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Semester 4 > case 9 - Yaffas > Flashcards

case 9 - Yaffas Flashcards

1
Q

where is the thyroid gland located

A

inferiorly to the larynx on each side and anteriorly to the trachea

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2
Q

what are the follicles of the thyroid gland lined with

A

cuboidal epithelial cells that secrete into the interior of the follicles

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3
Q

what is the secretory fluid inside the follicles

A

colloid

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4
Q

what is the major constituent of colloid

A

thyroglobulin which contains thyroid hormones within its molecule

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5
Q

what happens once thyroglobulin has entered the follicle

A

it undergoes various reactions in the colloid

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6
Q

where is the thyroglobulin absorbed

A

absorbed back through the follicular epithelium into the blood before it can function in thebody

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7
Q

what does the thyroid secrete

A

T4
T3
calcitonin

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8
Q

what do T4 and T3 do

A

increase metabolic rate

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9
Q

what does calcitonin do

A

calcium metabolism

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10
Q

what is thyroid secretion controlled by

A

thyroid secreting hormone, secreted by the anterior pituitary gland

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11
Q

what happens to thyroxine (T4)

A

it is the main hormone secreted and is converted into T3 in the tissues

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12
Q

what is different in T3 and T4

A

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

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13
Q

what is the role of iodine

A

to form normal quantities of thyroxine, about 50mg of ingested iodine in the form of iodides are required each year

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14
Q

how is iodine deficiency prevented

A

common table salt is iodised

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15
Q

where are iodides absorbed from

A

the GI tract into the blood, most of which is excreted by kidneys.

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16
Q

what happens once 1/5 of the circulating iodide has been excreted

A

the thyroid gland uses the iodide to synthesise the thyroid hormones

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17
Q

where are iodides transported

A

from the blood into the cuboidal epithelial cells of the follicles in the thyroid gland

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18
Q

what actively pumps the iodide into these follicular cells

A

the basal membrane of the thyroid.

this is called iodide trapping

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19
Q

what is the pump involved in iodide trapping

A

transport protein called Na+/I- symporter

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20
Q

what happens when the thyroid becomes more active

A

more iodide is actively transported into the follicle cells

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21
Q

what stimulates iodide trapping

A

TSH

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22
Q

what synthesises the thyroglobulin

A

the endoplasmic reticulum

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23
Q

where do the thyroid hormones form

A

within the thyroglobulin molecule

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24
Q

what is oxidation of the iodide ion

A

conversion of iodide to iodine

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25
Q

what is iodine able to do

A

combine directly with the amino acid tyrosine in thyroglobulin

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26
Q

what is the transporter protein that iodide ions are secreted into the follicle via

A

the pendrin protein

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27
Q

what is the oxidation of iodide ions catalysed by

A

the perioxidase enzyme

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28
Q

where is the perioxidase enzyme located

A

in the apical membrane of the follicle cells or attached to it

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29
Q

what does this allow

A

 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

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30
Q

what is organification of thyroglobulin

A

the binding of iodine with the thyroglobulin molecule

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31
Q

what is the iodination of tyrosine catalysed by

A

the enzyme iodinase

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32
Q

where does the iodine ion bind with tyrosine

A

in the thyroglobulin molecule

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33
Q

what are the steps of the iodination of tyrosine

A
  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’.
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34
Q

where are the thyroglobulin molecules stored

A

in the follicles

as a result, when synthesis of thyroid hormone ceases, the physiologic effects of the deficiency are not observed for several months

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35
Q

what doesnt happen to the thyroglobulin

A

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

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36
Q

what does this process allow for

A
  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.
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37
Q

what happens to the free tyrosine molecules that are released into the cytoplasm of the thyroid cells when thyroglobulin is digested

A
  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.
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38
Q

what happens when there is congenital absence of this deiodinase enzyme

A

patients become iodine deficient because of the failure of this recycling process

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39
Q

where do T3 and T4 bind when in the blood

A

 Thyroxine-binding globulin (mainly)
 Thyroxine-binding prealbumin (much less)
 Albumin (much less)

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40
Q

where do thyroid hormones bind when entering the cells

A

the intracellular proteins

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41
Q

what binds more strongly than T3

A

thyroxine

42
Q

what are the functions of the thyroid hormones

A

 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.

43
Q

what is the mechanism of action of the increased transcription of genes via thyroid hormones

A

 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.

44
Q

what else do T3 and T4 increase

A

increase in mitochondrial activity and ion active transport

45
Q

what do thyroid hormones promote in children

A

growth

46
Q

what aspects of carbohydrate metabolism does TH stimulate

A
  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.
47
Q

what do these effects result from

A

the overall increase in the cellular metabolic enzymes caused by the increased gene transcription and subsequent enzyme synthesis caused by thyroid hormones

48
Q

what are the effects of TH on the cardiovascular system

A

increased blood flow and cardiac output

increased HR

increased heart strength

49
Q

where is TSH secreted from

A

the anterior pituitary gland

50
Q

what does this hormone do

A

increases the secretion of T4 and T3 by the thyroid gland

51
Q

what are its specific effects on the thyroid

A
  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.
52
Q

what does TSH do to cAMP

A

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

53
Q

what is the result of this

A

both an immediate increase in secretion of TH and prolonged growth of the thyroid glandular tissue itself

54
Q

what is anterior pituitary secretion of TSH controlled by

A

a hypothalamic hormone, TRH

55
Q

where is TRH secreted from

A

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

56
Q

what does TRH directly affect

A

the anterior pituitary gland cells to increase their output of TSH

57
Q

what is the mechanism by which TRH causes the TSH secreting cells of the anterior pituitary to produce TSH

A
  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.
58
Q

what is the feedback system

A
  • Increased thyroid hormones in the body fluids decreases secretion of:
    1. TRH by the hypothalamus
    2. TSH by the anterior pituitary
59
Q

what does calcitonin do

A

decreases plasma calcium concentration

60
Q

what does parathyroid hormone do

A

controls extracellular calcium and phosphate concentrations by regulating:

 Intestinal reabsorption
 Renal excretion
 Exchange of these ions between the extracellular fluid and bone

61
Q

what does excess activity of the parathyroid gland cause

A

rapid absorption of calcium salts from the bones, resulting in hypercalcemia in the extracellular fluid

62
Q

how does PTH increase calcium and phosphate absorption

A
  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.
63
Q

what is hyperthyroidism and thyrotoxicosis

A
  • 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.
64
Q

what are the two types of hyperthyroidism

A

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

65
Q

what is the pathology of secondary hyperthyroidism usually due to

A

usually at the site of the pituitary gland and the main cause is a TSH secreting pituitary adenoma

66
Q

what are the most common causes of thyrotoxicosis also associated with

A
  1. Diffuse hyperplasia of the thyroid associated with Graves’ disease (85% of cases)
  2. Multinodular goitre
  3. Toxic adenoma of the thyroid
  4. Thyroiditis
67
Q

what is Graves disease the most common cause of

A

endogenous hyperthyroidism

68
Q

what is Graves disease characterised by

A
  • 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.
69
Q

what is the pathogenesis behind graves disease

A

the body produces antibodies to the TSH receptor

70
Q

what happens to these antibodies

A

they bind to TSHr and chronically stimulate them

71
Q

what is the result of this

A

abnormally high production of T3 and T4

72
Q

what does this cause in turn

A

clinical symptoms of hyperthyroidism and the enlargement of the thyroid gland visible as goitre

73
Q

what are the three types of antibodies to the TSHr that are currently recognised

A

thyroid-stimulating immunoglobulins (TSI)

thyroid growth stimulating immunoglobulins (TGI)

TSH/thyrotropin-binding inhibitor immunoglobulins (TBII)

74
Q

what happens in TSI

A

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

75
Q

what does TGI do

A

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

76
Q

what do TBII do

A

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

77
Q

in graves opthamology, the volume of the retro-orbital connective tissues and extra-ocular muscles is increased for several reasons including;

A
  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).
78
Q

what do orbital pre-adipocyte fibroblasts express

A

the TSHr and thus become targets of an autoimmune attack

79
Q

what happens to T cells reactive against these fibroblasts secrete

A

cytokines, which stimulate fibroblast proliferation and synthesis of extracellular matrix proteins and increase surface TSHr expression, perpetuating the autoimmune response

80
Q

what is the result of this

A

progressive infiltration of the retro-orbital space and opthalography

81
Q

what are the causes of hypothyroidism

A
  • 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.

82
Q

what is the clinical course of treatment

A
  • 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).
83
Q

what is Hashimoto thyroiditis

A
  • 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.
84
Q

what is the pathogenesis of hashimoto thyroiditis

A
  • 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.
85
Q

what are the multiple immunologic mechanisms that may contribute to thyroid cell death

A
  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
86
Q
  • 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

A
  • 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.
87
Q

what is first line treatment for hyperthyroidism

A

radioiodine

88
Q

what does the isotope emit

A

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

89
Q

what eventually occurd after treatment with radioiodine

A

hypothyroidism occurs, thyroxine is given to treat this

90
Q

what are anti thyroid substances

A
  • 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.
91
Q

what do thiyocyanate ions do

A
  • 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.
92
Q

what does carbimaxole do

A
  • 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
93
Q

what is the mechanism of action of carbimazole

A
  • 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.
94
Q

what is propranolol

A

a non-selective beta blocker

95
Q

what are the layers of the adrenal cortex

A
  1. Zona Glomerulosa – mineralocorticoids (e.g. aldosterone)
  2. Zona Fasciculosa – glucocorticoids (e.g. cortisol)
  3. Zona Reticulosa – sex steroid precursors (e.g. androstenedione)
96
Q

what does overproduction of hormones in each layer cause

A

 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)

97
Q

what does under production of these hormones cause

A

 ‘Primary’ – the entire cortex is affected (Addison Disease/ TB/ HIV)
 ‘Secondary’ - hypopituitarism, loss of ACTH

98
Q

what is the treatment for Conn syndrome

A

adrenalectomy or mineralcorticoid antagonists

99
Q

what is addisons disease

A

the under production of glucocorticoids and mineralcorticoids

100
Q

what is the treatment of addisons disease

A

 Hydrocortisone – this medication is given life-long.
 May need mineralocorticoid replacement (fludrocortisone)

Semester 4 (80 decks)

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