Case 9 Flashcards
where is thyroid gland located?
inferiorly to the larynx on each side of and anteriorly to the trachea.
• It is one of the largest endocrine glands.
functional anatomy of thyroid gland
- what is it composed of
- what lined with
- what is the secretory fluid inside the follicles called
- what is the major component of this
- 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.
what happens once the thyroglobulin secretion has entered the follicle
- 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.
what is the blood supply of the thyroid gland like?
rich
what is colloid?
a glycoprotein
what do C cell secrete?
calcitonin
what does the thyroid secrete? what does each secretion do?
Thyroxine (T4) – increase metabolic rate
Triiodothyronine (T3) – increase metabolic rate
Calcitonin – calcium metabolism
what can lack of thyroid secretion do to metabolic rate? what can excessive thyroid secretion do to metabolic rate?
- 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.
what is thyroid secretion controlled by? where is this secreted?
Thyroid Secreting Hormone (TSH), secreted by the anterior pituitary gland.
which is the main hormone secreted?
thyroxine
what happens to thyroxine in the tissues?
it’s converted to T3
what is the relationship between T3 and T4? are they same/different?
- 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.
the role of iodine in the synthesis of thyroid metabolic hormones
- how much iodine required for normal quantities of thyroxine
- how is iodine deficiency prevented
- 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.
what happens to iodides after ingestion?
- 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
- what is this
- how does it occur
- what happens when the thyroid gland becomes more active
- what stimulates 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.
what is T3?
triiodothyronine
formation of T4 and T3
- what does the endoplasmic reticulum synthesise large amounts of
- what happens to the substance produced next
- what does this mean for where the thyroid hormones are formed
• 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
- what iodide ions converted to
- what happens to substance produced
- transporter
- enzyme - where located - what does this allow
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.
what happens to the rate of formation of thyroid hormones when the peroxidase system is blocked ?
falls to zero
organification of thyroglobulin
- what is this
Organification of thyroglobulin is the binding of iodine with the thyroglobulin molecule.
Oxidised iodine binds directly to the thyroglobulin molecule.
iodination of tyrosine
- what enzyme
- what happens
- what is formed
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 syntehsis of thyroid hormone is complete, what does each thyroglobulin comprise of
- in this form, the thyroid hormones are stored in the follicles in amount sufficient to supply the body with its normal requirements of thyroid hormones for how long
- what does this mean
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.
- As a result, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months
is thyroglobulin released into circulation? how is
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.
how is T3 and T4 released from the thyroid gland?
- The apical surface of the thyroid cells allows for pinocytosis (endocytosis) of the thyroglobulin molecule, within which are the thyroid hormones.
- Lysosomes fuse with these vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with the colloid.
- Multiple proteases digest the thyroglobulin molecules and release T3, T4 and any uncoupled tyrosine molecules.
- Now, T3 and T4 diffuse through the base of the thyroid cell into the surrounding capillaries.
does any or how much iodinated tyrosine in the thyroglobulin remains as MIT and DIT and never becomes thyroxine?
75%
what happens to the free tyrosine molecules?
• These free tyrosine molecules area also released into the cytoplasm of the thyroid cells when thyroglobulin is digested.
- However, they are not secreted into the blood.
- 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, why do patients become iodine-deficient?
because of failure of this recycling process.
how much of the thyroid hormone secreted into the blood is T4 and how much T3? what happens to T4?
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.
once T3 and T4 have entered the blood, what happens?
99% of them bind to plasma proteins for transport to tissues.
what are the plasma proteins that T3 and T4 bind to?
Thyroxine-binding globulin (mainly)
Thyroxine-binding prealbumin (much less)
Albumin (much less)
what is the affinity of thyroid hormones to plasma-binding proteins like? what does this mean for release into tissues? does T3 or T4 have a high affinity? how much of each hormone released to tissues every how many days?
• 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.
what do the thyroid hormones do on entering the cells? what does this mean?
- 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.
what is the onset and duration of action of thyroid hormones like? what is this due to? what is the half-life of thyroxine?
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.
what are the functions of thyroid hormones?
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
- by what
- which genes
- what does this lead to
• 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.
what is the mechanism of action for increased 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.
- The variety of synthesis of proteins allows for the other aforementioned effects of thyroid hormone.
thyroid hormones increase the metabolic activity of which tissues? how much can the basal metabolic increase by?
- 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 of increased metabolic rate, the rate of many processes increases in the body, such as what?
- Utilisation of food for energy
- Protein synthesis/catabolism
- Growth rate
- Other endocrine glands
increase in mitochondrial activity
- how
- what does this result in
- T3/T4 causes an increase in the size and number of mitochondria.
- Also, the total membrane surface area of the mitochondria also increases in proportion to the increased metabolic rate.
- This results in increased ATP production and cellular function.
increase in ion active transport
- how
- which ions
- this is a mechanism for what and why
- T3/T4 increase the activity of the enzyme Na+/K+ ATPase.
- This increases the rate of transport of both Na+ and K+ ions.
- Because this process uses energy and increases the amount of heat produced in the body, it is a mechanism by which thyroid hormone increases the body’s metabolic rate.
increased growth
- thyroid hormone promotes growth in who
- in hypothyroid and hyperthyroid what happens
- promotes growth of what else and when
• Thyroid hormones promote growth in growing children.
1. In hypothyroid, the rate of growth is greatly reduced.
2. In hyperthyroid, excessive skeletal growth often occurs.
This causes the child to become considerably taller at an earlier age.
However, bones also mature more rapidly and the epiphyses close at an early age.
Therefore, the duration of growth and eventual height of the adult may actually be shortened.
- Thyroid hormone also promotes growth and development of the brain both during foetal life and for the first few years of postnatal life.
- If the foetus does not secrete sufficient quantities of TH, growth and maturation of the brain before birth and afterward are greatly retarded, and the brain remains smaller.
stimulation of carbohydrate metabolism
- which aspects does it stimulate
- what do these effects result from
• TH stimulates almost all aspects of carbohydrate metabolism including:
1. Rapid uptake of glucose by cells.
2. Enhanced glycolysis.
3. Enhanced gluconeogenesis.
4. Increased absorption rate from GI tract.
5. Increased insulin secretion with its resultant secondary effects on carbohydrate metabolism.
• These effects result from the overall increase in cellular metabolic enzymes caused by the increased gene transcription and subsequent enzyme synthesis caused by thyroid hormones.
simulation of fat metabolism
- which aspects are enhanced
- what happens in particular
- what does this lead to
• All aspects of fat metabolism are enhanced under the influence of TH.
- In particular, lipids are mobilised rapidly from the fat tissue, which decreases the fat stores of the body to a greater extent than almost any other tissue element, leading to a loss in weight.
- This also increases the free fatty acid concentration in the plasma and greatly accelerates the oxidation of free fatty acids by the cells.
- The oxidation of fatty acids results in the formation of acetyl-CoA, which can then enter the citric acid cycle, causing increased release of energy.
effect on plasma and liver fats
- what do they increase/decrease plasma concentrations of
- what does decreased thyroid secretion cause
- mechanism of action
• Even though thyroid hormones increase free fatty acids, they decrease the plasma concentrations of:
- Cholesterol
- Phospholipids
- Triglycerides
• Decreased thyroid secretion greatly increases the plasma concentrations of these molecules, causing excessive deposition of fat in the liver.
• Mechanism of Action:
The decrease in plasma cholesterol concentration is caused by increase rate of cholesterol secretion in the bile and consequent loss in the faeces.
A possible mechanism for the increased cholesterol secretion is that thyroid hormone induces increased numbers of low-density lipoprotein receptors on the liver cells, leading to rapid removal of low-density lipoproteins from the plasma by the liver and subsequent secretion of cholesterol in these lipoproteins by the liver cells
increased requirement for vitamins
- what are vitamins an essential part of
- what does TH do and why causes increased need
- what can occur when excess TH is secreted
• Vitamins are essential parts of some enzymes and coenzymes.
• TH increases quantities of bodily enzymes so it causes increased need for vitamins.
- Therefore, a relative vitamin deficiency can occur when excess TH is secreted.
what are the effect of TH on the cardiovascular system?
- increased blood flow and cardiac output
- increased HR
- increase heart strength
- normal arterial pressure
increased blood flow & cardiac output
- what does increased metabolism cause
- why does the rate of blood flow in the skin increase
• Increased metabolism in the tissues causes more rapid utilisation of oxygen than normal and release of greater than normal quantities of metabolic end products from the tissues
1. These effects cause vasodilation in most body tissues, thus increasing blood flow
• The rate of blood flow in the skin increases because of the increased need for heat elimination from the body.
1. As a consequence of the increased blood flow, cardiac output also increases.
increased heart rate
- how
- why is this effect important for doctors
- TH has a direct effect on the excitability of the heart, thus increasing the heart rate.
- This effect is important because the HR is one of the sensitive physical signs that clinicians use in determining whether a patient has excessive or diminished TH production.
increased heart strength
- what happens when TH is increased?
• When TH is increased, the heart muscle strength becomes depressed because of long-term excessive protein catabolism.
normal arterial pressure
- what happens to meal arterial pressure after administration of TH
- why
- what happens to systolic and diastolic pressure in hyperthyroidism
• The mean arterial pressure remains normal after administration of TH.
• Due to increased blood flow through the tissues between heartbeats, the pulse pressure is often increased.
1. Therefore, systolic pressure elevates in hyperthyroidism.
2. Diastolic pressure decreases.
increased respiration
- why
- The increased rate of metabolism increases the utilisation of oxygen and formation of carbon dioxide.
- These effects activate all the mechanisms that increase the rate and depth of respiration.
increased GI motility
- what else does it increase to do with the GI tract
- what does hyperthyroidism often result in
- what can hypothyroidism cause
• In addition to increased appetite and food intake, TH increases both:
1. The rates of secretion of digestive juices
2. The motility of the GI tract
• Hyperthyroidism often results in diarrhoea.
• Hypothyroidism can cause constipation.
CNS excitatory effects
- what does TH normally do
- what does hyperthyroidism lead to
- Generally, TH increases the rapidity of cerebration.
- Hyperthyroidism leads to extreme nervousness and many psychoneurotic tendencies such as:
- Anxiety complexes
- Extreme worry
- Paranoia
effect on muscle function
- what is the effect
- what does excessive increase in TH cause and why
- what does lack of TH cause
- Slight increase in TH makes muscles react with vigour.
- Excessive increase in TH causes the muscles to become weakened because of excess protein catabolism.
- Lack of TH causes the muscles to become sluggish, and they relax slowly after contraction.
what is the one of the most characteristic signs of hyperthyroidism?
a fine muscle tremor
muscle tremor
- what is it caused by
- what is the tremor an important means for assessing
- This tremor is caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that control muscle tone.
- The tremor is an important means for assessing the degree of thyroid hormone effect on the CNS.
effect on sleep
- what is the effect and why
• Due to the exhausting effect of TH on muscles and CNS, hyperthyroid subjects feel constantly tired because of the excitable effects of TH on synapses.
effect on other endocrine glands
- what does increased TH do
- what is an example
• Increased TH increases the rates of secretion of endocrine glands, but it also increases the need of the tissues for the hormones.
- E.g. Increased thyroxine secretion increases the rate of glucose metabolism everywhere in the body.
- This causes a corresponding need for increased insulin secretion by the pancreas.
effect on sexual function
- what does normal TH allow
- what does lack and excess TH cause in both men and women
- what is the action of TH on he gonads due to
- Normal TH allows for normal sexual function to occur
- In men:
- Lack of TH – loss of libido
- Excess TH – impotence
• In women:
1. Lack of TH – loss of libido, menorrhagia and polymenorrhoea/sometimes even amenorrhoea
(excessive and frequent menstrual bleeding/irregular periods)
2. Excess TH – oligomenorrhoea (greatly reduced bleeding)
• The action of TH on the gonads is due to the effects of metabolic activities combined with excitatory and inhibitory feedback effects operating through the anterior pituitary hormones that control the sexual functions.
what is needed to maintain normal levels of metabolic activity in the body? where do feedback mechanisms operate through to do this?
• To maintain normal levels of metabolic activity in the body, the right amount of TH must be secreted at all times:
- Specific feedback mechanisms operate through the hypothalamus and anterior pituitary gland to control the rate of thyroid secretion.
regulation of endocrine secretion of thyroid
- what secreted from where to control it
- what does it do
- what are its specific effects on the thyroid
- what is the most important early effect
• TSH (thyrotropin) is a glycoprotein secreted by the anterior pituitary gland.
• This hormone increases the secretion of T4 and T3 by thyroid gland.
• Its specific effects on the thyroid are as follows:
1. Increased proteolysis of thyroglobulin that is stored in the follicles, with resultant release of the TH into the circulation.
2. Increased activity of the iodide pump, which increases the rate of “iodide trapping”
3. Increased iodination of tyrosine to form the TH.
4. Increased size and increased secretory activity of the thyroid cells.
5. Increased number of thyroid cells + a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles.
• In summary, TSH increases all the known secretory activities of the thyroid glandular cells
- The most important early effect (30mins) being proteolysis of thyroglobulin to release T3 + T4 followed by the rest (hours-days).
effect of cAMP on TSH
- what effect does it have
- how does it have effect
- what does cAMP do
- what is the result
- TSH binds with TSH receptors on the basal membrane surfaces of the thyroid cell.
- This activates adenylyl cyclase in the membrane, which increases the formation of cAMP inside the cell.
- Finally, the cAMP acts as a 2nd messenger to activate protein kinase which causes multiple phosphorylations throughout the cell.
• The result is both an immediate increase in secretion of TH and prolonged growth of the thyroid glandular tissue itself
regulation of TSH secretion
- what is TSH secretion controlled by
- how
• Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone (TRH):
- This is secreted by nerve endings in the median eminence of the hypothalamus.
- From the median eminence, the TRH is then transported to the anterior pituitary by way of the hypothalamic-hypophysial portal blood.
• TRH directly affects the anterior pituitary gland cells to increase their output of TSH.
what is the molecular mechanism by which TRH causes the TSH-secreting cells of the anterior pituitary to produce TSH?
- First to bind with TRH receptors in the pituitary cell membrane.
- This, in turn, activates the phospholipase second messenger system inside the pituitary cells to produce large amounts of phospholipase C.
- This is followed by a cascade of other second messengers, including calcium ions and diacyl glycerol.
- Eventually, this leads to TSH release.
what is the feedback system for TSH secretion?
• Increased thyroid hormones in the body fluids decreases secretion of:
- TRH by the hypothalamus
- TSH by the anterior pituitary
what is calcitonin?
a peptide hormone secreted by the thyroid gland
what does calcitonin do?
decreases plasma calcium concentration
where is calcitonin synthesised and secreted?
in the C cells, lying in the interstitial fluid between the follicles of the thyroid gland.
what stimulates calcitonin secretion?
increased plasma calcium concentration
what is stimulated by decreased calcium concentration?
parathyroid hormone
what are the two ways that calcitonin decreases blood calcium ion concentration? how quickly?
• Calcitonin decreases blood calcium ion concentration rapidly in two ways:
- Immediate effect - decrease the absorptive activities of the osteoclasts thus shifting the balance in favour of deposition of calcium in the exchangeable bone calcium salts.
- Prolonged effect - decrease the formation of new osteoclasts.
how powerful is the effect of calcitonin on plasma calcium concentration? why? what else does calcitonin have minor effects on?
- Calcitonin has a weak effect on plasma calcium concentration.
- This is because any initial reduction of the calcium ion concentration caused by calcitonin leads within hours to a powerful stimulation of PTH secretion, which almost overrides the calcitonin effect.
• Calcitonin also has minor effects of calcium handling in the kidneys and intestines.
parathyroid hormone
- what does it control
- how
• Parathyroid hormone (PTH) controls extracellular calcium and phosphate concentrations by regulating:
Intestinal reabsorption
Renal excretion
Exchange of these ions between the extracellular fluid and bone
what does excess activity of the parathyroid gland cause? what does hypo-function of this gland cause?
- Excess activity of the parathyroid gland (increased release of PTH) causes rapid absorption of calcium salts from the bones, resulting in hypercalcemia in the extracellular fluid.
- Hypo-function of this gland causes hypocalcaemia.
what are the two ways through which PTH increases calcium and phosphate absorption from the bone?
- Rapid phase – this begins in minutes and increases progressively for several hours
This results from activation of osteocytes to promote calcium and phosphate absorption. - Slow phase – this requires several days/weeks
It results from proliferation of the osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself.
what is hyperthyroidism?
the over-activity of the thyroid gland.
what is thyrotoxicosis?
a hyper-metabolic state caused by elevated circulating levels of free T3 and T4, caused by hyperthyroidism.
what are the different types of hyperthyroidism? what causes each? which is more common?
- Hyperthyroidism can be primary or secondary.
- Primary hyperthyroidism is when the pathology is within the thyroid gland.
- Secondary hyperthyroidism is when the thyroid gland is stimulated by excessive TSH in the circulation.
- Secondary hyperthyroidism is rare. The pathology is usually at the site of the pituitary gland.
what is the main cause of secondary hyperthyroidism?
TSH-secreting pituitary adenoma (rare).
what are the most common causes of thyrotoxicosis also associated with?
• The most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following:
- Diffuse hyperplasia of the thyroid associated with Graves’ disease (85% of cases)
- Multinodular goitre
- Toxic adenoma of the thyroid
- Thyroiditis
epidemiology of hyperthyroidism
- lifetime risk in both genders
- what percentage of cases are due to Graves’ disease, when is peak onset
- remainder of cases due to what
- which gender does it affect more - what ratio
Prevalence
• 400/100,000 persons
• Lifetime risk of 1% in men and up to 2% in women.
• 60-80% of cases are due to Graves’ disease with a peak onset at 20-50 years.
• Remainder of cases are due to nodular thyroid disease that appears later in life.
• Affects females more than males (ratio 9:1)
Incidence
• 0.77/1,000 annually in women
• 0.14/1,000 annually in men
• In England the incidence of Graves’ disease has been reported as 0.5/1,000/year
risk factors for hyperthyroidism
- Family history – genetic susceptibility
- High iodine intake
- Smoking
- Toxic multi-nodular goitre
- Childbirth
- Highly active antiretroviral therapy (HAART)