case 9 Flashcards
surface anatomy of the thyroid gland
hyoid bone - c3, thyroid cartilage - c4-5, cricoid cartilage - c6-7. during swallowing hyoid bone moves up, forward then return. the isthmus of the thyroid gland overlies the 2,3,4 tracheal rings. Apex of each lobe extends superiorly to the oblique line of the thyroid cartilage, base extends inferiorly to the level 4,5th tracheal rings. gland has consistency of muscle tissue. can be difficult to palpate in females. Gland located c5-t1.
gross anatomy of the thyroid gland
the isthmus unites the two lobes over the trachea and is relativly thin. Pyramidal lobe extends from superior aspect of isthmus in 50% population. Enclosed by thin capsule from which septa project into glandular mass. External to capsule is a connective tissue sheath, derived from pretracheal layer of deep cervical fascia. Blood vessels lie between the capsule and sheath of pretracheal fascia.
anterolateral relations of the thyroid gland
Pretracheal fascia, sternohyoid muscle, superior belly of omohyoid. overlapped inf by the anterior border of SCM.
posterolateral relations of the thyroid gland
Prevertebral fascia, carotic sheath, parathyroid glands, trachea.
medial relations of the thyroid gland
recurrent laryngeal nerve, trachea, larynx, oesophagus.
relations of the isthmus
anterior: pretracheal fascia, sternothyroid.
Posterior: prevertebral fascia, oesophagus.
Arterial supply of the thyroid gland
rich blood supply so that hormones can be transported around the body. superior and inf thyroid arteries. lie between fibrous capsule and loose fascial sheath.
Superior thyroid arteries: arise from external carotid, supply anterosuperior aspect.
Inferior thyroid arteries: arise thyrocervical trunk of subclavian, largest branch. run posterior to carotid sheath supply post aspect of thyroid gland.
Thyroid ima artery is present in 10%. arises brachocephalic trunk. ascends on ant surface trachea, supplying small branches, continues to isthmus divides and supplies. due to position can be hard to perform tracheostomy of thyroidectomy.
venous drainage of thyroid gland
sup, middle and inf thyroid veins. Form a thyroid plexus on anterior surface of thyroid gland and ant to trachea. Superior thyroid veins: accompany superior thyroid arteries, drain superior poles of thyroid gland into internal jug veins.
Middle thyroid veins: run essentially parallel courses with inferior thyroid arteries. drain middle lobes into IJV.
Inf thyroid vein: run alone, drain inf poles into brachiocephalic veins.
innervation of the thyroid gland
vasomotor innervation by fibres of the cardiac and sup/inf thyroid periarterial plexus which acompany arteries. derived sup, middle and inf cervical sympathetic ganglia. Stimulation causes constriction of blood vessels.
lymphatic drainage of the thyroid gland
rich network run in interlobular connective tissue septa, usually near arteries, pass to prelaryngeal, pretracheal and paratracheal lymph nodes. the prelaryngeal nodes drain into superior cervical lymph nodes. Pretracheal and para nodes drain into inf deep cervical lymph nodes.
enlargment of the thyroid gland
A GOITRE IS A SWELLING OF THE NECK OR LARYNX RESULTING FROm enlargment of the thyroid gland. Its possible that enlargment of the gland compress trachea oesophagus or jug veins. may spread anterioly post laterally or inf. cant spread in a superior direction as this is occupied by thyroid cartalige.
embryology of the thyroid gland
originates from pharynx, site of origin being foramen caecum on dorsal surface tongue. during development gland descends into neck passing ant to hyoid bone and larynx. connected to foramen caecum by thyroglossal duct. this duct disapears however remnants persist and form thyroglossal duct cysts. abberations in embryological development can cause various forms of thyroid dysgenesis like ectopic thyroid.
histology of thyroid gland
connective tissue septa can be seen to project into gland, dividing into lobules. Thyroid follicles are lined by simple cuboidal epithelium, these cells are termed follicular cells-contain colloid and secrete thyroid hormones thyrocine T4 and triiodothyronine T3. A second cell type, with paler staining nucleus, termed parafollicular cell C cell is also present-secrete calcitonin.
parathyroid gland
four parathyroid glands are embedded into post aspect of thyroid. Located 1cm superior and inf to entry point of inf thyroid artery. Sup parathyroid glands lie at level inf border cricoid cartilage. The inf parathyroid glands are usually near the inf poles of the thyroid. theyre small flattened and oval shaped. branches of the inf thyroid arteries usually supply, drained by parathyroid veins into thyroid plexus, lymph drains with thyroid gland. Have and abundant nerve supply derived from branches of cervical sympathetic ganglia. Vasomotor.
imaging of the GI tract
contrast x rays-barium enema, ERCP.
thyroid metabolic hormones
93% is thyroxine T4, 7% Triiodothyronine T3. almost all T4 is deiodinated to T3 in tissues, which is what is delivered and used by tissues. The functions of the hormones are the same. T3 is more potent but is present in the blood in smaller quantities and persists for shorter time.
thyroid gland follicules
the gland is composed of follicules filled with colloid and lined with cuboidal epithelial cells that secrete into the follicles. major constituent of colloid is thyroglobulin-contains thyroid hormones. Once secretion has entered follicles it must be absorbed back through follicular epithelium into blood before it can function in the body.
recommended daily intale of iodine
at least 140ug and dietary supplementation of salt and bread has reduced the number of areas where endemic goitre occurs.
Iodide trapping
the sodium iodide symporter (NIS) cotransports 1 iodide ion along with 2 Na across the basolateral membrane into the cell. The energy for transporting iodide against a conc gradient comes from the Na K ATPase pump which pumps Na out of the cell so establishes a low intracellular Na conc and a gradient for facilitated diffusion of Na into the cell. This is iodide trapping.
Iodide transport out of the thyroid cell
out of the thyroid cell across the apical membrane into follicules by chloride Iodide ion counter transporter molecule called pendrin. The thyroid epithelial cells also secrete into the follicle thyroglobulin that contains 115 tyrosine amino residues. Its synthesised, glycosylated and secreted into lumen of the follicle wwhere iodination of the tyrosine residues occur.
formation of thyroid hormones first step
T4 and 3 formed from tyrosine remain part of the thyroglobulin molecule during sunthesis of the thyroid hormones and even afterwards as stored hormones in follicular colloid.
First step in formation is conversion of iodide ions to oxidised form iodine by thyroperoxidase and hydrogen peroxide, either nascent iodine I2 or I3. its then capable of combining directly with tyrosine.
organification of the thyroglobin
the binding of iodine with tyrosine residues in thyroglobulin is called organification of the thyroglobulin. In thyroid cells the oxidised iodine is associated with thyroid peroxidase that causes the process to occur rapidly.
tyrosine to thyroid hormones
tyrosine is first iodized to monoiodotyrosine and then diiodotyrosine. Then more iodotyrosine residues become coupled making T4-2 mols of diiodotyrosine are joined. T4 remains part thyroglobulin molecule. One mono can couple with diiodotyrosine to form T3. Small amounts of reverse T3 (RT3) are formed by coupling of diiodotyrosine with mono, but RT3 doesnt appear functional.
storage of thyroid hormones
stored in follicles in in amount sufficient to supply body for 2-3 months.
cleaving thyroxine and triiodothyronine
first cleaved from thyroglobulin molecule then free hormones released:
apical surface of thyroid cells send out pseudopod extensions that close small portions of the colloid to form pinocytic vesicles that enter the apex of the thyroid cell. then lysosomes in the cytoplasm fuse with these vesicles, multiple proteases among the enzymes digest the thyroglobulin molecules and release T4 and T3 in free form. These diffuse through base thyroid cell into surrounding capillaries.
fate after release of hormones
75% iodinated tyrosine in the thyroglobulin remain as monoiodotyrosine and diiodotyrosine. During digestion their iodine is cleaved from them by a deiodinase enzyme that makes virtually all iodine available again for forming additional thyroid hormones.
on entering the blood - thyroid hormones
Most T4/3 combines immediatly with plasma proteins synthesized in the liver. They combine mainly with thyroxine binding globulin and much less so with thyroxine binding prealbumin and albumin. Due to high affinity of plasma binding proteins with thyroid hormones substances especially thyroxine, are released to the tissue cells slowly.
on entering tissue cells-T3/4
bind with intracellular proteins. T4 binds stronger, so stored in target cells and used slowly over days or weeks. Binding proteins maintain serum unbound (free) T3/4 conc within narrow limits to ensure that hormones are readily available to tissues.
binding proteins
plasma proteins that bind thyroid hormones are albumin transthyretin thyroxine binding globulin.
deiosinases
T4 could be a precursor for more potent T3. Converted by deiodinase enzymes. Type 1 located in thyroid liver and kidney has a low affinity for T4.
type II deiodinase has a higher affinity for T4, found in pituitary gland, brain, brown fat and thyroid. expression of type 2 allows it to reg T3 conc locally.
Type III inactivates T4 and 3 and is the most important source of RT3.
All contain the amino acid selenocysteine
nuclear thyroid hormone receptors
thyroid hormones bind with high affinity to nuclear thyroid hormone receptors TRs. TRa is abundant in brain kidney gonads muscle and heart.
TRb expression is high in pituitary and liver.
The TRb2 isoform is selectively expressed in the hypothalamus and pituitary where it plays a role in feedback control of thyroid acis. The TRa2 isoform precludes thyroid hormone binding, it may function to block the action of other TR isoforms.
physiological function of thyroid hormones
activate nuclear transcription of genes, so protein enzymes, structural proteins, transport P and others are synthesized. Result is generalized inc in functional activity throughout the body.
before acting 1 iodide is removed from T4 forming T3, intracellular thyroid hormone receptors have high affinity for T3.
activation and inactivation of thyroid hormones
thyroxine binding globulin slows metabolic inactivation and urinary excretion of thyroid hormones thereby extending half lives.
Activation: 5’Deiodinase catalyzes the conversion of T4 to 3 by removal of Iodine atom. Present in liver kidneys thyroid.
Inactivation: seperate deiodinase enzyme targets another side on T4 forming inactive RT3. Occurs in liver and kidneys
thyroid hormone receptor
either attached to DNA strands or close. TH receptor forms a heterodimer with retinoid X receptor RXR as specific thyroid hormone response elements on DNA. On binding, receptors become activated and initiate transcription process. Large numbers of diff typres of mRNA are formed followed by translation to form new intracellular proteins. The actions of TH result from subsequent enzymatic and other functions of these new proteins.
Nongenomic actions of TH
some effects occur too rapidly to be changes in protein synth. The site of nongenomic TH action appears to be plasma mem, cytoplasm and cell organelles like mitochondria. Nongenomic actions of TH include regulation of ion channels and ocidative phosphorylation and appear to involve the activation of intracellular secondary messengers.
thyroid hormone metabolic activities
they increase metabolic activities in almost all tissues pf the body. rate of PS is increased, also rate protein catabolism inc. Growth rate in young people are inc, also mental processes are excited and activities of most of the other endocrine glands are inc.
T4 inc number and activity of mitochondria which inc rate of ATP formation to energize cell function. Could also be down to inc activity of cells.
TH inc activity of Na-K-ATPase. This inc metabolic rate. Also makes cells leaky to sodium which activates Na pump and further inc heat production.
overall effects of thyroid hormones
inc rate skeletal growth in children, essential for early brain development, stim carb metabolism, including rapid uptake of glucose by cells, inc glycolysis, enhanced gluconeogenesis, inc rate absorption from GI tract and inc insulin secretion.
stim all aspects of fat metabolism. inc free fatty acid conc in plasma and accelerate oxidation of free FA by cells.
Dec conc of cholesterol, phospholipids and triglyc in plasma.
Inc rate chol secretion in bile and loss in feaces. Inc number LDL receptors on liver so rapid removal of LDL from plasma by liver and subsequent sec of chol in lipoproteins.
inc need for vitamins.
Inc basal metabolic rate
Dec body weight with inc appetite
effect of thyroid hormones on the cardiovascular system
inc metabolism in the tissues causes more rapid utilization of oxygen than normal and release greater quantities of metabolic end products from tissues. these effects cause vasodilation in most body tissues so inc blood flow-cardiac output inc. TH inc heart rate by inc excitability of the heart. as inc blood flow through tissues between heartbeats pulse pressure is inc with systolic pressure elevated in hyperthyroidism and diastolic pressure reduced a corresponsing amount.
functional anatomy of the thyroid
- The thyroid gland is composed of large numbers of follicles.
- The follicles are lined with cuboidal epithelial cells that secrete into the interior of the follicles.
- This secretory fluid inside the follicles is called colloid.
- The major constituent of colloid is a large glycoprotein called thyroglobulin, which contains the thyroid hormones within its molecule.
- Once the thyroglobulin secretion has entered the follicle, it undergoes various reactions in the colloid.
- Following this, it is absorbed back through the follicular epithelium into the blood before it can function in the body.
- The thyroid gland has a very rich blood supply.
function of the thyroid gland
• The thyroid secretes:
Thyroxine (T4) – increase metabolic rate
Triiodothyronine (T3) – increase metabolic rate
Calcitonin – calcium metabolism
• Lack of thyroid secretion can decrease the metabolic rate by 40-50% below normal.
• Excessive thyroid secretion can increase the metabolic rate by 60-100% above normal.
• Thyroid secretion is controlled by Thyroid Secreting Hormone (TSH), secreted by the anterior pituitary gland.
secretion of thyroid metabolic hormones
- Thyroxine is the main hormone secreted.
- However, thyroxine is converted to T3 in the tissues.
- The functions of these two hormones are qualitatively the same, but they differ in rapidity and intensity of action.
- T3 is four times more potent than T4, but it is present in the blood in much smaller quantities and persists for a much shorter time than T4.
synthesis of thyroid metabolic hormones-role of iodine
- To form normal quantities of thyroxine, about 50mg of ingested iodine in the form of iodides (I-) are required each year, or about 1 mg/week.
- To prevent iodine deficiency, common table salt is iodized.
- Iodides are absorbed from the GI tract into the blood, most of which is excreted by kidneys.
- Once 1/5 of the circulating iodide has been excreted, the thyroid gland uses the iodide to synthesise the thyroid hormones.
iodide trapping
- Iodides are transported from the blood into the cuboidal epithelial cells of the follicles in the thyroid gland.
- The basal membrane of the thyroid, actively pumps the iodide into these follicular cells. This is called ‘iodide trapping’.
- The pumping of iodide ions into the follicle cells occurs via a transport protein called Na+/I- Symporter.
- When the thyroid gland becomes more active, more iodide is actively transported into the follicle cells.
- TSH stimulates iodide trapping
formation of Thyroxine T4 and Triiodothyronine T3
• The endoplasmic reticulum synthesizes large glycoprotein molecules called thyroglobulin.
• The Golgi apparatus packages these together with tyrosine amino acids.
• Each molecule of thyroglobulin contains about 70 tyrosine amino acids, and they are the major substrates that combine with iodine to form the thyroid hormones.
• Thus, the thyroid hormones form within the thyroglobulin molecule.
That is, T3 and T4 formed from the tyrosine amino acids remain part of the thyroglobulin molecule during synthesis of the thyroid hormones and even afterward as stored hormones in the follicular colloid. They will then be absorbed by the follicle cells.
oxidation of the iodide ion
Conversion of the iodide ions to iodine.
Iodine is able to combine directly with the amino acid tyrosine in thyroglobulin.
Iodide ions are secreted out of the follicle cell and into the follicle via a transporter protein called pendrin.
The oxidation of iodide ions is catalysed by the ‘peroxidase enzyme’, which produces hydrogen peroxide (H2O2).
The peroxidase enzyme is either located in the apical membrane of the follicle cells or attached to it.
This allows the oxidation of iodide ions to occur in close proximity to where the follicle cells secrete thyroglobulin into the follicle.
When the peroxidase system is blocked, the rate of formation of thyroid hormones falls to zero.
organification of thyroglobulin
Organification of thyroglobulin is the binding of iodine with the thyroglobulin molecule.
Oxidised iodine binds directly to the thyroglobulin molecule.
iodination of tyrosine
This process is catalysed by the enzyme iodinase.
The iodine binds with tyrosine in the thyroglobulin molecule.
- Tyrosine is first iodized to monoiodotyrosine (MIT).
- MIT is then converted to diiodotyrosine (DIT).
- Then, more and more of the iodotyrosine residues become coupled with one another, eventually forming thyroxine or T3.
- Thyroxine is formed by the coupling of two DIT molecules, hence ‘T4’.
- Thyroxine remains part of the thyroglobulin molecule.
- Triiodothyronine (T3) is formed by the coupling of one molecule of MIT and one molecule of DIT, hence ‘T3’.
thyroglobulin storage
After the synthesis of thyroid hormones is complete, each thyroglobulin molecule comprises of up to 30 thyroxine molecules and a few T3 molecules.
In this form, the thyroid hormones are stored in the follicles in an amount sufficient to supply the body with its normal requirements of thyroid hormones for 2 to 3 months.
1. As a result, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months
T4 release from the thyroid gland
• Thyroglobulin is not released into circulation – the thyroid hormones are cleaved from the thyroglobulin molecule and then absorbed back into the thyroid cells for release into the blood.
• This process occurs as follows:
1. The apical surface of the thyroid cells allows for pinocytosis (endocytosis) of the thyroglobulin molecule, within which are the thyroid hormones.
2. Lysosomes fuse with these vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with the colloid.
3. Multiple proteases digest the thyroglobulin molecules and release T3, T4 and any uncoupled tyrosine molecules.
4. Now, T3 and T4 diffuse through the base of the thyroid cell into the surrounding capillaries.
fate of MIT and DIT
• ¾ of the iodinated tyrosine in the thyroglobulin remains as MIT and DIT and never becomes thyroxine.
• These free tyrosine molecules area also released into the cytoplasm of the thyroid cells when thyroglobulin is digested.
1. However, they are not secreted into the blood.
2. Instead, their iodine is cleaved from them by a deiodinase enzyme and the iodine and tyrosine are available again for recycling within the gland for forming additional thyroid hormones.
• In the congenital absence of this deiodinase enzyme, patients become iodine-deficient because of failure of this recycling process.
• Even though most of the thyroid hormone that is secreted into the blood is T4, about 50% of this deiodinates into T3 once it reaches the tissue
T3/4 transport to tissues
• Once T3 and T4 have entered the blood, 99% of them bind to plasma proteins for transport to tissues.
• The plasma proteins include:
Thyroxine-binding globulin (mainly)
Thyroxine-binding prealbumin (much less)
Albumin (much less)
• The thyroid hormones have a high affinity to the plasma-binding proteins.
• This means that these hormones are released to the tissue cells slowly.
• Thyroxine has a much higher affinity than T3.
Half of thyroxine is released to tissue cells every 6 days.
Half of T3 is released to tissue cells every 1 day.
- On entering the cells, the thyroid hormones bind to intracellular proteins.
- Thyroxine binds more strongly than T3.
- In this way, the thyroid hormones are stored in the target cells themselves, and are used slowly over a period of days or weeks.
onset and duration of action of TH
Thyroid hormones have a slow onset and long duration of action.
Thyroxine has a half-life of 15 days (as shown in the graph).
Most of the latency and prolonged period of action of these hormones are caused by their high affinity for binding to the plasma and intracellular proteins, followed by their slow release.
function and mechanism of action of thyroid hormones
• Thyroid hormones have the following functions:
Increase in transcription of genes.
Increased cellular metabolic activity.
Increased growth.
Increased metabolism of carbohydrates and fats.
Increases need for vitamins by increasing enzymes in the body.
Increases blood flow, cardiac output, heart rate, heart strength.
Increased respiration.
Increased GI motility.
Increased CNS excitation, which can lead to muscle tremors.
Increased tiredness.
Maintains normal sex function.
increased transcription of genes
• Thyroid hormones activate nuclear transcription of large numbers of genes.
- This increases the synthesis of Therefore, in all cells of the body, great numbers of protein enzymes, structural proteins, transport proteins, and other substances are synthesised.
- The net result is generalised increase in functional activity throughout the body.
mechanism of action of inc transcription of genes
Thyroxine is deioditnated to T3.
Intracellular thyroid hormone receptors have a very high affinity for T3.
T3 binds to nuclear thyroid hormone receptors.
The thyroid hormone receptor usually forms a heterodimer with retinoid X receptor (RXR) on the DNA. (This means that the receptor joins together with RXR).
On binding with thyroid hormone, the receptors become activated and initiate the transcription process.
This leads to the formation of different types of mRNA and subsequent the RNA translation on the ribosomes to form hundreds of new intracellular proteins.
1. The variety of synthesis of proteins allows for the other aforementioned effects of thyroid hormone.
increased cellular metabolic activity
- Thyroid hormones increase the metabolic activity of most body tissues.
- The basal metabolic rate can increase to 60-100% above normal when large quantities of the hormones are secreted.
- As a result, the rate of many process increases in the body such as:
- Utilisation of food for energy
- Protein synthesis/catabolism
- Growth rate
- Other endocrine glands
