Ex 4 L3: Thyroid Hormones 1 (37) Flashcards
Thyroid C cells make
Calcitonin (Calcium)
Flip thyroid gland - see small glands
Parathyroid
Calcitonin and parathyroid regulate calcium amount in your body
Thyroid hormones
Thyroxine (T4)
Triiodothyronine (T3)
Thyroxine (T4)
Produce more (10x more)
4 iodide group (T4)
Reserved hormone
-kinda like a prodrug (but not officially)
Can be converted to T3
Triiodothyronine (T3)
More potent
3 iodide groups (T3)
These hormones have Similar relationships
Physiologic effects of thyroid hormones: Growth and development:
Essential for brain development (absent T3 = cretinism)
-If children do no get enough thyroid, they can come out with retardation
Promote protein synthesis (skeletal/muscle growth); anabolic at normal concentrations, but catabolic at the levels of hyperthyroidism
Physiologic effects of thyroid hormones: Metabolic effects:
Increase basal metabolic rate (BMR); increase oxygen consumption
Starvation lowers both T3 hormones and thyroid receptor
-Want to lose weight, boost thyroid hormone
If you do not eat enough, body decreases T3 hormones -> starving state, energy saving -> Gain weight (fat storage)
Physiologic effects of thyroid hormones: Thermogenesis
Increase resting heat production
Inability to adjust to environmental temperature is a characteristic symptoms of hyper - or hypothyroidism
-Feel hot
-hypo cannot burn energy because it is being saved - cold all the time
Physiologic effects of thyroid hormones: Cardiovascular effects
Increase catecholamine sensitivity
thyroid level goes up, heart pumps more (More sensitive to norepinephrine)
Too much hormone - hyper state - rushing heart
Biosynthesis of thyroid hormones
Need iodine
Thyroid follicular cell has sodium iodide transporter (symporter) -> iodide only goes to THIS cell
Transported - eventually goes to central follicular (chamber)
Thyroid cells synthesize thyroid protein
Used to make hormone
Reduced modified with iodine
-Two tyrosine residues combined = more like a thyroid hormone Cells take in proteins and digest completely using protease (T4 and T3)
Steps of thyroid hormone synthesis
A: Dietary iodine (I2) -> Iodide (-I) in the stomach
B. Iodide is actively transported into the cell by Na+ -I symporter (NIS)
C. In the follicular cell, iodide passes down its electrochemical gradient and into the follicular colloid (partially through the apical transporter, pendrin). It is oxidized by thyroid peroxidase to 1^0 at the apical membrane
D. Iodide-free thyroglobulin is transported to the apical membrane
E. Thyroglobulin is iodinated by thyroid peroxidase8* at one or two positions forming the hormone precursors mono-iodotyrosine (MIT) and di-iodotyrosine (DIT) (Iodide organification**)
F: MIT + DIT = tri-iodothyrone (3,5,3 prime - T3) and DIT + DIT = tetra-iodothyronine (T4) = thyroxine. Coupling is dependent on thyroid peroxidase
G. Thyroid hormone-containing thyroglobulin is retrieved back into the cytosol of the follicular cell as colloid droplets by pinocytosis
H. Lysosomal exopeptidases Cleave T4 (or T3) from thyroglobulin and the hormones are released into circulation where T4 can be converted to the more active T3 by 5 prime deiodinase
Iodide organification
Catalyzed by thyroid peroxidase
Only one – MIT
Two – DIT
Two DIT – T4
Concentration relatively low
-One MIT and Two DIT – T3
Hypothalamus-pituitary thyroid axis
TRH stimulates anterior pituitary
TSH
-TSH stimulates
T4 and T3 are produced
Iodine
Used for synthesis of thyroid hormones
The best natural food source is seafood (fish and seaweeds)
Deficiency was endemic in inhaled populations
Goiter - an enlargement of the thyroid gland due to a persistent rise in TSH
Cretinism - severely stunted physical and mental growth
Routinely add table salt
Transport
Transported in plasma by:
Thyroxine-binding globulin (TBG) - primary transport protein
Transthyretin (TTR)
Albumin
Transport proteins have greater affinity to T4
Only 0.004% of T4 is free
T4 has longer half life than T3; serves as a storage pool (2-3 months)
T3 has a more rapid onset
Its ok if level drops, your body has a sufficient amount
Thyroid Mechanism of action
Structurally similar
Enzyme (deiodinase) converts T4-T3
Goes to nucleus
Spits out mRNA, proteins
Metabolism
Deiodination
Conjugation to form glucuronide or sulfate with the phenolic group
Excreted via the bile
Some are hydrolyzed by bacteria; marginal enterohepatic circulation
Hypothyroidism
Deficiency of thyroid hormones
Symptoms:
Decrease in metabolic rate – fatigue, mental dullness, lethargy, inattention
Defective thermoregulation
May occur with thyroid enlargement (nontoxic goiter)
Dwarifsm and mental retardation (cretinism) in infants and children
Myxedema coma – end state of untreated hypothyroidism; water intoxication, shock and death
Causes:
Hashimoto’s thyroiditis – most common; autoimmune disease that destroys the thyroid gland
(no goiter – completely gone)
Destruction or removal of the gland (radiation, X-ray, thyroidectomy)
Iodine deficiency
Congenital (cretinism)
Secondary – TSH deficiency
Hyperthyroidism
Excessive levels of thyroid hormones (thyrotoxicosis)
Symptoms
-Excessive metabolism - poor thermoregulation and weight loss
-Increased heart rate and cardiac output
Causes:
-Grave’s disease - Most common; autoimmune; thyroid-stimulating IgG; enlargement of the entire thyroid gland (Diffuse toxic goiter)
-Toxic uninodular goiter and toxic multinodular goiter - Adenoma producing excess T3; occur mostly in older women
Subacute thyroiditis - Viral infection of the thyroid gland; transient release of stored thyroid hormones
Hypothyroidism symptoms presentaiton
Skin: pale, cool, puffy
Eyes: Drooping of eyelids
Cardiovascular: Bradycardia; Decreased cardiac output, increased vascular resistance
CNS: lethargy
Metabolism: Decreased appetite
Decreased BMR
Hypoglycemia
Increased cholesterol and triglycerides
Decreased drug metabolism
Hyperthyroidism symptoms presentation
Skin: Warm, moist, sweating
Eyes: Retraction of upper lids
Exophtalmos
Cardiovascular:
Tachycardia
Increased cardiac output
Decreased vascular resistance
Nervousness:
Increased appetite
Increased BMR
Hyperglycemia
Decreased cholesterol and triglycerides
Increased drug metabolism
Hypothyroidism: Thyroid hormone replacement therapy: Natural thyroid hormone preps
(not approved by FDA)
-Desiccated thyroid and thyroglobulin (bovine or porcine)
Variable T4/T3 blood levels due to inconsistencies in sources
Hypothyroidism: Thyroid hormone replacement therapy: Levothyroxine (T4)
Converted to T3 intracellularly
Slow onset, long half-life (7 days); 6-8 weeks to reach steady state levels
Hypothyroidism: Thyroid hormone replacement therapy: Liothyronine (T3):
Rapid onset, short duration of action (24hr) requiring multiple daily doses
Greater risk of cardiotoxicity
Difficult to monitor using conventional laboratory tests
Hypothyroidism: Thyroid hormone replacement therapy: Liotrix
Discontinued
4:1 mixture of T4 and T3
More expensive, but not shown to be more effective than T4 administration alone
Hyperthyroidism: Thioamides:
Antithyroid agents
Methimazole, propylthiouracil
Used to treat thyrotoxicosis
Inhibit thyroid peroxidases
-Block iodine organification
-Block coupling of the iodotyrosines
Slow onset (3-4 weeks)
Require depletion of stored T4
Hyperthyroidism: 131I
-Action:
Radioactive iodine emitting B particles and gamma rays
T 1/2 ~ 8 days
Localized destruction of thyroid follicles
-Admin orally in solution as Na 131 I
-Problems:
Hypothyroidism occurs in 80% of patients
Potential increase in certain cancers
Radiation thyroiditis (in rare cases leading to thyroid storm) - prevent with pretreatment of antithyroid drugs
-Advantage: no surgery and lower cost
-Contraindication: Not for pregnant/nursing women
Hyperthyroidism: Iodide:
Large dose of I- inhibits its own uptake, iodine organification (Wolff-Chaikoff block), release of thyroid hormones, and decreases vascularity of the thyroid gland
Beneficial effect is transient and thus not used for long-term management
Lugols solution
- Aqueous solution of elemental I and KI
Clinical uses:
-Prep for thyroidectomy
-Severe thyrotoxicosis
-Protection from radioactive iodine fallout (nuclear accident or military exposure)
Side effects:
-Hypothyroidism
-Sensitivity to iodine in some patients (ex. agioedema)
