Graves' Disease - Pathophysiology

Pathophysiology

In Graves' disease, an autoimmune disorder, the body produces antibodies to the TSH-Rs. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.) These antibodies (TSHR-Ab) bind to the TSH-Rs, which are located on the cells that produce thyroid hormone in the thyroid gland (follicular cells), and chronically stimulate them, resulting in an abnormally high production of T3 and T4. This causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland (visible as goitre).

The infiltrative exophthalmos, frequently encountered, has been explained by postulating the thyroid gland and the extraocular muscles share common antigens recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball. This swelling may be the consequence of mucopolysacharide deposition posterior to the eyes, a symptom tangentially related to Graves'. The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

Three types of autoantibodies to the TSH-R are currently recognized:

• Thyroid-stimulating immunoglobulins (mainly immunoglobulin G) act as long-acting thyroid stimulants, activating the cells in a longer and slower way than the normal thyroid-stimulating hormone (TSH), leading to an elevated production of thyroid hormone.

• Thyroid growth immunoglobulins bind directly to the TSH-Rs, and have been implicated in the growth of thyroid follicles.

• Thyrotropin binding-inhibiting immunoglobulins inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent thyroid-stimulating immunoglobulin and TSH from binding to and stimulating the receptor.

In their study of thyrotoxic patients, Sensenbach et al. found cerebral blood flow is increased, cerebral vascular resistance is decreased, arteriovenous oxygen difference is decreased, and oxygen consumption is unchanged. They found, during treatment, brain size was decreased significantly, and ventricular size was increased. The cause of this remarkable change is unknown, but may involve osmotic regulation. A study by Singh et al. showed for the first time that differential thyroidal status induces apoptosis in adult cerebral cortex. T3 acts directly on cerebral cortex mitochondria and induces release of cytochrome C to induce apoptosis. The adult cerebellum seems to be less responsive to changes in thyroidal status.

Hyperthyroidism causes lower levels of apolipoprotein (A), HDL, and ratio of total/HDL cholesterol. The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones in almost all tissues. Protein formation and destruction are both accelerated in hyperthyroidism. The absorption of vitamin A is increased and conversion of carotene to vitamin A is accelerated (the requirements of the body are likewise increased, and low blood concentrations of vitamin A may be found). Requirements for thiamine and B₆ and B₁₂ are increased. Lack of the B vitamins has been implicated as a cause of liver damage in thyrotoxicosis. Hyperthyroidism can also augment calcium levels in the blood by as much as 25% (hypercalcaemia). An increased excretion of calcium and phosphorus in the urine and stool can result in bone loss from osteoporosis. Also, parathyroid hormone levels tend to be suppressed in hyperthyroidism, possibly in response to elevated calcium levels.