2008: Outline the physiological pathways controlling thyroid function and growth. How is such control altered in hyperthyroidism?

The thyroid is a small gland located in the anterior part of the neck just inferior to the larynx. It has two lobes that lie along the side of the trachea. They are connected via a narrow band of thyroid tissue known as the isthmus. Thyroid tissue is made up of specialised cells which are organized into spheres called follicles. The production of thyroid hormones is ultimately controlled by the hypothalamic-pituitarythyroid axis through the actions of TRH and TSH. This is a tightly controlled negative feedback system, whereby increased levels of thyroid hormone will feedback to suppress TRH and TSH production. The function of the thyroid is to take up iodine from the diet and convert it to two hormones. These thyroid hormones are thyroxine (T4) and triiodothyronine (T3). Circulating Iodide is transported into the thyroid via the Sodium Iodide Symporter (NIS) which is promoted by TSH. The Iodide is then organified to Iodine by the enzyme thyroid peroxidise (TPO) in the presence of hydrogen peroxidise (H 2O2). The Iodine then iodinates thyroglobulin which is cleaved in order to form T4 and T3. Once these hormones are released into the bloodstream they regulate metabolism in every cell. A normally functioning thyroid gland will produce about 80% T4 and about 20% T3. T4 can be converted to T3 by a deiodinase such as Selenoprotein by eliminating one iodide. T3 is approximately 4 times more biologically active that T4 and is the most important thyroid hormone. The effects of thyroid hormone are dependent on the quantity of hormone that reaches the cell. Mono Carboxylate Transporter 8 (MCT8) is a specific thyroid hormone transporter which transports T3 into the cell. Thyroid hormones travel to the nucleus of the cell where they bind to the thyroid hormone receptors (TR). There are four isoforms of the TR receptor; 1, 2, 1 and 2. They are all found in various locations around the body but the 2 isoform is more common and is found almost everywhere. Hyperthyroidism refers to overactivity of the thyroid gland, with resultant excessive secretion of thyroid hormones and accelerated metabolism in the periphery. There are many causes of hyperthyroidism, the most common being Graves Disease which accounts for about 95% of cases. This is an autoimmune disease in which there is toxic diffuse goitre (enlargement of the thyroid gland) where all thyroid cells are affected. There will be an increase in serum T4 and T3 and a decrease in serum TSH. Other clinical signs of hyperthyroidism include increased metabolic activity, weight loss, tremor and bulging eyes (endocrine exophthalmos). Other causes of hyperthyroidism may be due to toxic nodular goitre also known as Plummers Disease. Thyroid autoantibodies play an important role in the regulation of thyroid function. They can stimulate or destruct the thyroid gland. Normally TSH will bind to TSH receptors on the outside of thyroid follicles. This will stimulate the uptake of iodide and in turn the production of thyroid hormones. However, in Graves Disease, TSH receptor antibodies (TRAb) will bind to the TSH receptor and prevent TSH from binding. This binding will result in continuous stimulation of the gland and goitre (enlargement) and a loss of regulation from the pituitary gland. Circulating levels of TSH by the pituitary will decline in response to negative feedback by an abundance of thyroid hormone.

2009: Explain how both hypo and hyperthyroidism can result in the appearance of goitre. The thyroid gland is associated with many thyroid disorders, including hyperthyroidism and hypothyroidism. Both of these can result in an enlargement of the gland. (Hyperthyroidism goitre explained above) Hypothyoridism results from insufficient secretion of thyroid hormones. It can be due to a variety of abnormalities and can be subdivided into primary, secondary and tertiary hypothyroidism. Primary is due to a disease of the thyroid gland itself, secondary is due to a disease of the pituitary and tertiary is due to a disease of the hypothalamus. Hypothyroidism will cause decreased metabolic activity so will usually present with weight gain. There will also be decreased serum levels of T4 and T3 and increased TSH levels (in primary disease only). The most common cause of hypothyroidism worldwide is iodine deficiency. In 1990 the WHO estimated that 1.6 billion people of the worlds population were at risk of iodine deficiency. It usually arises in countries that do not use iodized salt in their diet. The primary activity of the thyroid gland is to concentrate iodine from the blood to make thyroid hormone. The gland cannot make enough thyroid hormone if it does not have enough iodine. Iodine deficiency can lead to goitre as the thyroid senses the deficiency and makes itself bigger in order to capture as much iodine as possible in order to make thyroid hormones. The reduction in thyroid hormones will be sensed by the pituitary gland and there will be an increase in the production of TSH which will overstimulate the thyroid to produce thyroid and to grow in size. Wherever iodine deficiency is common, goiter will be common. [In countries that do use iodized salt, an autoimmune disease known as Hashimotos thyroiditis can also cause hypothyroidism with goitre. The exact cause of this disease is still unknown but it tends to appear in families. The bodys immune system inappropriately attacks the thyroid gland as if it was foreign tissue. The body recognises autoantigens as foreign and produces antibodies against them. In this case, serum tests will show an increased antibody level to the enzyme thyroid peroxidise which is involved in the production of thyroid hormones. This will destroy the gland so it is less able to make adequate supplies of thyroid hormone. The pituitary gland senses a low thyroid hormone level and will secrete more TSH to stimulate the thyroid. This will cause growth of the thyroid resulting in goitre.