case 9 - Yaffas Flashcards
where is the thyroid gland located
inferiorly to the larynx on each side and anteriorly to the trachea
what are the follicles of the thyroid gland lined with
cuboidal epithelial cells that secrete into the interior of the follicles
what is the secretory fluid inside the follicles
colloid
what is the major constituent of colloid
thyroglobulin which contains thyroid hormones within its molecule
what happens once thyroglobulin has entered the follicle
it undergoes various reactions in the colloid
where is the thyroglobulin absorbed
absorbed back through the follicular epithelium into the blood before it can function in thebody
what does the thyroid secrete
T4
T3
calcitonin
what do T4 and T3 do
increase metabolic rate
what does calcitonin do
calcium metabolism
what is thyroid secretion controlled by
thyroid secreting hormone, secreted by the anterior pituitary gland
what happens to thyroxine (T4)
it is the main hormone secreted and is converted into T3 in the tissues
what is different in T3 and T4
T3 is four times more potent than T4 but it is present in the blood in much smaller quantities and perisists for a much shorter time than T4
what is the role of iodine
to form normal quantities of thyroxine, about 50mg of ingested iodine in the form of iodides are required each year
how is iodine deficiency prevented
common table salt is iodised
where are iodides absorbed from
the GI tract into the blood, most of which is excreted by kidneys.
what happens once 1/5 of the circulating iodide has been excreted
the thyroid gland uses the iodide to synthesise the thyroid hormones
where are iodides transported
from the blood into the cuboidal epithelial cells of the follicles in the thyroid gland
what actively pumps the iodide into these follicular cells
the basal membrane of the thyroid.
this is called iodide trapping
what is the pump involved in iodide trapping
transport protein called Na+/I- symporter
what happens when the thyroid becomes more active
more iodide is actively transported into the follicle cells
what stimulates iodide trapping
TSH
what synthesises the thyroglobulin
the endoplasmic reticulum
where do the thyroid hormones form
within the thyroglobulin molecule
what is oxidation of the iodide ion
conversion of iodide to iodine
what is iodine able to do
combine directly with the amino acid tyrosine in thyroglobulin
what is the transporter protein that iodide ions are secreted into the follicle via
the pendrin protein
what is the oxidation of iodide ions catalysed by
the perioxidase enzyme
where is the perioxidase enzyme located
in the apical membrane of the follicle cells or attached to it
what does this allow
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
what is organification of thyroglobulin
the binding of iodine with the thyroglobulin molecule
what is the iodination of tyrosine catalysed by
the enzyme iodinase
where does the iodine ion bind with tyrosine
in the thyroglobulin molecule
what are the steps of the iodination of tyrosine
- 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’.
where are the thyroglobulin molecules stored
in the follicles
as a result, when synthesis of thyroid hormone ceases, the physiologic effects of the deficiency are not observed for several months
what doesnt happen to the thyroglobulin
it is not released into the circulation - the thyroid hormones are cleaved from the thyroglobulin molecule and absorbed back into the thyroid cells for release into the blood
what does this process allow for
- 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.
what happens to the free tyrosine molecules that are 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.
what happens when there is congenital absence of this deiodinase enzyme
patients become iodine deficient because of the failure of this recycling process
where do T3 and T4 bind when in the blood
Thyroxine-binding globulin (mainly)
Thyroxine-binding prealbumin (much less)
Albumin (much less)
where do thyroid hormones bind when entering the cells
the intracellular proteins
what binds more strongly than T3
thyroxine
what are the functions of the 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.
what is the mechanism of action of the increased transcription of genes via thyroid hormones
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.
what else do T3 and T4 increase
increase in mitochondrial activity and ion active transport
what do thyroid hormones promote in children
growth
what aspects of carbohydrate metabolism does TH stimulate
- Rapid uptake of glucose by cells.
- Enhanced glycolysis.
- Enhanced gluconeogenesis.
- Increased absorption rate from GI tract.
- Increased insulin secretion with its resultant secondary effects on carbohydrate metabolism.
what do these effects result from
the overall increase in the cellular metabolic enzymes caused by the increased gene transcription and subsequent enzyme synthesis caused by thyroid hormones
what are the effects of TH on the cardiovascular system
increased blood flow and cardiac output
increased HR
increased heart strength
where is TSH secreted from
the anterior pituitary gland
what does this hormone do
increases the secretion of T4 and T3 by the thyroid gland
what are its specific effects on the thyroid
- Increased proteolysis of thyroglobulin that is stored in the follicles, with resultant release of the TH into the circulation.
- Increased activity of the iodide pump, which increases the rate of “iodide trapping”
- Increased iodination of tyrosine to form the TH.
- Increased size and increased secretory activity of the thyroid cells.
- Increased number of thyroid cells + a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles.
what does TSH do to cAMP
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 secondary messenger to activate protein kinase which causes multiple phoshporylation throughout the cell
what is the result of this
both an immediate increase in secretion of TH and prolonged growth of the thyroid glandular tissue itself
what is anterior pituitary secretion of TSH controlled by
a hypothalamic hormone, TRH
where is TRH secreted from
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-hypophyial portal blood
what does TRH directly affect
the anterior pituitary gland cells to increase their output of TSH
what is the 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
- Increased thyroid hormones in the body fluids decreases secretion of:
1. TRH by the hypothalamus
2. TSH by the anterior pituitary
what does calcitonin do
decreases plasma calcium concentration
what does parathyroid hormone do
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
rapid absorption of calcium salts from the bones, resulting in hypercalcemia in the extracellular fluid
how does PTH increase calcium and phosphate absorption
- 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 and thyrotoxicosis
- Hyperthyroidism – this is the over-activity of the thyroid gland.
- Thyrotoxicosis is a hyper-metabolic state caused by elevated circulating levels of free T3 and T4, caused by hyperthyroidism.
what are the two types of hyperthyroidism
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
what is the pathology of secondary hyperthyroidism usually due to
usually at the site of the pituitary gland and the main cause is a TSH secreting pituitary adenoma
what are the most common causes of thyrotoxicosis also associated with
- Diffuse hyperplasia of the thyroid associated with Graves’ disease (85% of cases)
- Multinodular goitre
- Toxic adenoma of the thyroid
- Thyroiditis
what is Graves disease the most common cause of
endogenous hyperthyroidism
what is Graves disease characterised by
- It is characterised by a triad of clinical findings:
- Hyperthyroidism due to diffuse, hyperfunctional enlargement of the thyroid
- Infiltrative ophthalmopathy with resultant exophthalmos (protrusion of eyeball)
This is an autoimmune inflammatory response affecting the orbit, leading to bulging eyes. - Pretibial myxoedema – this is localised, infiltrative dermopathy, which is present in a minority of patients.
Red, swollen skin, usually on the shins and tops of feet.
Texture of the skin is similar to that of an orange peel.
what is the pathogenesis behind graves disease
the body produces antibodies to the TSH receptor
what happens to these antibodies
they bind to TSHr and chronically stimulate them
what is the result of this
abnormally high production of T3 and T4
what does this cause in turn
clinical symptoms of hyperthyroidism and the enlargement of the thyroid gland visible as goitre
what are the three types of antibodies to the TSHr that are currently recognised
thyroid-stimulating immunoglobulins (TSI)
thyroid growth stimulating immunoglobulins (TGI)
TSH/thyrotropin-binding inhibitor immunoglobulins (TBII)
what happens in TSI
these antibodies, mainly IgG act as long acting thyroid stimulants, activating the cells in a longer and slower way that TSH
they bind to the TSHr and mimic the action of TSH, increasing the release of TH
individuals with Graves disease have detectable levels of this autoantibody
TSI are relatively specific for Graves disease in contrat to thyrobglobulin and thyroid perioxidase antibodies
what does TGI do
these antibodies bind directly to the TSHr and have been implicated in the growth of thyroid follicular epithelium
what do TBII do
these anti-TSH receptor antiobodies prevent TSH from binding normally to its receptor on thyroid epithelial cells
some forms of TBII mimic the action of TSH, resulting in the stimulation of thyroid epithelial cell activity
in graves opthamology, the volume of the retro-orbital connective tissues and extra-ocular muscles is increased for several reasons including;
- T-cell infiltration of the retro-orbital space.
- Inflammatory oedema and swelling of extra-ocular muscles.
- Accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate.
- Increased numbers of adipocytes (fatty infiltration).
what do orbital pre-adipocyte fibroblasts express
the TSHr and thus become targets of an autoimmune attack
what happens to T cells reactive against these fibroblasts secrete
cytokines, which stimulate fibroblast proliferation and synthesis of extracellular matrix proteins and increase surface TSHr expression, perpetuating the autoimmune response
what is the result of this
progressive infiltration of the retro-orbital space and opthalography
what are the causes of hypothyroidism
- Hypothyroidism is caused by inadequate function of the thyroid gland (primary hypothyroidism) or by not enough stimulation by TSH (central hypothyroidism).
- Primary hypothyroidism is 1000x more common than central hypothyroidism.
Most common causes:
1. Iron deficiency is the most common cause of primary hypothyroidism and endemic goitre worldwide.
2. Hashimoto’s Thyroiditis in places with sufficient dietary iodine.
3. After treatment of hyperthyroidism – usually after radioiodine treatment.
what is the clinical course of treatment
- The earliest biochemical abnormality is an increase in serum TSH concentration with normal serum T4 and T3 concentrations (subclinical hypothyroidism).
- This is followed by a decrease in serum T4, causing symptoms - require treatment (overt hypothyroidism).
- Hypothyroidism results from insufficient secretion of TH and can be due to a variety of abnormalities; the severest form is myxoedema (cutaneous and dermal oedema).
what is Hashimoto thyroiditis
- Hashimoto thyroiditis is the most common cause of hypothyroidism in areas of the world where iodine levels are sufficient.
- This disease describes patients with goitre and intense lymphocytic infiltration of the thyroid.
- It is characterised by gradual thyroid failure due to autoimmune destruction of the thyroid.
what is the pathogenesis of hashimoto thyroiditis
- In Hashimoto thyroiditis, there are various antibodies against thyroid peroxidase, thyroglobulin and TSH receptors.
- Induction of thyroid autoimmunity is accompanied by a progressive depletion of thyrocytes by apoptosis and replacement of the thyroid parenchyma by mononuclear cell infiltration and fibrosis.
what are the multiple immunologic mechanisms that may contribute to thyroid cell death
- CD8+ cytotoxic T cell-mediated cell death of thyrocytes.
- Cytokine-mediated cell death: Excessive T-cell activation leads to the production of TH1 inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruitment and activation of macrophages and damage to follicles
- Antibody-dependent cell-mediated cytotoxicity - anti-thyroglobulin, and anti-thyroid peroxidase antibodies
- These decrease iodide trapping by causing competitive inhibition of Na+/I- symporter when administered in high concentrations.
- However, a problem with this drug is that even though no TH is produced, the deficiency in TH in the plasma sends a positive feedback to the APG to increase TSH production.
As a result, there is overgrowth and goitre formation of the thyroid without adequate TH production.
what is diffuse nontoxic goitre
- This is enlargement of the entire gland without producing nodularity.
- Formation of Goitre:
Low iodine levels
Decreased synthesis and secretion of TH
Compensatory increase in TSH
Follicular cell hypertrophy and hyperplasia
Growth and enlargement of thyroid gland (goitre) - Increasing dietary iodine supplementation has decreased the frequency and severity of goitre.
what is first line treatment for hyperthyroidism
radioiodine
what does the isotope emit
both beta and gamma rays
the beta particles have short range - absorbed by the tissue and exert a powerful cytotoxic action, resulting in destruction of the cells of the thyroid follicles
the gamma rays pass through the tissue without causing damage
what eventually occurd after treatment with radioiodine
hypothyroidism occurs, thyroxine is given to treat this
what are anti thyroid substances
- These are drugs that supress thyroid secretion.
- The substances involved in the suppression include:
Thiyocyanate Ions – decrease iodide trapping
Propylthiouracil (PTU)/Carbimazole/Methimazole – block peroxidase and iodination of tyrosine
High concentrations of inorganic iodides - - They have different mechanisms to block thyroid secretion.
what do thiyocyanate ions do
- These decrease iodide trapping by causing competitive inhibition of Na+/I- symporter when administered in high concentrations.
- However, a problem with this drug is that even though no TH is produced, the deficiency in TH in the plasma sends a positive feedback to the APG to increase TSH production.
As a result, there is overgrowth and goitre formation of the thyroid without adequate TH production.
what does carbimaxole do
- These compounds decrease TH formation from iodides and tyrosine.
- The mechanism involves:
Partly blocking the peroxidase enzyme that is required for iodination of tyrosine.
Partly blocking the coupling of two iodinated tyrosines to formT4 or T3. - However, a goitre can form due to the feedback system
what is the mechanism of action of carbimazole
- Thioureylenes decrease the output of TH from the gland.
- They also cause a gradual reduction in:
1. Signs and symptoms of thyrotoxicosis,
2. Basal metabolic rate
3. Pulse rate returning to normal over a period of 3-4 weeks - They inhibit the iodination of tyrosyl residues in thyroglobulin.
- It is thought that they inhibit the thyroperoxidase-catalysed oxidation reactions by acting as substrates for the peroxidase-iodinium complex, thus competitively inhibiting the interaction with tyrosine.
- Propylthiouracil has the additional effect of reducing the deiodination of T4 to T3 in peripheral tissues.
what is propranolol
a non-selective beta blocker
what are the layers of the adrenal cortex
- Zona Glomerulosa – mineralocorticoids (e.g. aldosterone)
- Zona Fasciculosa – glucocorticoids (e.g. cortisol)
- Zona Reticulosa – sex steroid precursors (e.g. androstenedione)
what does overproduction of hormones in each layer cause
Zona Glomerulosa – mineralocorticoid excess (Conn Syndrome)
Zona Fasciculosa – glucocorticoid excess (Cushing Syndrome)
Zona Reticulosa – excess sex steroid precursors
Mixed overproduction is indicative of (rare) adrenocortical cancer.
Medulla – excess catecholamine secretion (Phaeochromocytoma tumour)
what does under production of these hormones cause
‘Primary’ – the entire cortex is affected (Addison Disease/ TB/ HIV)
‘Secondary’ - hypopituitarism, loss of ACTH
what is the treatment for Conn syndrome
adrenalectomy or mineralcorticoid antagonists
what is addisons disease
the under production of glucocorticoids and mineralcorticoids
what is the treatment of addisons disease
Hydrocortisone – this medication is given life-long.
May need mineralocorticoid replacement (fludrocortisone)
