Regulation of Thyroid Functions Flashcards
What are thyroid hormones?
They are derivatives of the amino acid tyrosine bound covalently to iodine
What are the thyroid hormones?
Tri-iodothyronine (T3) and thyroxine (T4)
Calcitonin
Where are T3 and T4 secreted from?
Follicular cells
Where is calcitonin secreted from?
Parafollicular cells
What is the inactive form of T3?
Reverse T3
What are the different roles of calcitonin? (4)
- Lowers calcium levels in the blood
- Inhibits Ca2+ absorption by the intestines
- Promotes deposition of Ca2+ into bones (inhibits osteoclasts and stimulates osteoblasts)
- Inhibits Ca2+ reabsorption in the kidney (excreted in the urine)
What is the characteristic of thyroid in regards to storage?
The thyroid gland has a unique capacity for storing substantial amounts of pre-synthesized hormone thyroid hormone is stored within the thyroid colloid
What does the colloid material contain?
T3 and T4 attached to thyroglobulin
What are dietary sources of iodine?
Sea fish
Eggs
Milk
Water
How is iodine transported in the bloodstream?
As an inorganic iodide
What is the recommended daily dose of iodide intake?
150mg which increases to 200mg during pregnancy and breast feeding
What is thyroglobulin?
A protein that contains large numbers of tyrosine amino acids
What is the synthesis of thyroid hormones like? (9)
- Iodide trapped by the thyroid follicular cells
- Diffusion of iodide to the apex of the cells
- Transport of iodide into the colloid
- Oxidation of inorganic iodide to iodine
- Incorporation of iodine into tyrosine residues within thyroglobulin
- Combination of two diiodotyrosine molecules to form T4 or combination of monoiodotyrosine molecule with one diiodotyrosine molecule to form T3
- Uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, a fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT
- Release of T4 and T3 into the circulation
- Deiodination of DIT and MIT to yield tyrosine
How is T3 alternatively formed?
From monodeiodination of T4 in the thyroid and in peripheral tissues
Where are T3 and T4 secreted into?
Diffuse into the blood
What happens to the 75% of iodinated tyrosine?
It remains in the monoiodotyrosine and diiodotyrosine. Their iodine is cleaved by a deiodinase enzyme that makes the iodine available for recycling to form now thyroid hormones
What enzyme combines MIT and DIT to form T3 and T4 species?
Peroxidase combines MIT and DIT residues to generate T3 and T4 species within the thyroglobulin protein
What is the potency of T3 and T4?
T3 is 4 times more potent than T4
T4 is less active than T3
What is the rate of secretion of T3 and T4?
T4 us 10 folds more secreted than T3
What is the onset of action of T3 and T4?
T3 is rapid in onset (2 to 3 hours), whilst T4 is slow in onset (2 to 3 days)
What are the half-lives of T3 and T4?
T3 –> 3 days
T4 –> 7 days
What is the storage of T3 and T4 like?
T4 is more stored as it has a higher affinity for proteins
What is the inactivation of T3 and T4 like?
T3 is rapidly inactivated whilst T4 is slowly inactivated
What % of T3 and T4 are bound to serum proteins?
99.98%
What are the serum proteins that T3 and T4 are bound to? (3)
- Thyroxine binding globulin (TBG - alpha-globulin) –> 75%
- Thyroxine binding prealbumin (TBPA) –> 15 to 20%
- Thyroxine binding albumin –> 5 to 10%
What does TBG protein bind?
99.9% binds T4
What does TBPA protein bind?
Very small amount unbound, this is free and biologically active
What does Thyroxine Binding Albumin bind?
99.7% binds T3
What are the stimulatory factors in the thyroid hormone synthesis? (3)
- Thyroid stimulating hormone (TSH)
- Thyroid stimulating immunoglobulin
- Increased thyroid binding globulin (TBG)
In which case is there increased thyroid binding globulin?
In cases of pregnancy
Where is TSH released from?
Released by the pituitary gland
What is the function of ΤSH?
It instructs the thyroid gland to secrete thyroid hormones, T3 and T4
How is TSH controlled?
Negative feedback by the thyroid hormones
What can TSH measurement be used as?
To assess thyroid function
How does TSH cause the secretion of thyroid hormones?
It increases the size and vascularity of the thyroid gland, and follicular cells become active and columnar
What does prolonged stimulation of the gland because of TSH lead to?
Induces hypertrophy and hyperplasia of follicular cells –> enlargement of the thyroid gland –> Goiter
What controls/ regulates TSH secretion?
- Hypothalamic TRH
- Negative feedback effect
How does TRH regulate TSH?
Through the hypothalami-hypophyseal portal circulation,
–> The hypothalamus releases TRH, which then signals the anterior pituitary to secrete TSH, which causes the thyroid gland to secrete thyroid hormones
What does TRH stand for?
Thyrotropin-releasing hormone
What stimulates TRH?
Cold
What inhibits TRH?
Cortisol
What is the negative feedback effect of TSH like?
It is more directly at the level of the anterior pituitary instead of the hypothalamus if thyroid hormones are too high, then they signal the anterior pituitary to prevent the production of TSH and vice versa
What is TSI?
Thyroid Stimulating Immunoglobulin: a form of immunoglobulin G, produced by B-lymphocytes if patients with Grave’s disease
What is Grave’s disease ?
Autoimmune thyroid disease
What does TSI bind to?
It binds to thyrotropin (TSH) receptors on the thyroid gland
What is the action of TSI/
It mimics the actions of TSH, causing excess secretion of T3 and T4 thyroid hormones
What are the differences between TSI action and TSH action?
TSI:
1. Has prolonged action (12 hours)
2. It is not inhibited by negative feedback of T3 and T4
3. It can cross the placenta and stimulate the fetal thyroid
What are the inhibitory factors of thyroid hormone synthesis?
- Iodine deficiency
- Deiodinase deficiency
- Decreased thyroid binding globulin
- Excessive iodine intake
In which cases is there a decrease in thyroid-binding globulin?
Liver diseases
What does exposure to cold cause in terms of regulation of thyroid synthesis?
- Increase in TRH and TSH
- Increase in basal metabolic rate by 15 to 20%
What do emotional reactions cause in terms of regulation of thyroid synthesis?
Increase in TRH and TSH
What is the effect of emotional stress on the regulation of thyroid hormones synthesis?
Under emotional stress, the hypothalamus perceives a need for increased energy and heightened physiological responses to cope with the perceived threat or challange
What is the effect of high levels of iodine on thyroid activity?
It can temporarily inhibit thyroid hormone synthesis and release, a phenomenon known as the Wolff-Chaikoff effect
What does the Wolff-Chaikoff effect lead to?
Reduction in:
1. Thyroid hormone levels
2. Decrease in metabolic activity
3. Thyroid gland sie and blood supply
What is the mechanism of Wolff-Chaikoff effect?
- Reduced rate of iodine trapping, which decreased the rate of iodination of tyrosine
- Marked decrease in endocytosis of colloid from the follicles by the thyroid glandular cells
Why are iodides frequently administered to patients undergoing surgical removal of the thyroid gland?
Administered 2 to 3 weeks prior to surgical procedure to decrease the amount of bleeding
What are the effects of the thyroid on the body?
- It has a role in growth
- IT has a role in development
- It stimulates heart rate and BP
- It stimulates heart contractions, stroke volume, and cardiac output
- Stimulates synthesis of proteins and carbohydrates
- Degrades cholesterol and triglycerides
- Enhances beta-adrenergic receptors to catecholamine
- Increases activity or number of membrane Na+/K+ ATPase
- Increases GI motility and secretions
- Increases body metabolism and body heat
What are many of the actions of the thyroid hormones mediated by?
The binding to nuclear receptors
How do T3 and T4 enter the cell?
Via diffusion or carrier-mediated transport mechanisms
Once inside the cell what happens to the inactive T4?
It is converted to the active form, T3, by the enzyme 5’/3’ mono-deiodinase in the cytosol
What is the process of T3 binding to the thyroid hormone receptors?
T3 enters the nucleus and binds to thyroid-hormone receptors; these receptors are bound to retinoid X receptors, forming a heterodimer
What does the T3-THR-RXR complex bind to?
Specific DNA sequences are known as thyroid response elements (TRE)
What does the binding of T3-THR-RXR to TRE lead to?
Activation of gene transcription or repression of gene transcription
What are the physiological effects fo thyroid hormones?
Na+/K+ pumps: increase basal metabolic rate
Gluconeogenic enzymes: enhance glucose production
Respiratory enzymes: increase ATP production
Myosin heavy chains: affect cardiac muscle contraction
Beta-adrenergic receptors: enhance responsiveness to catecholamines like adrenaline
What are the effects of thyroid hormones on growth?
Brain growth and development
How do thyroid hormones help with brain growth and devlopment?
- Thyroid receptors are present in brain tissue before the fetus synthesizes its own hormone
- During fetal life and first few years after birth, thyroid hormones help brain growth and development
What is the effect of hypothyroidism on brain development?
Delay the brain maturation leading to mental retardation
What does the thyroid hormone help with during the fetal brain development stage?
Assists activation of genes (HRE) involved with terminal stages of brain differentiation:
1. Synaptogenesis
2. Growth of dendrites and exons
3. Myelination
4. Neuronal migration
What are the metabolic actions of thyroid hormones?
- Stimulation of Carbohydrate metabolism
- Stimulation of Lipid Metabolism
- Protein Metabolism
- Vitamins & Drugs Metabolism
What is the stimulation of carbohydrate metabolism like because of thyroid hormone? (6)
- Increases GI motility –> enhances glucose absorption
- Increase PEPCK activity, increase glyconeogenesis, increase in glycogenolysis –> increase hepatic glucose output
- Increase lipolysis –> increase serum-free fatty acids
- Increase GLUT4 –> increase glucose uptake
- Increase beta cell development and function –> stimulate insulin secretion
- Increase glucagon secretion from alpha cells
What is the stimulation of lipid metabolism because of thyroid hormone?
It stimulates all aspects of lipid metabolism:
1. Increases lipid mobilization from fat tissue –> increased levels of free fatty acids and glycerol
2. Decreases the level of cholesterol, triglycerides and phospholipids in the blood
How does thyroid hormone lead to decreased levels of cholesterol, triglycerides, and phospholipids in the blood? (2)
- Increases cholesterol (LDL) secretion in bile and loss in the feces
- Increases the number of LDL receptors on the liver cells –> rapid removal of it
What will hypothyroidism lead to in terms of lipid metabolism?
Incraese level of cholesterol and triglycerides
What is the protein metabolism like because of thyroid hormone?
Normal levels of thyroid hormones stimulate protein synthesis and growth, excess thyroid hormone causes protein catbolism
What is the vitamins and drug metabolism like because of thyroid hormone?
- Increases the need of the body for vitamins, as it stimulates the synthesis of different enzymes
- Accelerates the formation of vitamin A
- Increase utilization and clearance of all vitamins
What is the effect of thyroid hormone on the CVS?
- Increased heart rate
- The biphasic effect of thyroid hormones of myocardial contractility
Why is there an increase in HR because of thyroid hormones?
Due to increased excitability of the heart
What is increased HR used as a marker for?
Excessive thyroid hormone
What does the thyroid hormone have the ability to in terms of increasing the heart rate?
- Stimulate metabolism of SA node
- Increase sensitivity of SA node to circulating catecholamines
What is the biphasic effect of thyroid hormones on myocardial contractility?
- T3-induced increases in the sarcoplasmic reticulum calcium ATPase protein expression
- The increased number of this pump causes increased in strength of the heart even in slight excess of thyroid hormone
- The heart muscle strength becomes depressed because of long-term excessive protein catabolism in severely thyrotoxic patients
What is the effect of thyroid hormone on GIT?
Stimulate secretion of digestive juices (including HCl)
Increased appetite
Stimulate intestinal motility
What is the effect of thyroid hormone on the hematopoietic system?
Stimulate erythropoiesis through:
–> Increased metabolism of the bone marrow
–> Increased secretion of erythropoietin hormone
–> Increased absorption of Vitamin B12 from the ileum
What are the disorders of the thyroid gland?
Hypofunction –> Hypothyroidism –> Hashimoto’s syndrome
Hyperfunction –> hyperthyroidism –> Grave’s disease
What is Grave’s disease?
Autoimmune disease in which thyroid-stimulating immunoglobulin (TSI) binds to TSH receptor in the thyroid gland
What are the abnormalities in hyperthyroidism?
Increased basal metabolic rate
Weight loss
Increased heat production
Sweating
Increased cardiac output
Dyspnea
Tremor, muscle weakness
Exophthalmos
What are TRH and TSH levels like in hypothyroidism?
Decreased TRH or TSH
TSH Levels decreased (feedback inhibition of T3 on the anterior lobe)
What are the abnormalities in hypothyroidism?
Decreased basal metabolic rate
Weight gain
Decreased heat production
Cold sensitivity
Decreased cardiac output
Hypoventilation
Lethargy, mental slowness
Drooping eyelids
Myxedema
Growth retardation
Mental retardation (prenatal)
What are the TSH levels like in hyperthyroidism?
TSH increased if primary thyroid defect
TSH decreased if hypothalamus or anterior pituitary defect
