smoking and Grave's disease, and especially with exophthalmos.

Symptoms

The predominant symptoms of Grave's disease are those of hyperthyroidism, which include:

• Weight loss despite normal or increased appetite,
• Anxiety and swings of emotion,
• Tremor,
• Palpitations,
• Heat intolerance and increased sweating,
• Hyperdefeacation - passing more frequent stools, but not diarrhoea,
• Urinary frequency,
• Erectile dysfunction and gynecomastea (breast enlargement) in men,
• Atrial fibrillation,
• Deteriorated glycaemic control in diabetics,
• Osteoporosis or hypercalcaemia, and/or
• Itchy swollen lower legs (pretibial myxoedema).

Older patients tend to have more weight loss than younger patients, and more heart-related symptoms, such as rapid pulse, atrial fibrillation, shortness of breath with exertion, and obvious oedema.

In patients with eye complications, the exophthalmos or protruding eyes may be totally symptom-free, and be more of a cosmetic concern. In severe exophthalmos, there may be pain behind the eye, excessive tear production or blurring of vision.

Diagnosis

The general impression of patients with hyperthyroidism is that they seem to be in a terrible hurry - they are hyperactive and speak rapidly. There is a fast pulse, which may be irregular (atrial fibrillation) and often there is raised blood pressure. A tremor is noticeable with hand movements and reflexes are very brisk, but large muscles may be weaker than normal. Skin is typically warm and moist, and hair is fine.

There is often retraction of the eyelids as part of the general hyperstimulated state, but true exophthalmos may be found, sometimes with limitation of eye movements, and swelling of the tissues around the eyes.

A characteristic of Grave's disease is pretibial myxoedema: a thickening and hardening of the skin, usually of the lower legs, with an orange-peel appearance. These areas are usually not painful, but may be itchy. The swelling is due to deposits of hyaluronic acid in the tissues.

Special tests

Blood tests of thyroid function are simple and reliable.

The most cost-effective screening test is measuring serum thyroid stimulating hormone (TSH). If the value is normal, the patient is very unlikely to have hyperthyroidism.

If the TSH is low, then levels of thyroid hormones T3 and T4 are measured. The pattern of low TSH with high T3 and T4 is diagnostic of hyperthyroidism.

Other blood tests are not needed to make the diagnosis, but may be done to investigate associated symptoms, such as osteoporosis.

Further tests to clarify thyroid function may be done to establish the cause of the overactive gland, including:

• Radio-iodine uptake scan - a high uptake with hyperthyroidism proves that the gland is producing excess hormone;
• Thyroid stimulating antibodies can be measured in the blood;
• Ultrasound of the thyroid to measure blood flow (raised in Graves disease);
• Suppression scan - for patients whose TSH is only slightly lowered, a thyroid scan is repeated after giving a large enough does of exogenous hormone to suppress TSH to minimal levels. This may be dangerous in elderly patients.

Treatment

The dual aim of treatment is to relieve the symptoms of hyperthyroidism, and to decrease the amount of thyroid hormones being produced. Beta blockers are usually prescribed (unless there are specific contraindications) to reduce symptoms of anxiety, rapid pulse, tremor and heat intolerance.

To decrease hormone production, treatment options are:

• Anti-thyroid drugs, such as thionamides - these have a relapse rate of 37 percent;
• Radio-iodine therapy. This is the treatment of choice in nearly all major centres worldwide, and is aimed at destroying the thyroid gland, to prevent recurrences. It has the risk of worsening the exophthalmos, and 20 percent of patients will need a second treatment course for a total cure;
• Surgery - total or sub-total thyroidectomy - has a 6 percent relapse rate. This is not a popular choice, and reserved for the following conditions:
  • Very large goitre,
  • Goitre causing obstruction to the airway/oesophagus,
  • Pregnant women allergic to anti-thyroid drugs, or
  • Patients who refuse radio-iodine and who are allergic to anti-thyroid drugs or who fail to take medication correctly.

Regardless of the treatment type, there may be a paradoxical worsening of the exophthalmos if hypothyroidism is caused, especially with radio-iodine therapy. Also, radio-iodine therapy may worsen the pre-tibial myxoedema; the reason for this is unknown. Total thyroidectomy has been found to cause total disappearance of the antibodies responsible for Grave's disease.

Outcome

It is often difficult to achieve a perfectly normal level of thyroid function after treatment, so to prevent relapses, treatment may aim at inducing a mildly underactive thyroid. Total thyroidectomy will naturally cause hypothyroidism. However, an underactive thyroid is easy to treat. After treatment for Grave's disease, most patients will need to take thyroid hormone tablets for life.

The exophthalmos (protruding eyes) and the swollen legs may not improve regardless of which treatment is used.

(Dr A G Hall)