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Reg Phys and Pharm > Thyroid Hormones > Flashcards

Thyroid Hormones Flashcards

- Outline the TRH/TSH/T3 endocrine exis - Briefly summarise the basic structure and function of the Thyroid Gland - Describe the processes of Thyroid hormone (T4, T3, rT3) biosynthesis - Analyse the effects of THs on BMR, growth and development - Compare the causes and effects of hyper- and hypo-thyroidism - Learn the standard clinical treatments for thyroid-related disorders

1
Q

Structure of thyroid gland

A
  • C cells (secrete calcitonin)
  • Follicular cells (secrete thyroid hormone)
  • Colloid (glycoprotein)
  • Capillary
  • Capsule of connective tissue
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2
Q

Hormones secreted by the thyroid

A
  • T3
  • T4
  • Calcitonin (parafollicular cells)
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3
Q

T4 vs T3

A
  • T4 is secreted in much larger amounts (90%) than T3 (10%)
  • T3 is more potent than T4
  • T4 is converted to T3 by deiodinase (found in peripheral tissues)
  • T3 binds with T3Rs associated with DNA in cell nucleus (can either activate or repress gene transcription, regulation of mRNA synthesis and protein synthesis)
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4
Q

What are deiodinases

A
  • type I deiodinase occurs in tissues with high blood flows and rapid exchanges with plasma (supplies circulating T3 for uptake)
  • type II deiodinase expressed by glial cells in CNS provides T3 even when free T4 falls to low levels
  • type III deiodinase inactivates thyroid hormones
  • type I and II catalyse thyroid hormones, type III inactivates
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5
Q

Describe the biosynthesis of thyroid hormone in the follicular cell

A
  • iodide and sodium is transported into the cell through the Na/I symporter
  • Thyroglobulin is secreted from the nucleus in the ER
  • Iodide is transported across apical membrane into the colloid space via the Pendrin cotransporter (1 iodide in exchange for 1 chloride)
  • thyroperoxidase oxidises two iodide ions to form iodine -> iodination of tyrosil residues caluses thyroperoxidase to conjugate neighbouring tyrosyl residues
  • results in either T4, T3, or r-T3 synthesis
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6
Q

Describe thyroid hormone synthesis in Thyrocytes

A
  • thyroglobulin is synthesised by thryoid epithelial cells and secreted into the lumen of the follicle
  • iodine is taken up from blood via sodium-iodine symporter and transported into colloid with thyroglobulin
  • synthesis of THs conducted by enzyme thyroid peroxidase, which catalyses iodination and coupling sequential reactions
  • colloid-laden endosomes fuse with lysosomes, which contain enzymes that digest thyroglobulin
  • free thyroid hormones diffuse out of lysosomes into blood and bind to carrier proteins
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7
Q

Carrier proteins that bind free thyroid hormones

A
  • thyroxine-binding globulin
  • transthyretin
  • albumin
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8
Q

What is thyroglobulin

A
  • large protein with 134 tyrosine residues
  • makes up most of thyroid follicular colloid
  • iodination and coupling reactions upon tyrosine residues in thyroglobulin are carried out by peroxidase enzyme
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9
Q

Iodine distribution and turnover

A
  • 400 ug of iodide is ingested and excreted daily
  • ~70-80ug of iodide is taken up daily by the thyroid gland whose total iodide content averages 7500ug
  • ~70-80ug (about 1% of total) released daily
  • large ratio (100:1) of iodide stored in form of hormone to the amount turned over daily protects the individual from the effects of iodide deficiency for many days
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10
Q

Transcriptional regulation of the thyroid receptor

A
  • functions as heterodimer with Retinoic Acid X receptor (RXR)
  • TR-RXR bind to thyroid response element (TRE) on that target gene
    -Retinoic acid binds to RXR
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11
Q

Gene expression in absence of TH

A

TR-RXR represses gene transcription through the recruitment of a corepressor complex containing histone deacetylase (HDAC)

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12
Q

Gene expression in presence of TH

A
  • corepresser complex is released and coactivator complexes including histone acetyltransferase (HAT) activity are recruited
  • HAT-containing complexes increase histone acetylation to promote transcription
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13
Q

Physiological effects of thyroid hormones

A
  • two primary categories of biological responses
  • effects on cellular differentiation and development on the nervous system
  • effects on metabolic pathways and use of carbohydrates, lipids, and proteins
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14
Q

Describe how T3 and T4 promote accelerated metabolism

A
  • increase carbohydrate, fat and protein turnover, ensuring that adequate cellular energy is available to support metabolically demanding activites
  • increase oxygen consumption and increase heat production
  • help regulate basal metabolic rate and body temperature
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15
Q

Importance of thyroid hormones during development and growth

A
  • between week 11 and birth, TH is essential
  • after birth, TH is required for correct mental development and body growth
  • deficiency in childhood = mental retardation or cretinism
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16
Q

Sympathomimetic action

A

increases responsiveness to catecholamines by increasing numbers of receptors

17
Q

Cardiovascular and respiratory effects of thyroid hormones

A
  • alter expression of ryanodine calcium channels in SR, promoting calcium release
  • enhances the sensitivity and expression of adrenoceptors to stimulation by noradrenaline
18
Q

Thyroid hormone effects on BMR

A
  • increase basal rate of oxygen consumption
  • increase heat production
  • adjust heat loss through sweating and ventilation
  • change in body temperature parallel fluctuations in thyroid hormone avaliability
  • overall metabolic effect - accelerating response to starvation
19
Q

Thyroid hormone effects on ANS and catecholamine action

A
  • increase number of beta-adrenergic receptors in heart muscle
  • increase the generation of intracellular second messengers such as cAMP
20
Q

Regulation of thyroid hormone secretion

A
  • Low BMR, cold, trauma, stress stimulate the release of TRH from the hypothalamus
  • TSH is released
21
Q

Short and long term effects of thyroid hormone secretion

A
  • increase iodide uptake
  • increase synthesis of peroxidase
  • increase synthesis of TG
  • increase colloid uptake
22
Q

What is hyperthyroidism

A
  • overproduction of thyroid hormone by thyroid gland
  • primary hyperthyroidism is due to thyroid pathology
  • secondary hyperthyroidism is due to overstimulation of thyroid stimulating hormone (TSH) from hypothalamus or pituitary
23
Q

Causes of hyperthyroidism

A
  • autoimmune disease - autoantibodies that stimulate thyrotropin receptors on thyroid gland follice cells leading to continual stimulation of thyroid hormone synthesis
  • benign tumour of thyroid cells causing enlargement of gland and increased hormone secretion
  • excessive secretion of TSH from a TSH-producing tumour (i.e. secondary hyperthyroidsim)
24
Q

Causes of hypothyroidism

A
  • inflammatory/autoimmune disease - antibodies attacking specific thyroid cellular components, causing gland damange
  • defective hypothalamic and pituitary function causing insufficient thyrotropin secretion for normal stimulation of thyroid gland
  • dietary iodine deficiency
25
Q

What is Goitre

A
  • excessive thyroid hormone
  • enlarged thyroid gland
  • over 90% of cases worldwide caused by iodine deficiency
  • “iodine pump” is very effective
  • when dietary iodine intake is insufficient for normal TH production, TSH secretion increases and thyroid cells proliferate
  • other causes such as Grave’s disease or excessive TSH production from pituitary tumour can result in hyperthyroid goitre
26
Q

What is Graves Disease

A
  • weight loss despite increase intake of food
  • increased heat = excessive sweating, increased water intake
  • trouble with HR and function and tremor (increased rate and involuntary muscle contraction)
  • difficulty in swallowing or breathing due to compression of the oesophagus or trachea by goitre
  • exophthalmos (eye bulging), periorbital edema (eye swelling), pertibial myoxedema (mucin deposits under skin)
  • elevated serum free and total T4 or T3 level
  • low TSH levels due to inhibition by TH
27
Q

Treatment of hyperthyroidism

A
  • surgery (complete or partial removal of gland)
  • drugs: thioureylene compounds, iodine-containing preparations, beta-andreoceptor antagonists
28
Q

Thioureylene antithyroid drugs

A
  • thiocarbamide group (S-C-N) essential for activity
  • carbimazole is metabolised in body to active drug methimazole
  • inhibits thyroid peroxidase
  • drugs accumulate in thyroid gland
29
Q

Effects of Thioureylenes

A
  • orally active - inhibit thyroid hormone synthesis
  • prevent iodination of tyrosine residue in thyroglobulin, probably by interfering with peroxidase enzyme action
  • prevent coupling reactions of monoiodo- and di-iodotyrosines
  • carbimazole or methimazole; skin rash
  • propylthiouracil; inhibit deiodinase enzyme converting T4 to T3
30
Q

Why does a fall in hormone levels of Thioureylenes take several weeks

A
  • gland has pre-existing hormone stress
  • T4 is tightly bound to binding protiens in blood plasma - leads to slow T4 metabolism in the body and slow T4 excretion from the body in urine
  • when hormone levels decrease to normal range, this can be maintained by using lower drug doses
31
Q

Iodine-containing preparations (radioiodine)

A
  • major method of treating hyperthyroidism
  • taken orally as capsules of radioactive sodium iodide - radioiodine in blood accumulates in thyroid gland
  • produces gamma-rays and (mainly) beta-particles; short range of beta-particles cause localised cell damage to thyroid follicular cells
  • used as single aministration
  • radioactive half-life of ~8 days
  • may produce hypothyroidism if too much gland damage; may need hormone replacement therapy
32
Q

Iodine-containing preparations (potassium iodide and iodine)

A
  • given as mixture of Kl and iodine in water; iodine converted to iodide in liver
  • transient inhibitory effects last for up to two weeks
  • used for short-term thyroid suppression
  • used with other antithyroid drugs for emergency treatment of “thyroid storm”
33
Q

Describe the Wolff-Chaikoff effect

A

if intake of iodide exceeds 2mg/day, intraglandgular concentration of iodide reaches a level that suppresses NADPH oxidase activity and the NIS and TPO genes, and thereby the mechanism of hormone synthesis

34
Q

Beta-Adrenoceptor antagonists

A
  • propranolol
  • no direct effect on thyroid hormone synthesis
  • used to block noradrenaline overstimulation of cardiac beta1-adrenoceptors
  • used in patients that are either awaiting gland surgery or when waiting for suppression of thyroid hormone levels by thioureylenes to take effect
35
Q

Treatment of hypothyroidism

A
  • synthetic T4 and T3 used as “replacement therapy”
  • T4 is first choice as daily oral tablets
  • take days to develop effects as inital T4 molecules bind reversibly to blood plasma proteins, and enough T4 accumulation needs to saturate these binding sites in order for free hormone to enter plasma
  • T3 as i.v. injection in emergencies to treat hypothyroid coma
36
Q

Side effect of administered thyroid hormones

A

cardiac dysfunction is replacement therapy dose is too high

37
Q

Source and transport of T3 in brain

A
  • T4 enters glial cell and is converted to T3 by D2 deiodinase
  • T3 exits cell and is transported into a neuron via MCT8
  • inside neuron, it either enters nucleus binding a TR or is inactivated to T2 by D3 diodinase
38
Q

MCT8 mutations in males

A
  • MCT8 gene located on X chromosome
  • deleterious mutations result in Allan-Herdon-Dudley syndrome
  • absormal plasma TH concentrations and neurological abnormalities
  • failure to deliver TH to specific foetal brain areas irreversibly impairs CNS development
39
Q

MCT8 mutations in females

A
  • two copies of MCT8 gene
  • heterozygous mutant females have mind thyroid phenotype and no neurological defects
  • 50% chance of passing mutation onto son

Reg Phys and Pharm (16 decks)

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