case 9 Flashcards

Question

cleaving thyroxine and triiodothyronine

Answer 1

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.

Answer 2

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.

Answer 3

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.

Answer 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.

Answer 5

plasma proteins that bind thyroid hormones are albumin transthyretin thyroxine binding globulin.

Answer 6

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

Answer 7

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.

Answer 8

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.

Answer 9

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

Answer 10

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.

Answer 11

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.

Answer 12

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.

Answer 13

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

Answer 14

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.

Answer 15

* 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.

Answer 16

• 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.

Answer 17

* 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.

Answer 18

* 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.

Answer 19

* 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

Answer 20

• 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.

Answer 21

 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.

Answer 22

 Organification of thyroglobulin is the binding of iodine with the thyroglobulin molecule.  Oxidised iodine binds directly to the thyroglobulin molecule.

Answer 23

 This process is catalysed by the enzyme iodinase.  The iodine binds with tyrosine in the thyroglobulin molecule. 1. Tyrosine is first iodized to monoiodotyrosine (MIT). 2. MIT is then converted to diiodotyrosine (DIT). 3. Then, more and more of the iodotyrosine residues become coupled with one another, eventually forming thyroxine or T3. 4. Thyroxine is formed by the coupling of two DIT molecules, hence ‘T4’. 5. Thyroxine remains part of the thyroglobulin molecule. 6. Triiodothyronine (T3) is formed by the coupling of one molecule of MIT and one molecule of DIT, hence ‘T3’.

Answer 24

 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

Answer 25

• 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.

Answer 26

• 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

Answer 27

• 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.

Answer 28

 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.

Answer 29

• 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.

Answer 30

• Thyroid hormones activate nuclear transcription of large numbers of genes. 1. 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. 2. The net result is generalised increase in functional activity throughout the body.

Answer 31

 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.

Answer 32

* 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: 1. Utilisation of food for energy 2. Protein synthesis/catabolism 3. Growth rate 4. Other endocrine glands

Answer 33

• Thyroid hormones activate nuclear transcription of large numbers of genes. 1. 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. 2. The net result is generalised increase in functional activity throughout the body.

Answer 34

 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.

Answer 35

* 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: 1. Utilisation of food for energy 2. Protein synthesis/catabolism 3. Growth rate 4. Other endocrine glands

Answer 36

* 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.

Answer 37

* 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.

Answer 38

• 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.

Answer 39

• 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

Answer 40

• All aspects of fat metabolism are enhanced under the influence of TH. 1. 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. 2. This also increases the free fatty acid concentration in the plasma and greatly accelerates the oxidation of free fatty acids by the cells. 3. 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.

Answer 41

• 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

Answer 42

 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

Answer 43

• Vitamins are essential parts of some enzymes and coenzymes. • TH increases quantities of bodily enzymes so it causes increased need for vitamins. 1. Therefore, a relative vitamin deficiency can occur when excess TH is secreted.

Answer 44

• 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

Answer 45

Increased HR • 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 • When TH is increased, the heart muscle strength becomes depressed because of long-term excessive protein catabolism. Normal Arterial Pressure • 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.

Answer 46

* 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

Answer 47

• 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.

Answer 48

* Generally, TH increases the rapidity of cerebration. * Hyperthyroidism leads to extreme nervousness and many psychoneurotic tendencies such as: 1. Anxiety complexes 2. Extreme worry 3. Paranoia

Answer 49

• Increased TH increases the rates of secretion of endocrine glands, but it also increases the need of the tissues for the hormones. 1. E.g. Increased thyroxine secretion increases the rate of glucose metabolism everywhere in the body. 2. This causes a corresponding need for increased insulin secretion by the pancreas.

Answer 50

* One of the most characteristic signs of hyperthyroidism is a fine muscle tremor. * 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

Answer 51

• 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

Answer 52

• Increased TH increases the rates of secretion of endocrine glands, but it also increases the need of the tissues for the hormones. 1. E.g. Increased thyroxine secretion increases the rate of glucose metabolism everywhere in the body. 2. This causes a corresponding need for increased insulin secretion by the pancreas.

Answer 53

* Normal TH allows for normal sexual function to occur * In men: 1. Lack of TH – loss of libido 2. 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.

Answer 54

• To maintain normal levels of metabolic activity in the body, the right amount of TH must be secreted at all times: 1. Specific feedback mechanisms operate through the hypothalamus and anterior pituitary gland to control the rate of thyroid secretion.

Answer 55

• 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 1. The most important early effect (30mins) being proteolysis of thyroglobulin to release T3 + T4 followed by the rest (hours-days).

Answer 56

1. TSH binds with TSH receptors on the basal membrane surfaces of the thyroid cell. 2. This activates adenylyl cyclase in the membrane, which increases the formation of cAMP inside the cell. 3. 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

Answer 57

• Anterior pituitary secretion of TSH is controlled by a hypothalamic hormone, thyrotropin-releasing hormone (TRH): 1. This is secreted by nerve endings in the median eminence of the hypothalamus. 2. 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.

Answer 58

1. First to bind with TRH receptors in the pituitary cell membrane. 2. This, in turn, activates the phospholipase second messenger system inside the pituitary cells to produce large amounts of phospholipase C. 3. This is followed by a cascade of other second messengers, including calcium ions and diacyl glycerol. 4. Eventually, this leads to TSH release.

Answer 59

• Increased thyroid hormones in the body fluids decreases secretion of: 1. TRH by the hypothalamus 2. TSH by the anterior pituitary

Answer 60

* Calcitonin is a peptide hormone secreted by the thyroid gland. * It decreases plasma calcium concentration. * Synthesis and secretion of calcitonin occur in the C cells, lying in the interstitial fluid between the follicles of the thyroid gland. * Increased plasma calcium concentration stimulates calcitonin secretion. * This contrasts with PTH secretion, which is stimulated by decreased calcium concentration * 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

Answer 61

1. 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. 2. Prolonged effect - decrease the formation of new osteoclasts.

Answer 62

• 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 * 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.

Answer 63

1. Rapid phase – this begins in minutes and increases progressively for several hours  This results from activation of osteocytes to promote calcium and phosphate absorption. 2. Slow phase – this requires several days/weeks  It results from proliferation of the osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself.

Answer 64

* 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

Answer 65

* 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. The main cause is a TSH-secreting pituitary adenoma (rare). • The most common causes of thyrotoxicosis are also associated with hyperfunction of the gland and include the following: 1. Diffuse hyperplasia of the thyroid associated with Graves’ disease (85% of cases) 2. Multinodular goitre 3. Toxic adenoma of the thyroid 4. Thyroiditis

Answer 66

* 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)

Answer 67

* 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

Answer 68

* Family history – genetic susceptibility * High iodine intake * Smoking * Toxic multi-nodular goitre * Childbirth * Highly active antiretroviral therapy (HAART) • The clinical manifestations of hyperthyroidism include changes referable to the hypermetabolic state induced by excess TH and to over-activity of the sympathetic nervous system (i.e. an increase in the β-adrenergic tone).

Answer 69

• Most common cause of endogenous hyperthyroidism. • It is characterised by a triad of clinical findings: 1. Hyperthyroidism due to diffuse, hyperfunctional enlargement of the thyroid 2. Infiltrative ophthalmopathy with resultant exophthalmos (protrusion of eyeball)  This is an autoimmune inflammatory response affecting the orbit, leading to bulging eyes. 3. 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

Answer 70

• Graves’ disease has a peak incidence between ages 20-40. • Women are affected 10 times more than men. • This disorder is said to be present in 1.5-2% of women. • Genetic factors are important in the aetiology of Graves’ disease 1. There is a concordance rate in monozygotic twins of 30-40% 2. This is less than 5% among dizygotic individuals

Answer 71

* In Graves’ disease, the body produces antibodies to the TSH-receptor (TSHr). * Antibodies to thyroglobulin, T3 and T4 may also be produced. * These antibodies can bind to TSHr and chronically stimulate them. * This result of chronic stimulation is an abnormally high production of T3 and T4. * This, in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goitre. • Three types of antibodies to the TSHr are currently recognised

Answer 72

1. These antibodies, mainly IgG, act as long-acting thyroid stimulants, activating the cells in a longer and slower way than TSH. 2. 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 contrast to thyroglobulin and thyroid peroxidase antibodies.

Answer 73

3. These antibodies bind directly to the TSHr and have been implicated in the growth of thyroid follicular epithelium.

Answer 74

4. These anti-TSH receptor antibodies 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.  Other forms may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor. These patients will experience hypothyroidism

Answer 75

• Autoimmunity also plays a role in the development of the infiltrative ophthalmopathy that is characteristic of Graves’ disease. • In Graves ophthalmopathy, the volume of the retro-orbital connective tissues and extra-ocular muscles is increased for several reasons including: 1. T-cell infiltration of the retro-orbital space. 2. Inflammatory oedema and swelling of extra-ocular muscles. 3. Accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate. 4. Increased numbers of adipocytes (fatty infiltration). • These changes displace the eyeball forward (bulging eyes) and can interfere with the function of the extra-ocular muscles. * Orbital pre-adipocyte fibroblasts express the TSHr and thus become targets of an autoimmune attack. * T-cells reactive against these fibroblasts secrete cytokines, which stimulate fibroblast proliferation and synthesis of extracellular matrix proteins (glycosaminoglycans) and increase surface TSHr expression, perpetuating the autoimmune response. * The result is progressive infiltration of the retro-orbital space and ophthalmopathy

Answer 76

* The thyroid gland is usually symmetrically enlarged because of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. * Parenchyma has a soft, meaty appearance resembling normal muscle. * Histologically, the follicular epithelial cells in untreated cases are tall and more crowded than usual.

Answer 77

• Hypothyroidism – this is the under-activity of the thyroid gland. Causes • 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.

Answer 78

* 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).

Answer 79

* Hypothyroidism increases with age – most common around 60 years of age. * Autoimmune hypothyroidism (Hashimoto’s) is more common in Japan.

Answer 80

* Overt form = 2% women and 0.2% men. * Subclinical form = 6-8% women and 3% men. * 2.5% of pregnant women develop hypothyroidism

Answer 81

* 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. • Hashimoto thyroiditis has a strong genetic component. 1. Concordance of the disease is in 40% in monozygotic twins, 2. Circulating anti-thyroid antibodies are present in approximately 50% of asymptomatic siblings of Hashimoto patients.

Answer 82

* This disorder is most prevalent between 45-65 years. * It is more common in women than in men. * Female predominance is 10:1 - 20:1 * Although it is primarily a disease of older women, it can occur in children and is a major cause of non-endemic goitre in the paediatric population.

Answer 83

• 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. • Multiple immunologic mechanisms may contribute to thyroid cell death, including: 1. CD8+ cytotoxic T cell-mediated cell death of thyrocytes. 2. 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 3. Antibody-dependent cell-mediated cytotoxicity - anti-thyroglobulin, and anti-thyroid peroxidase antibodies

Answer 84

• 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.

Answer 85

2nd most common cause hyperthroidism. arises from long standing dissuse simple goitres. continuous cell hyperplasia predisposes risk of TSH receptor mutation, continuously active toxic levels of T3/4. clinical course: enlarged gland-airway obstruction, dysphagia, compression of large vessels, SVC syndrome. Autonomous nodule may develop-plummers syndrome. fine needle aspiration distinguish between follicular hyperplasia and neoplasm. Neoplastic nodules more likely to be solitary younger patients male cold nodules in RAIU.

Answer 86

solitary masses from follicular epithelium-follicular adenomas. distinguished from a multinodular goiter as solitary and neoplasm from genetic mutation in a single precursor cell. Whereas in a multinodular goiter usually from hyperplastic response of entire thyroid to a stimulus like iodine deficiency.

Answer 87

cold intolerance. Weight gain loss appetite. fatigue. constipation. dec reflexes. dry skin. inc TSH dec T4/3

Answer 88

heat intolerance, weight loss, inc appetite, hyperactivity, diarrhea, inc reflexes, chest pain, warm skin. dec TSH inc T4 free and total and inc T3 uptake

Answer 89

• Radiodine is a first-line treatment for hyperthyroidism. • The isotope used is 131I (usually as the sodium salt). • Given orally, it is taken up and processed by the thyroid in the same way as the stable form of iodide. • Eventually, it becomes incorporated into thyroglobulin. • The isotope emits both β radiation and ϒ rays: 1. The ϒ rays pass through the tissue without causing damage. 2. The β particles have a short range - absorbed by the tissue and exert a powerful cytotoxic action, resulting in destruction of the cells of the thyroid follicles. • 131I has a half-life of 8 days.  So, by 2 months its radioactivity has effectively disappeared.  Due to the emission of gamma rays, people are advised to keep their distance from patients on radioiodine. • Hypothyroidism will eventually occur after treatment with radioiodine, particularly in patients with Graves' disease – thyroxine can be given to treat this. • There is a theoretical risk of developing thyroid cancer.

Answer 90

• 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.

Answer 91

• 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.

Answer 92

• 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.

Answer 93

* When iodides are present in the blood in high concentration, most activities of the thyroid gland are decreased. * The effect is to reduce the rate of iodide trapping, so that the rate of iodination of tyrosine to form thyroid hormones is also decreased. * Because iodides in high concentrations decrease all phases of thyroid activity, they slightly decrease the size of the thyroid gland and especially decrease its blood supply. * For this reason, iodides are frequently administered to patients for 2 to 3 weeks before surgical removal of the thyroid gland to decrease the necessary amount of surgery, especially to decrease the amount of bleeding.

Answer 94

• This drug is part of a group of drugs, known as thioureylene, which also comprise of methimazole and propylthiouracil. • They all have anti-thyroid activity. Mechanism of action • 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.

Answer 95

* Thioureylenes are given orally. * Carbimazole is rapidly converted to methimazole, which is distributed throughout the body water. * It has a plasma half-life of 6-15 hours * An average dose of carbimazole produces more than 90% inhibition of thyroid incorporation of iodine within 12 hours. * Propylthiouracil acts more rapidly because of its additional effect as an inhibitor of the peripheral conversion of T4 to T3. * Both methimazole and propylthiouracil cross the placenta and also appear in the milk. * After degradation, the metabolites are excreted in the urine.

Answer 96

• The most important unwanted effect is granulocytopenia (decrease in granulocytes). • This is relatively rare, having an incidence of 0.1-1.2%.  It is reversible on cessation of treatment. • Rashes are more common (2-25%). • Other symptoms include:  Headaches  Nausea  Jaundice  Pain in joints

Answer 97

• Another way of treating hyperthyroidism is administering iodine. • Iodine is converted in vivo to iodide (I-), which temporarily inhibits the release of TH. • When high doses of iodine are given to thyrotoxic patients there is inhibition of the secretion of TH.  Over a period of 10-14 days, there is marked reduction in vascularity of the gland, which becomes smaller and firmer. • Iodine is given orally in a solution with potassium iodide. • The mechanism of action is not entirely clear; it may inhibit iodination of thyroglobulin, possibly by reducing the H2O2 generation that is necessary for this process. • It could also be that an increase in iodide ions, causes a negative feedback in TSH. • This method is mainly used: 1. In preparation of patients for surgical resection of the gland. 2. As part of severe thyrotoxic treatment. • Allergic reactions are possible when this method is used.

Answer 98

thyroxine given orally has all the actions of endogenous thyroxine. Liothyronine-has all actions of endogenous triiodothyronine, given intravenously

Answer 99

* These are used to treat the symptoms of heart failure. * They are also used to treat congestive heart failure and in the management of cardiac arrhythmias, protecting the heart from a second heart attack (myocardial infarction). * As β-adrenergic receptor antagonists, they diminish the effects of adrenaline and other stress hormones. • Other uses for beta-blockers include: ```  Hypertension  Tachycardia  Dysrhythmias  Tremor  Agitation ```

Answer 100

* There are 3 main types of β receptors - β1, β2 and β3: * β1 – mainly in heart and kidneys * β2 – lungs, GIT, liver, uterus, vascular smooth muscle, skeletal muscle * β3 – adipocytes • Stimulation of β1 receptors by adrenaline/noradrenaline induces a positive chronotropic and inotropic effect, thus increasing cardiac conduction velocity and automaticity • The increase in cardiac output is by:  Increasing the HR in the SA node  Increasing the atrial muscle contractility  Increasing the contractility and the automacity of ventricular cardiac muscle  Increasing the conduction and automacity of AV nodes • Stimulation of β1 receptors in kidneys causes renin release. • Stimulation of β2 receptors causes:  Smooth muscle relaxation/ bronchodilation  Induces tremor in skeletal muscle  Increases glycogenolysis in the liver and skeletal muscle * Stimulation of β3 receptors induces lipolysis. * β-blockers inhibit these normal adrenaline/noradrenaline mediated sympathetic actions, but have minimal effect on resting subjects.

Answer 101

* Beta-blockers are β1- β2 receptor antagonists. * Reduce HR, thus giving the left ventricle more time to fill up * REDUCE BP!!! by decreasing the contractility, thus putting less load on the heart.

Answer 102

• Nausea; diarrohea; bronchospasm and dyspnea (if β2 receptor antagonists used); bradycardia; hypertension; heart failure; fatigue; dizziness. • Other adverse effects include the following:  Blockade of β1, especially at macula densa, inhibits renin release  Thus decreasing release of aldosterone  This causes hyponatremia (low Na+) and hyperkalaemia (high K+)  Blockade of β2 receptors can cause hypoglycaemia as β2 adrenoreceptors normally stimulate glycogenolysis (hepatic glycogen breakdown) and pancreatic release of glucagon  These work together to increase plasma glucose  Therefore, blocking β2 receptors lowers plasma glucose

Answer 103

* This specifically is a non-selective β-blocker - It blocks both β1 and β2. * It is not an anti-thyroid agent but it’s useful for decreasing many of the signs and symptoms of hyperthyroidism: 1. Tachycardia 2. Dysrhythmias 3. Tremor 4. Agitation 5. Anxiety • They are used in hyperthyroid patients during the initial treatment period while the thioureylenes or radioiodine take effect. • They are also used as part of the treatment of acute hyperthyroid crisis. (Uncommon medical emergency caused by an exacerbation of hyperthyroidism characterised by decompensation of one or more organ systems in people with untreated or poorly treated hyperthyroidism) • Adverse side effects include: 1. Insomnia and nightmares due to the lipophilic state of this beta-blocker so there is high penetration across the BBB 2. GI tract disturbances

Answer 104

``` • Haemoglobin concentration 13g/dl  Normal:  Men = 14.0-17.5 (mean 15.7) g/dL  Women = 12.3-15.3 (mean 13.8) g/dL  Reason = none; normal in patient ```

Answer 105

``` • Haematocrit concentration 0.4  (This is the volume of RBCs in blood)  Normal:  Male = 40.7-50.3%  Female = 36.1-44.3%  Reason = none; normal in patient ```

Answer 106

• Leucocyte count 4.0x109/l with 40% lymphocytes  Normal:  1.5 – 4.0x109/l  Reason = normal in patient but very baseline due to the chronic stress

Answer 107

 Normal = not elevated or too low  Reason = hyperthyroidism; graves’ disease which is an autoimmune disorder where antibodies of the immune system stimulate thyroid to produce too much T4 because they have the same shape that binds the thyroid cell receptors

Answer 108

 Normal = shouldn’t be too high or too low; 0.4-4.5 |  Reason = this is due to the increased T4 levels which cause a negative feedback to the APG to stop producing TSH

Answer 109

 Normal = uptake between 15-25% |  Reason = due to hyperthyroidism, the patient had an increased uptake

Answer 110

• A measure of relative size based on the mass and height of an individual • The BMI for a person is defined as their body mass (in kg) divided by the square of their height (metres)  The value universally being given in units of kg/m2 • There are a wide variety of contexts where the BMI of an individual can be used as a simple method to assess how much the recorded body weight departs from what is healthy or desirable for a person of that height • Once the BMI score is worked out, a scale can be used to categorise what the score actually shows in terms of health of the individual with that specific height and mass * A low BMI can lead to a risk of developing problems such as nutritional deficiency and osteoporosis * A high BMI can lead to risks of developing heart disease, high blood pressure, stroke and diabetes

Answer 111

1. Zona Glomerulosa – mineralocorticoids (e.g. aldosterone) 2. Zona Fasciculosa – glucocorticoids (e.g. cortisol) 3. Zona Reticulosa – sex steroid precursors (e.g. androstenedione)

Answer 112

 The three layers of the adrenal cortex comprise of different enzymes, thus allowing them to produce different hormones.  Cholesterol is used to form all of the adrenal cortex hormones. 1. Zona Glomerulosa –Early action of the HSD3B2 enzyme steers away from sex steroid precursors to aldosterone or cortisol. 2. Zona Fasciculosa – this contains the CYP11B2 enzyme, thus allowing for the production of cortisol. 3. Zona Reticulosa – this contains the CYP17A1 enzyme, thus allowing for the production of sex steroid precursors (andostenedione)

Answer 113

• Pathology of the adrenal glands can be split into two major categories: 1. Overproduction of hormones  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) 2. Under-production of hormones  ‘Primary’ – the entire cortex is affected (Addison Disease/ TB/ HIV)  ‘Secondary’ - hypopituitarism, loss of ACTH

Answer 114

* This is the overproduction of adrenal cortical hormones. * Symptoms include: hypertension, hypokalaemia, weakness, lethargy • Diagnosis:  Looking for inappropriate aldosterone secretion (test negative feedback loop)  Screening test: aldosterone/renin ratio (in Conn syndrome, this will be higher than normal) • Treatment:  Adrenalectomy  Mineralcorticoid receptor antagonists

Answer 115

• This is excessive endogenous cortisol secretion. • It is characterised clinically and biochemically by:  Features of glucocorticoid excess.  Loss of circadian rhythm to cortisol secretion.  Disruption of negative feedback loop. • Causes:  Benign pituitary adenoma (Cushing’s Syndrome characterised by this tumour is called Cushing’s Disease)  Adrenal hyperplasia  Benign/ malignant tumour of the adrenal gland  Ectopic ACTH secreting tumour  Long-term use of glucocorticoid medication (e.g. prednisolone)

Answer 116

• Main Signs and symptoms:  Round face with purplish plethora  Central obesity (face and trunk mainly, arms are skinny)  Diabetes  Hypertension • Diagnosis:  Loss of circadian rhythm  Cortisol levels raised in urine – not very good test (poor sensitivity and specificity)  Low dose dexthamethasone suppression test (give this overnight, in the morning the levels of cortisol should be suppressed)  Exclude pseudo-Cushing syndrome (clinical features of Cushing Syndrome, which disappear when underlying cause is resolved (alcohol, depression))

Answer 117

 Benign pituitary adenoma - trans-sphenoidal hypophysectomy  Adrenal hyperplasia - adrenalectomy  Benign/ malignant tumour of the adrenal gland - adrenalectomy  Ectopic ACTH secreting tumour – palliative care, surgery, chemotherapy  Long-term use of glucocorticoid medication (e.g. prednisolone) – stop the use of this medication

Answer 118

• This is the under-production of glucocorticoids and mineralocorticoids. ``` • Primary Causes:  Tuberculosis/ AIDs  Autoimmune – this is called Addison Disease • Secondary Causes:  Pituitary insufficiency (ACTH low) ``` • Main Signs and symptoms:  Weakness and tiredness  Darkened areas of skin (pigmentation) – due to loss of negative feedback  Hypotensive, Hyperkalaemic patient (major sign) • Diagnosis:  ACTH stimulation test (Short synacthen test) – stimulate ACTH secretion and measure cortisol level after 30 mins. In hypoadrnalism, the cortisol level

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