Structural Biochemistry/Graves Disease

Overview


Graves Disease is an autoimmune disorder that leads to over activity of the thyroid gland (hyperthyroidism).

What is the thyroid gland? The thyroid gland is an important organ of the endocrine system. It is located in the neck, below the voice box. This gland releases the hormones thyroxine (T4) and triiodothyronine (T3), which control body metabolism. Controlling metabolism is critical for regulating mood, weight, and mental and physical energy levels.

Causes
Graves disease is caused by an abnormal immune system response that causes the thyroid gland to produce too much thyroid hormone. Graves disease is most common in women over age 20. However, the disorder may occur at any age and may affect men as well.

One normal immune system response is the production of antibodies designed to target a specific virus, bacterium or other foreign substance. In Graves' disease — for reasons that aren't well understood — the body produces an antibody to a particular protein on the surface of cells in the thyroid, a hormone-producing gland in the neck.

Normally, thyroid function is regulated by a hormone released by a tiny gland at the base of the brain (pituitary gland). The antibody associated with Graves' disease — thyrotropin receptor antibody (TRAb) — can essentially mimic the action of the regulatory pituitary hormone. Therefore, TRAb overrides normal regulation of the thyroid and results in overproduction of thyroid hormones (hyperthyroidism).

Symptoms

 * Anxiety
 * Breast enlargement in men (possible)
 * Difficulty concentrating
 * Double vision
 * Erectile dysfunction or reduced libido
 * Eyeballs that stick out (exophthalmos)
 * Eye irritation and tearing
 * Fatigue
 * Frequent bowel movements
 * Goiter (possible)
 * Heat intolerance
 * Increased appetite
 * Increased sweating
 * Insomnia
 * Irregular menstrual periods in women
 * Muscle weakness
 * Nervousness
 * Rapid or irregular heartbeat (palpitations or arrhythmia)
 * Restlessness and difficulty sleeping
 * Shortness of breath with activity
 * Tremor
 * Weight loss (rarely, weight gain)
 * Thick, red skin usually on the shins or tops of the feet (Graves' dermopathy)
 * Graves' ophthalmopathy

About half the people with Graves' disease show some signs and symptoms of a condition known as Graves' ophthalmopathy.

In Graves' ophthalmopathy, inflammation and other immune system events affect muscles and other tissues around your eyes.

The resulting signs and symptoms may include:
 * Bulging eyes
 * Excess tearing
 * Dry, irritated eyes
 * Gritty sensation in the eyes
 * Pressure or pain in the eyes
 * Puffy eyelids
 * Reddened or inflamed eyes
 * Light sensitivity
 * Double vision
 * Limited eye movements, resulting in a fixed stare
 * Blurred or reduced vision (rare)
 * Ulcers on the cornea (rare)

Graves' dermopathy

An uncommon manifestation of Graves' disease, called Graves' dermopathy, is the reddening and thickening of the skin, most often on your shins or the top of your feet.

Risk Factors

 * Family history. Because a family history of Graves' disease is a known risk factor, there is likely a gene or genes that can make a person more susceptible to the disorder.
 * Gender. Women are much more likely to develop Graves' disease than are men.
 * Age. Graves' disease usually develops in people younger than 40.
 * Other autoimmune disorders. People with other disorders of the immune system, such as type 1 diabetes or rheumatoid arthritis, have an increased risk.
 * Emotional or physical stress. Stressful life events or illness may act as a trigger for the onset of Graves' disease among people who are genetically susceptible.
 * Pregnancy. Pregnancy or recent childbirth may increase the risk of the disorder, particularly among women who are genetically susceptible.
 * Smoking. Cigarette smoking, which can affect the immune system, increases the risk of Graves' disease. The degree of risk is linked to the number of cigarettes smoked daily — the larger the number, the greater the risk. Smokers who have Graves' disease are also at increased risk of developing Graves' ophthalmopathy.

Treatment
The purpose of treatment is to control the overactive thyroid gland. Beta-blockers such as propranolol are often used to treat symptoms of rapid heart rate, sweating, and anxiety until the hyperthyroidism is controlled.

Hyperthyroidism is treated with one or more of the following:
 * Antithyroid medications
 * Radioactive iodine
 * Surgery

If you have radiation or surgery, you will need to take replacement thyroid hormones for the rest of your life, because these treatments destroy or remove the gland.

Some of the eye problems related to Graves disease usually improve when hyperthyroidism is treated with medications, radiation, or surgery. Radioactive iodine can sometimes make eye problems worse. Eye problems are worse in people who smoke, even after the hyperthyroidism is cured.

Sometimes prednisone (a steroid medication that suppresses the immune system) is needed to reduce eye irritation and swelling.

You may need to tape your eyes closed at night to prevent drying. Sunglasses and eyedrops may reduce eye irritation. Rarely, surgery or radiation therapy (different from radioactive iodine) may be needed to return the eyes to their normal position.

The primary treatment goals are to inhibit production of thyroid hormones and lessen the severity of symptoms.

Complications

 * Complications from surgery, including:
 * Hoarseness from damage to the nerve leading to the voice box
 * Low calcium levels from damage to the parathyroid glands (located near the thyroid gland)
 * Scarring of the neck
 * Eye problems (called Graves ophthalmopathy or exophthalmos)
 * Heart-related complications, including:
 * Rapid heart rate
 * Congestive heart failure (especially in the elderly)
 * Atrial fibrillation
 * Thyroid crisis (thyrotoxic storm), a severe worsening of overactive thyroid gland symptoms
 * Increased risk for osteoporosis, if hyperthyroidism is present for a long time
 * Complications related to thyroid hormone replacement
 * If too little hormone is given, fatigue, weight gain, high cholesterol, depression, physical sluggishness, and other symptoms of hypothyroidism can occur
 * If too much hormone is given, symptoms of hyperthyroidism will return

Tests and Diagnosis
A diagnosis of Graves' disease is based primarily on your answers to the doctor's questions and findings from a physical exam.

He or she may also order laboratory tests to confirm a diagnosis or gather more evidence if a diagnosis isn't clear.

Diagnostic procedures may include:
 * Physical exam. Your doctor examines your eyes to see if they're irritated or protruding and looks to see if your thyroid gland is enlarged. Because Graves' disease increases your metabolism, your doctor will check your pulse and blood pressure and look for signs of tremor.
 * Blood sample. Your doctor may order blood tests to determine your levels of thyroid-stimulating hormone (TSH), the pituitary hormone that normally stimulates the thyroid gland, as well as levels of thyroid hormones. People with Graves' disease usually have lower than normal levels of TSH and higher levels of thyroid hormones. Another laboratory test measures the levels of the antibody known to cause Graves' disease. This test usually isn't necessary to make a diagnosis, but a negative result might indicate another cause for hyperthyroidism.
 * Radioactive iodine uptake. Your body needs iodine to make thyroid hormones. By giving you a small amount of radioactive iodine and later measuring the amount of it in your thyroid gland with a specialized scanning camera, your doctor can determine the rate at which your thyroid gland takes up iodine. A high uptake of radioactive iodine indicates your thyroid gland is overproducing hormones.
 * Imaging tests. If the diagnosis of Graves' ophthalmopathy isn't clear from a clinical assessment, your doctor may order an imaging test, such as computerized tomography (CT), a specialized X-ray technology that produces thin cross-sectional images. Magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to create either cross-sectional or 3-D images, may also be used.