Thyroid gland and paraphysiology

Thyroid peroxidase

(located on apical/luminal membrane of the secretory epithelium) mediates the oxidation of iodide, the iodination of tyrosyl residues within thyroglobulin forming MITs and DITs, and the coupling of MITs and DITs within the thyroglobulin molecule to form the hormonally active iodothyronines, T4 and T3.

Effects of hyperthyroidism/thyrotoxicosis on energy metabolism

- increased energy and heat production. (heat intolerant) - at high levels, protein degradation and loss of protein mass (due to gluconeogenesis) - oral glucose tolerance due to the stimulation of hepatic glycogenolysis and gluconeogeneiss & an increase in absorption of glucose from the gut - increase in lipid degradation leading to an increase in free fatty acids and glycerol

Effects of hypothyroidism on the skin

-mucinous edema (accumulation of hyaluronic acid in the dermis) HA binds water which creates a puffy appearance in the skin and affects organs as well. -cutaneous vasoconstriction (pale and cool skin) -dry/coarse skin due to lack of secretion from sweat/sebaceous glands

Release of thyroid hormones

First the cell takes up the thyroglobulin from the luminal membrane by pinocytosis. The vesicles fuse with lysosomes containing proteases and peptidases which release T3 and T4 which then pass into the blood. The leftover amino acids are reused to synthesize more thyroglobulin and the unused iodine is reused to make new thyroid hormones.

Hyperthyroidism (thyrotoxicosis)

Graves disease: caused by immuoglobulin an autoantibody known as LATS (long acting thyroid stimulator) which binds to TSH receptors on the thyroid gland and its actions are long lasting.

Effects of hyperthyroidism/thyrotoxicosis on the GI system

Increased energy demand of the tissues leads to increase in appetite. increase in GI motility and function (can cause diarrhea * thyroid hormone usually checked when diarrhea is a chief complaint.)

Graves disease feedback loop

LATS stimulates the thyroid gland to cuase excess secretion of thyroid hormone. The high levels of T3 and T4 exert a long-loop negative feedback on the hypothalamic-pituitary axis to inhibit release of TRF from the hypothalamus and TSH from the anterior pituitary

T3 vs T4

T4 - main circulating hormone (70:1 ratio to T3) - prohormone for T3 - used for thyroid hormone replacement therapy b/c its half-life is longer (6.7:1 day ratio to T3) T3 -come from deiodination of T4 by liver, kidney and target tissues - active metabolite in the cells.

Hypothyroid etiology

absence of functioning thyroid tissue - infections - thyroidectomy - developmental defect * most common is autoimmune destruction (Hashimoto's disease) insufficient production of TSH by pituitary (hypothalmaic/pituitary failure) biochemical defects (impaired ability to synthesize thyroid hormone) leads to hypersecretion of TSH causing "goitruos hypthyroidism"

Juvenile hypothyroidism

beginning in childhood. intermediate between infantile and adult hypothyroidism. growth and sexual development are predominately affected. linear growth is severely retarded and the onset of puberty is delayed

Thyroid stimulating hormone (TSH) or thyrotropin

a major regulator of the thyroid. Increases the synthesis and release of T3 and T4, Increases the synthesis and proteolysisi of thyroglobulin, Increases thyroid uptake of iodide, increases the plasma concentrations T3 and T4 and increases the size of vascularity of the thyroid gland.

Graves disease clinical features

characterized by diffuse goiters and exphthalmos. Diffuse goiters -visible bulging of the neck around the trachea. Exphthalmos- retraction of the upper eyelids causing a "starey-eyed" appearance and protrusion of the eyes. caused by LATS which increases connective tissue and muscle behind the eyes causing them to bulge.

Effects of hypothyroidism on the nervous system

cretinism (if during fetal life/at birth) where there is infantile characteristics of the brain, hypoplasia of cortical neurons with poor development of cellular processes, retarded myelination and reduced vascularity of the neurons. adult effects are not as profound. intellectual slowing, loss of initiative, show-wittedness, memory defects, lethargic and somnolent. mucinous edema present in CNS

Effects of hypothyroidism on metabolism

decrease in BMR (30-45% decrease) decreased energy production decreased heat production cold intolerance

Effects of hypothyroidism on the GI tract

decreased GI motility and function leads to decreased appetite and constipation swelling of the bowel due to mucinous edema

Effects of hypothyroidism on the cardiovascular system

decreased cardiac output decreased heart rate (bradycardia) decreased stroke volume increase in peripheral vasoconstriction due to decreased tissue metabolism and decreased BMR decrease in blood volume (partly due to mucinous edema) increase in the size of the heart due to mucinous edema "myxedema heart"

Effects of hypothyroidism on skeletal system

deficiency in childhood results in impaired linear bone growth and dwarfism (disproportionately short to the body)

Effects of hyperthyroidism/thyrotoxicosis on the muscle

hyperkinesia and catabolism of proteins weakness and fatigability of the muscles

Other influences on the thyroid gland via hypothalamus

hypothalamus is influenced by: - environmental cold stimulates the increase in thyroid hormone, whereas heat decreases. - Decreased BMR increases thyroid hormone whereas increased BMR decreases thyroid hormone levels. - Emotional distress can inhibit thyroid hormone levels

Thyroid feedback control

hypothalamus releases thyrotropin releasing hormone (TRH) to stimulate thyrotrophic cells of the anterior pituitary to release thyroid stimulating hormone (TSH). THS stimulates the thyroid gland to release T3 and T4 which have a long-loop negative feedback on the hypothalamus and anterior pituitary to inhibit further release of TRH and TSH.

Adult myxedema

hypothyroidism when appears in adults

Effects of hyperthyroidism/thyrotoxicosis on the skeletal system

increased bone resorption increased excretion of calcium, phosphorus and hydroxyproline.

Effects of hyperthyroidism/ thyrotoxicosis on the cardiovascular system

increased cardiac output, increased heart rate, increase stroke volume due to increase in # of and sensitivity of beta1-adrenergic receptors to epinephrine. increase in peripheral vasodilation and dissipation of heat due to increase tissue metabolism and heat production. increase in systolic blood pressure and decrease in diastolic blood pressure. No change in mean aterial BP

Effects of hyperthyroidism/thyrotoxicosis on the nervous system

increased sensitivity to beta1-adrenergic receptors to catecholamines increased irritability [CNS] Clinical signs: nervousness, emotionally labile (ups and downs), hyperkinesia, tremor and insomnia

Thyroid hormones effects on BMR

increases BMR, Na+, K+-ATPase activity, oxygen consumption, energy production and heat production. increases respiratory enzymes in the mitochondria. rate of breathing is also increased by thyroid hormone, increase in the oxygen carrying capacity of the red blood cells.

Thryoid effects on fat metabolism

increases lipolysis in adipose tissue, leads to increase in free fatty acids (ffa) in the plasma. increases oxidation of ffa by cells.

Hypothyroidism feedback loop due to pituitary failure

lack of negative feedback but only TRF is secreted in large amount

T3 and T4 synthesis

mediated by peroxidase, - the oxidation of iodide - the iodination of tyrosyl residues within thyroglobulin forming MITs and DITs, and - the coupling of MITs and DIs within the thyroglobulin molecule form the hormonally active iodothyronines, T4 and T3. Coupling occurs when MITs and DITs are brought in close proximity to the structure of thyroglobulin.

Chemistry of T3 and T4

monoiodotyrosine (MIT) and diiodotyrosine (DIT) are molecules that have iodine attached to their phenol rings. MIT has one iodine molecule where DIT has two. T3 is composed of one MIT and one DIT (3 iodine molecules) whereas T4 is composed of two DITs (4 iodine molecules).

Infantile hypothyroidism (cretinism)

most profound and tragic severe retardation or mental development and growth early recognition and treatment within the first 4 months of life is crucial

Thyroid hormones effects on protein metabolism

normal levels are necessary for normal synthesis high levels lead to protein breakdown (hyperthyroidism)

Thyroid effects on CNS

normal levels are needed for proper development and function stimulates neuron cell body growth and branching of dendrites stimulates axon myelination so that action potentials can be rapidly propagated along nerves low levels result in impaired mental function whereas high levels cause increased irritability and excitability.

Thyroid effects on growth and maturation

normal levels are needed for proper growth. hypothyroid decreases growth rate. thyroid hormone potentiates the secretion and action of GH at time of puberty.

Effects of hyperthyroidism/thyrotoxicosis on the skin

peripheral vasodilation results in cutaneous vasodilation giving the skin a rosy appearance. Excessive sweating is present to dissipate heat generated by increased BMR of the tissues.

Thyroid hormones effects on carbohydrate metabolism

potentiates the effects of epinephrine in the liver and of insulin in muscle and adipose. Increases hepatic glycogenolysis and gluconeogenesis (epi-like) increases blood glucose levels (epi-like), increases absorption of glucose from the GI tract, increases the uptake and utilization of glucose by muscle and adipose (insulin-like)

Hypothyroidism feedback loop due to thyroid defect (iodine deficiency , autoimmune destruction, infection, etc...)

results in hypersecretion of TRF and TSH but the thyroid gland remains small

Effects of hypothyroidism on the muscle

stiffness and aching contraction and relaxation is slow and the tendon jerk response is delayed. mucinous edema is present

Treatment of hypothyroidism

synthetic thyroid hormone or thyroid extract. Dietary iodine (iodinized salt) is used in areas of environmental iodine deficiency (Great Lakes region)

"Iodine trap"

the extremely efficient concentration of iodine involves transport active transport of iodide into thyroid epithelial cells by the Na+-I- cotransport system

Treatment of hyperthyroidism/thyrotoxicosis

thioamides inhibit the following: - actions of thyroid peroxidase - iodination of MIT and DIT - coupling of MIT and DIT to form T3 and T4 - peripheral conversion of T4 to T3 Or beta-adrenergic blocking agents (propranolol), thyroidectomy and radioactive iodine (which destroys the thyroid)

Goitrous hypothyroidism

thyroid enlargement due to hypersecretion of TSH. caused by iodine deficiency, antithyroid agents and genetics. Certain foods (brocc, brussel sprouts, cauliflower, cabbage) contain thiocyanate or isothiocyanate that interfere with iodine transport.

Thyroidgloulin

a large glycoprotein containing large quantites of tyrosine. It is where thyroid hormones are stored as aa residues until needed. It is synthesized in the thyroid epithelial cells and released into the follicle lumen by reverse pinocytosis.

Thyroxine Binding Globulin (TBG)

a glycoprotein synthesized by liver and prevents loss of T3 and T4 by the kidneys buffers against acute changes in thyroid hormone concentrations. each protein binds to one molecule of T4. main binding protein for T3 and T4 in the plasma.