Graves' Disease
Clinical Features


Hyperthyroidism is a clinical syndrome that is produced by persistent, inappropriately high levels of circulating thyroxine. Hyperthyroidism may also be called thyrotoxicosis. It is more common in women and can affect a wide range of ages. The causes of hyperthyroidism are as follows.

Of these causes, the first three account for the vast majority of cases. Acute thyroiditis tends to induce hyperthyroidism only for a short period of time.

Excess ingestion of thyroxine, either due to the prescription of an excessive dose, inadvertent incorrect taking of the medication or deliberate self overdose, can cause hyperthyroidism.
A surfeit of ingested iodine may also send the thyroid into overdrive.
Amiodarone is a drug used to treat cardiac arrhythmias and contains iodine.
The hormone human chorionic gonadotrophin shares part of its amino acid sequence with TSH and high levels of HCG can overstimulate the thyroid.
TSH-secreting tumours are rare but could be either a pituitary adenoma or the accomplished producer of endocrine substances, small cell carcinoma.
Struma ovarii is a type of ovarian teratoma that is composed mainly of thyroid tissue.

Graves' Disease

Graves' disease is an autoimmune condition that accounts for approximately three-quarters of cases of hyperthryoidism. It tends to present between the ages of 20-40 years and has a male : female ratio of 1 : 5. The hyperthyroidism is produced by autoantibodies which react with the TSH receptor on the follicular epithelial cells of the thyroid and stimulate this receptor, mimicking the action of TSH. However, the generation of the autoantibodies is not subject to the usual homeostasis of the thyroid-pituitary axis and proceeds out of control. The HLA-associations include HLA-DR3.

The thyroid is uniformly enlarged in Graves' disease. This is a consequence of the stimulatory action of autoantibodies on the whole gland. The thyroid follicles do not contain much colloid because the epithelial cells are beavering away converting it into thyroxine. The outlines of the follicles exhibit infoldings in order to maximise the surface area of the colloid that can be used by the epithelial cells. A chronic inflammatory cell infiltrate is present.

Clinical Features

The clinical features of hyperthyroidism are largely predictable from the role of thyroxine and reflect overstimulation of the metabolic rate and excessive augmentation of the effects of the sympathetic nervous system.

The thyroid gland is frequently enlarged, particularly in the three most common causes of hyperthyroidism.

The resting pulse rate is increased and will often be sufficient to be classified as sinus tachycardia (a normally organised rhythm that exceeds 100 beats per minute). In some people, the overexcitation of the heart can cause the heart rhythm to degenerate into atrial fibrillation. Hypertension can sometimes occur.

The patient's appetite is increased but their weight decreases. The weight loss occurs because the elevated levels of thyroxine cause the body to burn carbohydrates and fat to generate heat. Conditions in which there is weight loss despite an increased appetiate are rare.

Water diarrhoea may occur.

One of the effects of the sympathetic nervous system is to make skeletal muscles more susceptible to depolarisation. This is a useful adaptation in the flight or fight response but is probably less helpful in situations of nervousness. The potentiation of the sympathetic nervous system in hyperthyroidism means that patients often have a fine tremor that is present at rest and can be seen best in the hands. Tendon reflexes are exaggerated. Muscle weakness can also be encountered in hyperthyroidism if the body's protein metabolism is shifted into a net catabolic state that causes muscle proteins to be broken down. Disturbances of potassium metabolism can also induce muscle weakness.

Patients who have hyperthyroidism frequently feel anxious or irritable. This is a combination of the action of thyroxine on the brain and the heightened state of sympathetic arousal. Rarely, the effect can be sufficient to induce a psychotic disorder.

Excessive sweating is a common feature of hyperthyroidism. The palms may be red (palmar erythema). A less common dermatoloical manifestation is pretibial myxoedema, a skin rash which affects the shins and features thickened, raised, itchy skin that may be hyperpigmented. Clubbing is an uncommon component of hyperthyroidism that is caused by Grave's disease.

Heat intolerance is a characteristic feature of hyperthyroidism. The energy transduced by the elevated metabolic rate is released as heat, so patients feel uncomfortable in warm environments.

Amenorrhoea and infertility can be encountered in female patients who have hyperthyroidism.

Thyroid Eye Disease

Changes to the eyes are a characteristic and often striking feature of hyperthyroidism. Many of these features are specific to Graves' disease. However, most patients who have hyperthyroidism, regardless of the cause, will manifest a staring appearance. This is produced by lid retraction which widens the palpebral fissure (the space between the eyes). The levator palpebrae superioris muscle, which lifts the upper eyelid, is partly innervated by the sympathetic nervous system. The enhanced activity of the sympathetic nervous system in hyperthyroidism makes this muscle overactive. This lifts the upper eyelid to the extent that sclera is visible between the iris and the upper eyelid (normally the white of the eye is not seen between top of the iris and the upper eyelid). This phenomenon of lid retraction is accompanied by lid lag, in which the normal descent of the upper eyelid when the eye looks downwards is delayed.

Other ophthalmic changes that are encountered in hyperthyroidism are specific to Graves' disease but because Graves' disease is a common cause of hyperthyroidism these feature can be incorrectly believed to be a generic feature of all cases of hyperthyroidism.

The opthalmic aspects of Graves' disease are an extension of the autoimmune basis of the disorder. The autoantibodies of Graves' disease react with the soft tissues of the orbit, including the extraocular muscles and fat. These tissues demonstrate chronic inflammation, as would be expected in an autoimmune response and can become enlarged, fibrotic and damaged.

The bulking out of the orbital soft tissues by the chronic inflammation makes the eye bulge out of the orbit: exophthalmos or proptosis. This exacerbates the staring appearance of the eyes. In severe cases this can interfere with the closure of the eyelids and this in turn prevents proper lubrication of the eyes by the tears, with the risk of corneal ulceration. Eye pain, watering and photophobia can accompany these features. One or more of the extraocular muscles can malfunction, yielding diplopia (double vision). The optic nerve may become inflamed and/or atrophic. Rarely, the ophthalmopathy of Graves' disease can result in loss of vision in one or both eyes.


Confirmation of hyperthyroidism is achieved through thyroid function tests. These simply measure the levels of TSH and T4 in the blood. In hyperthyroidism the T4 (and T3) levels are elevated. In almost all cases the levels of TSH are very low because the excess thyroxine feeds back on to the pituitary gland to suppress the release of TSH.

Other blood tests are related to excluding background complications or exarcerbating factors.

FBC Anaemia is not a good combination with tachyarrhythmias because it increases the strain on the heart so a full blood count is prudent.
U+E The urea and electrolytes should usually be normal in hyperthyroidism. However, there can occasionally be potassium disturbances in association with muscle disease. Profuse diarrhoea may also induce abnormalities.
Glucose Glucose levels may be checked to exclude the rare complication of secondary diabetes mellitus.
Calcium Hyperthyroidism is a rare cause of hypercalcaemia.

The first line of imaging for the thyroid gland is ultrasound. This can idenfity solitary lesions and delineate the shape of a goitre. Radionucleide scans can identify hot and cold nodules. These are parts of the thyroid gland that are hyperactive or hypoactive relative to the rest of the gland.

Investigation of hyperthyroidism will seldom need to proceed beyond this stage. The more unusual investigations will generally be focused on locating extrathyroid sources of thyroxine or TSH.


Control of hyperthyroidism can usually be acheived by the drugs carbimazole and propylthiouracil which block the synthesis of thyroxine. Beta-blockers can provide relief from many of the symptoms of hyperthyroidism by their inhibition of the actions of many parts of the sympathetic nervous system.

Multinodular goitres and follicular adenomas will require surgery, the latter particularly to permit the tumour to be assessed to exclude follicular carcinoma. Some cases of Graves' disease will resolve with medical treatment while others will require surgery to remove the thyroid gland.