Flashcards
Thyroid hormone
Cards in this deck (27)
- 1Describe the structure of the thyroid glandC cells are also called parafollicular cells; secrete calcitonin, a peptide hormone; can cause medullary carcinomas
thyroid epithelial cells, also called thyrocytes, are organized into spherical follicles
The thyroid thus secretes 3 hormones
T3
T4 and
calcitonin - 2Describe the thyroid gland products3,5,3',5'-tetraiodothyronine (L-thyroxine/L-T4) secreted in greater amounts than 3,5,3’-triodothyronine (L-triiodothyronine/L-T3) (90% vs 10%)
1% is in the form of 3,3',5'-triiodothyronine (reverse T3, or rT3) which is inactive
T3 more potent than T4
T4 converted to T3 by a “deiodinase” enzyme found in many peripheral tissues
T3 binds with high affinity to T3 receptors (TRa and TRb) associated with DNA in cell nucleus -> can either activate or repress gene transcription -> regulation of mRNA synthesis and protein synthesis
Also, calcitonin secreted by parafollicular cells - 3What are deiodinases?type 1 deiodinase (low affinity, Km of 1 μM) occurs in tissues with high blood flows and rapid exchanges with plasma, supply circulating T3 for uptake by other tissues in which local T3 generation may not be sufficient.
type 2 deiodinase (high affinity, Km of 1 nM) expressed by glial cells in CNS provides T3 even when free T4 falls to low levels Also present in the thyrotropes of the pituitary and acts as a "thyroid axis sensor” - 4Describe thyroid hormone synthesis in thyrocytesThyroglobulin (TG/TRG) is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle (colloid, is essentially a pool of thyroglobulin). One TG contains 134 tyrosines.
Iodide (I-), is avidly taken up from blood by thyroid epithelial cells via a sodium-iodide symporter or "iodine trap". Iodide is transported into the colloid along with thyroglobulin.
Synthesis of thyroid hormones is conducted by the enzyme thyroid peroxidase, an integral membrane protein present in the apical (colloid-facing) plasma membrane. It catalyzes 1) iodination and 2) coupling sequential reactions
Thyroid epithelial cells ingest TG-decorated with thyroid hormone colloid by endocytosis from their apical borders
Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes that digest thyroglobluin, thereby liberating free thyroid hormones. - 5Describe diffusion of free thyroid hormonesFree thyroid hormones diffuse out of lysosomes into blood and bind to carrier proteins
(Thyroxine-binding globulin (TBG, major),
transthyretin (minor, particularly important for delivery to the CNS),
albumin (minor). - 6Describe iodine distribution and turnover400 μg of iodide is ingested and excreted daily
minimum daily requirement
150 μg for adults,
90 to 120 μg for children,
200 μg for pregnant women
About 70 to 80 μg of iodide is taken up daily by the thyroid gland whose total iodide content averages 7500 μg (all as iodothyronines). 70 to 80 μg (about 1% of the total) is released daily.
The large ratio (100:1) of iodide stored in the form of hormone to the amount turned over daily protects the individual from the effects of iodide deficiency for many days.
Iodide is also conserved by a marked reduction in the renal excretion of iodide as the concentration in serum falls. - 7Describe the regulation of thyroid synthesisIn high doses, glucocorticoids reduce the conversion of active thyroxine (T4) to the more active triiodothyronine (T3). Glucocorticoids may also decrease pituitary production of TSH, if given in sufficiently high doses.
Can also act via TBG levels
high estrogen levels can cause high TBG levels. TBG will therefore bind more thyroid hormone, decreasing the free hormone available in the blood, which leads to stimulation of TSH, and the production of more thyroid hormone. Thus, total thyroid hormone level will be high.
Ccorticosteroids lower TBG levels, thus the total thyroid hormone in the blood will be low. - 8Describe the effect of thyroid hormones on metabolismT3 and T4 promote accelerated metabolism.
increase carbohydrate, fat and protein turnover, ensuring that adequate cellular energy is available to support metabolically demanding activities
increase oxygen consumption and increase heat production.
Help regulate basal metabolic rate and body temperature - 9Describe the effect of thyroid hormones on growth and developmentImportant during development and growth. TH’s promote growth of neurones and stimulate maturation of the central nervous system
Between week 11 and birth TH is essential.
After birth, TH are required for correct mental development and body growth. (deficiency in childhood leads to mental retardation or “cretinism”) - 10Describe the sympathomimetic action of thyroid hormonesSympathomimetic (permissive) action. Increases responsiveness to catecholamines by increasing numbers of receptors.
- 11Describe the effect of thyroid hormones on cardiovascular and respiratory systemsT3 increases oxygen use and cardiac output, ensuring sufficient oxygen delivery to the tissues. It alters cardiac function by altering the expression of many proteins e.g. increases the ryanodine Ca2+ channels in the sarcoplasmic reticulum, promoting Ca2+ release. It also enhances the sensitivity (and expression) of adrenoceptors (especially beta1-receptors) to stimulation by noradrenaline
- 12Describe the effect of thyroid hormones on the basal metabolic rateThyroid hormones increase the basal rate of oxygen consumption and heat production (e.g., basal metabolic rate) moderated by a compensatory increase in heat loss through appropriate thyroid hormone-mediated increases in blood flow, sweating, and ventilation. Changes in body temperature parallel fluctuations in thyroid hormone availability. The overall metabolic effect has been described as accelerating the response to starvation.
- 13Describe the effect of thyroid hormones on the autonomic nervous system and catecholamine actionT3 may enhance sympathetic nervous system activity by increasing the number of β-adrenergic receptors in heart muscle and by increasing the generation of intracellular second messengers, such as cAMP
- 14Describe the effect of thyroid hormones on the nervous systemDevelopment but also enhances wakefulness, alertness, responsiveness to various stimuli, auditory sense, awareness of hunger, memory, and learning capacity. The speed and amplitude of peripheral nerve reflexes and gastrointestinal tract motlity are increased by thyroid hormone
- 15Describe hyperthyroidism causesAutoimmune disease (Graves Disease) – autoantibodies (immunoglobulins) that stimulate thyrotrophin receptors on thyroid gland follicle 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 tumor (i.e., secondary hyperthyroidism) - 16Describe hypothyroidism causesInflammatory/Autoimmune disease (Hashimoto Disease) – antibodies attacking specific thyroid cellular components (e.g. thyroglobulin), causing gland damage
Defective hypothalamic and pituitary function causing insufficient thyrotrophin secretion for normal stimulation of thyroid gland
Dietary iodine deficiency - 17What is goitre?Enlarged thyroid gland
Worldwide, over 90% cases of goitre are caused by iodine deficiency
The "iodide pump “ of thyroid gland is very effective. Up to 30% of ingested iodide is taken up by the thyroid. When dietary iodide intake is insufficient for normal TH production, TSH secretion increases and thyroid cells proliferate:- a normal human thyroid gland of 25 g may grow to become a 250 g goitre under such circumstances. This is hypothyroid goitre. Hypothyroidism secondary to hypothalamic or ant.pit. failure does not result in goitre.
NB:- Other causes may result in hyperthyroid goitre, these include-
Grave’s Disease
Excess TSH production from pituitary tumour - 18Describe hyperthyroidism (Graves disease)highly characteristic symptom of weight loss despite an increased intake of food. increased heat production causes excessive sweating, and a greater intake of water. trouble with heart rate and function and tremor (increased rate and involuntary muscle contraction)
difficulty in swallowing or breathing due to compression of the esophagus or trachea by the enlarged thyroid gland (goitre).
Major clinical signs in Graves disease are exophthalmos and periorbital edema
diagnosed by an elevated serum free and total T4 or T3 level
Serum TSH levels are low, because the hypothalamus and the pituitary gland are inhibited by the high levels of T4 and T3.
Assaying TSH levels, and for the presence of circulating TSI (thyroid stimulating immunoglobulin) will distinguish Graves disease from a rare adenoma of the pituitary thyrotrophs (a secondary endocrine disease). The latter etiology generates elevated TSH levels unaccompanied by TSI. - 19What is treatment for hyperthyroidism?SURGERY
Partial or complete removal of gland – especially if enlarged gland obstructs neck veins and trachea, or if malignant tumour present
DRUGS
(1) Thioureylene (also called thiourea or thionamide) compounds
(2) Iodine-containing preparations
(3) Beta-adrenoceptor antagonists - 20Describe the action of thioureylenesOrally active - inhibit thyroid hormone synthesis:
(i) prevent iodination of tyrosine residues in thyroglobulin – probably by interfering with peroxidase enzyme action
(ii) prevent coupling reactions of monoiodo- and di-iodotyrosines
CARBIMAZOLE or METHIMAZOLE often used first; common side effect is “skin rash”, so patient then switched to ..
PROPYLTHIOURACIL – additional useful action of inhibiting deiodinase enzyme that converts T4 to T3 in many tissues
Hormone synthesis inhibited rapidly (within 24 hr) BUT fall in hormone levels and effects takes several weeks because…
(i) gland has large pre-existing hormone stores
(ii) T4 is tightly bound to binding proteins 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 often be maintained by using lower drug doses – withdraw drug completely after 1 year in some patients - 21Describe the iodine-containing preparation radioiodine (I^131)Major method of treating hyperthyroidism
Taken orally as capsules of radioactive sodium iodide (NaI) – radioiodine in blood accumulates in thyroid gland
Produces -rays and (mainly) -particles; short range of -particles causes localized cell damage to thyroid follicular cells
Used as single administration (given to adults and children but
not to pregnant mothers – could harm foetal thyroid)
Radioactive half-life of about 8 days – total cytotoxic effect
develops over 1 – 2 months
May produce hypothyroidism if too much gland damage – if so, may need thyroid hormone replacement therapy - 22Describe the iodine-containing preparation potassium iodide (KI) and iodineif the intake of iodide exceeds 2 mg/day, the intraglandular concentration of iodide reaches a level that suppresses NADPH oxidase activity and the NIS and TPO (thyroid peroxidase) genes, and thereby the mechanism of hormone biosynthesis. This autoregulatory phenomenon is known as the Wolff-Chaikoff effect.
Hence, given as mixture of KI + iodine in water (called Lugol’s solution) – iodine converted to (I_) in liver
Transient inhibitory effects for up to 2 weeks – then effects
decline as gland becomes “tolerant” to iodine overload
Used for short-term thyroid suppression (along with other antithyroid drugs) especially for a few days before surgery to gland
Used with the other antithyroid drugs for emergency treatment of “thyroid storm” – life-threatening excessive hormone levels! - 23Describe thyroid gland function regulation by iodideAn important regulator of thyroid gland function is iodide itself, which has a biphasic action. At relatively low levels of iodide intake, the rate of thyroid hormone synthesis is directly related to iodide availability. However, if the intake of iodide exceeds 2 mg/day, the intraglandular concentration of iodide reaches a level that suppresses NADPH oxidase activity and the NIS and TPO (thyroid peroxidase) genes, and thereby the mechanism of hormone biosynthesis. This autoregulatory phenomenon is known as the Wolff-Chaikoff effect.
- 24Describe the beta-Adrenoceptor Antagonist propranololNo direct effect on thyroid hormone synthesis, release etc.
Used to block noradrenaline overstimulation of cardiac 1-adrenoceptors
[Increased sympathetic nervous system (noradrenaline) activity in hyperthyroidism can cause dangerously increased heart rate (tachycardia) and abnormal heart rhythms (dysrhythmias)]
Particularly used in patients (a) awaiting gland surgery or (b) when waiting for suppression of thyroid hormone levels by thioureylenes to take effect - 25What is the treatment for hypothyroidism?Hypothyroid individuals have weight gain despite poor appetite, cold intolerance, constipation and lethargy.
Synthetic (manufactured) L-THYROXINE (T4) and L-TRIIODOTHYRONINE (T3 or L- IOTHYRONINE) used as “replacement therapy”
T4 – first choice, daily oral tablets, initial build-up to maximum effects takes several days because ….
At start of treatment, initially absorbed T4 molecules bind reversibly to blood plasma proteins; need these binding sites to become saturated with T4 before enough accumulates as “free” hormone in the plasma to enter and have effects in body tissues
T3 – i.v. injection in emergencies to treat “hypothyroid coma” due to its more rapid action than T4
Important side effect of administered thyroid hormones:
Cardiac dysfunction if “replacement therapy” dose too high - 26What is the source and transport of T3 in the brain?T4 enters a glial cell and is converted to T3 by the D2 deiodinase. T3 exits the cell and is transported into a neuron via MCT8. Inside the neuron, it either enters the nucleus, binding a TR, or is inactivated to T2 by D3 deiodinase.
- 27What is the result of MCT8 mutations in males and females?Monocarboxylate transporter 8 (MCT8) gene is located on the X chromosome
Males:-
One copy of MCT8 gene.
Deleterious mutations result in Allan-Herndon-Dudley syndrome
Affected males have abnormal plasma TH concentrations and neurological abnormalities. Failure to deliver TH to specific foetal brain areas irreversibly impairs CNS development (global developmental delay, central hypotonia, spastic quadriplegia, impaired gaze and hearing).
Females:-
Two copies of MCT8 gene .
Heterozygous mutant females have mild thyroid phenotype and no neurological defects. 50% chance of passing mutation onto a son.
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- Regulatory physiology and pharmacology Flashcards on Thyroid hormone, created by Megan MacLeod on 16/06/2019.
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