The Endocrine System Thyroid Gland

Department of Physiology Diponegoro University Faculty of Medicine

Thyroid Gland
The largest endocrine gland, located in the anterior neck, consists of two lateral lobes connected by a median tissue mass called the isthmus Composed of follicles that produce the glycoprotein thyroglobulin Colloid (thyroglobulin + iodine) fills the lumen of the follicles and is the precursor of thyroid hormone Other endocrine cells, the parafollicular cells, produce the hormone calcitonin

Thyroid Gland

Histologic Section of Normal Thyroid

C cells Follicular cells

colloid

Thyroid Hormones
Thyroid hormone the bodys major metabolic hormone Consists of two closely related iodinecontaining compounds
T4 thyroxine; has two tyrosine molecules plus four bound iodine atoms T3 triiodothyronine; has two tyrosines with three bound iodine atoms Calcitonin

Thyroid Hormones
OH
I I

OH
I

O I I I

O I

CH2 NH2CHCOOH

CH2 NH2CHCOOH

Thyroxine (T4)

Triiodothyronine (T3)

Synthesis of T3 and T4
Thyroglobulin is synthesized and discharged into the lumen Iodides (I) are actively taken into the cell, oxidized to iodine (I2), and released into the lumen Iodine attaches to tyrosine, mediated by peroxidase enzymes, forming T1 (monoiodotyrosine, or MIT), and T2 (diiodotyrosine, or DIT) Iodinated tyrosines link together to form T3 and T4 Colloid is then endocytosed and combined with a lysosome, where T3 and T4 are cleaved and diffuse into the bloodstream

I + tyrosine

monoiodotyrosine (MIT)

MIT + I
DIT + DIT DIT + MIT

diiodotyrosine (DIT)
thyroxine (T4) triiodothyronine (T3)

hormones still attached to thyroglobulin

Synthesis of Thyroid Hormone

Transport and Regulation of TH

T4 and T3 bind to thyroxine-binding globulins (TBGs) produced by the liver Both bind to target receptors, but T3 is ten times more active than T4 T3 also being produced in the peripheral tissues by deiodination of T 4 (~ 80% of T 3 ) reverse T 3 (rT 3 ) is inactive Mechanisms of activity are similar to steroids Regulation is by negative feedback Hypothalamic thyrotropin-releasing hormone (TRH) can overcome the negative feedback

T3 and T4

Bound to carrier proteins in the plasma - thyroid binding globulin (TBG) - albumin (10%) - transthyretin (20%) Mainly thyroxine (t4) is released

- T4:T3 ratio = 25 - T3 is formed by the deiodination of T4

Iodine The minimum adult metabolisme daily requirement to maintain thyroid function 100-150 g The thyroid secretes 80 g of I- per day as T3 & T4, of which 60 g is metabolised in the liver with release of I- into the ECF The total I- added to the plasma per day : 500 g - average dietary intake 60 g - from the liver metabolism of T3 & T4 40 g - diffusion from the thyroid to the ECF

Iodine metabolisme
About 600 g of iodide is distributed throughout the ECF daily: Thyroid takes up ~ 20% or ~ 120 g/day Remaining 80% is taken up by the kidney and excreted in the urine

Iodine balance

Action of Thyroid Hormone in Cell Nuclei

The active form of thyroid hormone, triiodothyronine (T3), is produced by deiodination of thyroxine (T4) by the enzymes T4 5'-deiodinase (5'-D) types I and II1. Type I T4 5'-deiodinase is found predominantly in the liver and kidneys; its action is responsible for the production of two thirds of the total T3 in the body. Type II T4 5'-deiodinase is responsible for most of the T3 found in the pituitary, the brain, and brown fat. T3 enters the cell or is produced locally and then transported into the nucleus. Transcriptionally active forms of thyroid hormone receptors (TR) include monomers, homodimers, and heterodimers with nuclear protein partners, such as the retinoid X receptor (RXR). The T3-receptor complex interacts with specific sequences in DNA regulatory regions and modifies gene expression. T3 causes both increases and decreases in gene expression and may also influence the stability of messenger RNA (mRNA). 9-cis RA denotes 9-cis-retinoic acid, the ligand for RXR

Physiological Actions of Thyroid Hormones

effects of T3 and T4 are nearly identical except for latency and potency essential for growth in childhood various metabolic effects:

- increase breakdown of carbohydrates - increase breakdown of lipids - determine metabolic rate - level of heat production

Effects on Organ Systems

HEART increases rate, decreases force

VASCULAR vasodilation
GI increased motility and absorption SKELETAL increased bone turnover NEUROMUSCULAR hyperactivity, increased muscle contraction

 TH isEffects concerned ofwith: Thyroid

Glucose oxidation Increasing metabolic rate Heat production

Hormone

TH plays a role in:

Maintaining blood pressure Regulating tissue growth Developing skeletal and nervous systems Maturation and reproductive capabilities

Regulation of Thyroid Hormone Release

Production and secretion of T3 and T4 is controlled by thyroid stimulating hormone (TSH) released from the anterior pituitary

increasing plasma TSH causes: release of formed T3 and T4 increased rate of iodide uptake increased rate of synthesis increased size and number of follicles TSH release under feedback control

Thyroid Hormone Control Pathways

Thyroid hormone pathway

Additional Mechanism of T3/T4 Release

Cold exposure: a decrease in temperature acts via the hypothalamic thermoregulatory centre to increase release of TRH an increase in temperature has the reverse effect

TPOAb= Thyroid Peroxidase Antibody

 Increase in thyroid binding globulin due to increase in estrogen (stimulation of hepatic production and decreased degradation) Increase in total T4 and T3 Increase in GFR leads to increase in renal iodine clearance HCG has similar properties to TSH therefore has intrinsic thyroid stimulating activity Increase FT4 and FT3 levels during first trimester

Department of Physiology Diponegoro University Faculty of Medicine

 TSH upper reference limit (2.53.0 mIU/L). Below 2.5 mIU/L in the first trimester and preconception and 3.0 mIU/L in the second and third trimesters The range of normal serum total T4 changes during pregnancy Rapid increases in TBG levels T4 increase Total T4 level 50% higher than non-pregnant levels (512 g/dL or 50150 nmol/dL) In the second and third trimester multiply this range by 1.5-fold.

Thyroid Dysfunctions

Hypothyroidism

Hyperthyroidism

Cretinism Congenital absence of T3 and T4 or chronic iodine deficiency during childhood - Retarded growth - Sluggish movements - Mental deficiencies - Big tongue

Adult hypothyroidism - Low rate of metabolism and lethargy - Decreased body temp - Decreased heart rate - Outer skin becomes scaly - Myxedema non pitting edema due to swelling of subcutaneuous connective tissues

Myxedema

Hyperthyroidsm
Hyperthyroidism: the thyroid becomes over-active and produces too much of its hormones thyrotoxicosis Hyperthyroidism over-activity of the organs resulting in symptoms such as sweating, feeling hot, rapid heartbeats, weight loss, and sometimes eye problems. Thyroid storm: the levels of thyroid hormones become very high in a patient who has hyperthyroidism. One major sign of thyroid storm is a marked elevation of body temperature 41o C. It is a life-threatening emergency.

Adult hyperthyroidism Graves disease Tall stature Hyperactive High rate of metabolism High body temperature High heart rate

Exophthalmus

edematous swelling at the rear of eye socket

Goiter
swelling in neck due to thyroid hypertrophy both hypo- and hyperthyroidism