Thyroid 101

The thyroid gland is one branch of the endocrine system that is located in the neck that has two lobes connected by an isthmus. The hypothalamus secretes Thyrotropin-releasing hormone (TRH) which stimulates the anterior pituitary to secrete Thyroid-stimulating hormone (TSH). TSH acts on the thyroid gland to secrete the hormones triiodothyronine (T3) and thyroxine (T4). Within the circulation T4 is converted to its active metabolite T3. There are two different types of thyroid cells. Follicular cells produce the thyroid hormones T3 and T4. The parafollicular cells produce calcitonin. Calcitonin causes calcium reabsorption and maintains calcium homeostasis.

Synthesis of Thyroid Hormones is from iodine and tyrosine. Triiodothyronine (T3) has three atoms of iodine per molecule and thyroxine (T4) has four atoms of iodine per molecule. The hormones are created from thyroglobulin which is a protein within the follicular space that is originally created within the rough endoplasmic reticulum (RER). Thyroglobulin contains 123 units of tyrosine with reacts with iodine within the follicular space. A sodium-iodide symporter pumps iodide actively into the cell where it enters the follicular lumen from the cytoplasm by the transporter pendrin. In the colloid, iodide is oxidized to iodine by the enzyme called thyroid peroxidase. Iodine is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain. This forms the precursors of the thyroid hormones monoiodotyrosine (MIT), and diiodotyrosine (DIT). The adjacent tyrosyl residues are then paired together and subsequently the entire complex re-enters the follicular cell by endocytosis. Proteolysis liberates triiodothyronine and thyroxine and they enter the blood stream. Of the hormones secreted from the gland, 80-90% is T4, and only about 10-20% is T3. The production of T3, and T4 is primarily regulated by thyroid-stimulating hormone (TSH) which is released by the anterior pituitary gland. The thyroid hormones provide negative feedback to the thyrotropes TSH and TRH; when the thyroid hormones are high, TSH production is suppressed, and when levels are low, TSH secretion is increased.

After secretion, there is a very small percentage of the thyroid hormones that travel freely in the blood and that are metabolically active. Most are bound to thyroxine-binding globulin (TBG), transthyretin, and albumin. They act upon their respective tissues by crossing the cell membrane and binding to intracellular nuclear thyroid hormone receptors, which bind with hormone response elements and transcription factors to modulate DNA transcription. This modulation is what drives protein synthesis within the target tissue to actively project its physiological function within on the tissue and body.

Calcitonin is secreted by the parafollicular cells which helps maintain calcium homeostasis. Calcitonin is produced in response to high blood calcium. This causes inhibition of the release of calcium from the bone by decreasing the activity of osteoclasts. Osteoclasts are cells which break down bone. Bone is constantly reabsorbed by osteoclasts and created by osteoblasts, so calcitonin is effectively stimulates movement of calcium into bone. The effects of calcitonin are opposite of those of the parathyroid hormone (PTH) produced by the parathyroid gland.

Function

The primary function of the thyroid gland is the production of the thyroid hormones that have downstream metabolic, cardiovascular, and developmental effects. The basal metabolic rate is increased which effects all tissues. Gut adsorption and motility is increased. The generation, uptake by cells and breakdown of glucose is increased. The thyroid hormones also increase the breakdown of fats which increases free fatty acids, but contrary to believe, thyroid hormones decrease cholesterol levels.

There is an increase in cardiac output, as well as rate of breathing, intake and consumption of oxygen and increase in oxidative respiration within the mitochondria. These factors combine increase vascular pressure and elevate the bodies temperature.

The thyroid hormones are important for normal development. The cells of the developing brain are a major target for the thyroid hormones. They play a crucial role in brain maturation during fetal development. The thyroid hormones also play a role in maintaining normal sexual function, circadian sleep rhythm, and thought patterns.

The overarching effect is an augmented flight-or-fight response. It increases the release of the catecholamines which drives sympathetic innervation.

Clinical Significance

Hyperthyroidism is an excessive production of the thyroid hormones, most commonly a result of Graves Disease. Graves disease, also known as toxic diffuse goiter is an autoimmune disease that results in an enlarged thyroid. The exact cause is unknown, however it appears to be a combination of both genetic and environmental factors. An antibody, called the thyroid-stimulating immunoglobulin (TSI) which mimics the effect of TSH. This causes an increased T3 and T4, and an increased radio iodine uptake. Laboratory tests will show a decreased level of TSH, because there is negative feedback on the pituitary, but because of the antibody, production of the thyroid hormones continuous. One of the classic findings of Graves disease is exophthalmos, which is bulging of the eyes. This is often accompanied by irritability, muscle weakness, sleeping problems, increased heart rate and blood pressure and unintentional weight loss. Patients may complain of being “hot” all the time, illustrating a poor tolerance of heat.

Hypothyroidism is an underactive thyroid gland which results in decreased secretion of thyroid hormones. One of the most common causes is an autoimmune disorder called Hashimotos thyroiditis or chronic lymphocytic thyroiditis. The disease is characterized by gradual destruction of the thyroid gland. There are various antibodies that have been identified targeting against thyroid peroxidase, thyroglobulin, and TSH receptors. There is activation of cytotoxic T-cells in response to a cell mediated immune response affected by helper T-cells that drives thymocyte destruction. Cytokine release recruits macrophages within the gland to further drive destruction. Early on in the disease there may be no clinical evidence or symptoms of Hashimotos, but as the disease progresses, so does the clinical presentation. The most common symptoms are fatigue, weight gain, feeling cold, joint and muscle pain, depression, and bradycardia. This disease is about seven times more common in women than in men. Diagnosis is from TSH and T4 levels, imaging, along with other clinical symptoms. The thyroid gland may become firm, large and lobulated. There is lymphocytic infiltration and fibrosis that is seen.

These are not all the causes of hyper/hypothyroidism, but these are the most common, and in most cases, the most severe.

 

 

 

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General Endocrinology

Hormones make up the endocrine system and act on almost every tissue in the body. Hormones are substances that are produced by a specialized cell that circulates in the blood. The best example of this is insulin which is secreted by the beta cells in the pancreas.

hormoneoverview

Credit for the photo goes to Pearson Education, Inc.

There are multiple forms of chemical signaling that hormones utilize. The first is autocrine where the cell targets itself. Signaling across gap junctions occurs when a specialized cell targets another cell that is connected via a gap junction. Paracrine is when the targeted cell is nearby. Endocrine which will be the primary focus for today is when the cell produces hormones or chemical signals that have to travel through the blood stream to act on distant cells. Depending on the receptor type to these hormones distinguishes the action it has on the recipient tissue or cell. Receptors can by cytoplasmic, ion channels, tyrosine kinase receptors, or a G-protein coupled receptor. There can also be different types of hormones. Protein hormones utilize calcium as a secondary messenger. The action potential of protein hormones is quick as opposed to steroid hormones. The action of steroid hormones is slow as steroids are not as membrane permeable as protein hormones. Its important to note that hormones are released in pulses. Each pulse has an amplitude and period.

The endocrine system needs feedback control loops to function properly. Negative control loops maintain hormonal balance. Positive control loops are actually what causes physiological changes in the tissues involved.

The endocrine system starts in the hypothalamus. The hypothalamus releases releasing hormones to stimulate the anterior and posterior pituitary to secrete effector hormones that act on various sites of the body.

The anterior pituitary otherwise known as the adenohypophysis secretes the majority of the hormones. Releasing hormones are secreted by the hypothalamic neurons into the hypothalamopituitary portal system. These hormones are then carried down the pituitary stalk by this portal system into the adenohypophysis. The anterior pituitary secretes adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). These all act on their respectable tissues/cells to secrete specific hormones. ACTH acts on the adrenal gland, which sits on top of the kidneys. The adrenal gland is responsible for secretion of catecholamines (epinephrine/norepinephrine) that influences the flight or fight response as well as glucocorticoids such as cortisol which have physiological effects throughout the entire body. TSH acts on the thyroid gland to secrete the thyroid hormones T3 and T4. These hormones also have wide-spread physiological function throughout the body. GH acts on the liver and influences bone, muscle, and tissue growth. PRL acts on the mammary glands such as the breast glands to stimulate growth and to start lactation. FSH and LH act on the testes of males to secrete inhibin and testosterone as well on the ovaries in females to secrete estrogen, progesterone, and inhibin. Decreased or elevated levels of any of these hormones can have detrimental effects on normal physiological processes. These discrepant levels can either be from primary disease (In the organ where the hormones are produced) or it can be secondary disease, i.e. from the hypothalamus, or pituitary.

Oxytocin and vasopressin (ADH) are the hormones secreted by the posterior or neurohypophysis pituitary. These are synthesized in the paraventricular supraoptic nuclei of the hypothalamus and are carried down the pituitary stalk by axonal transport. These hormones are then released into the general circulation in the neurohypophysis. Oxytocin works in females and males. It effects the uterine smooth muscle and mammary glands in females and in males it effects the smooth muscle in the ductus deferens and the prostate gland. Vasopressin or ADH promotes water retention in the distal tubules and collecting ducts of the kidneys. SIADH is excess ADH secretion and results in concentrated urine, and a low serum concentration. In other words there is low serum sodium which is bad! Diabetes insipidus on the other hand is deficiency in ADH.

-Caleb