AP thyroid Flashcards
Anatomy and Histology of tyroid
Two-lobed structure at front & sides of upper portion of trachea
Comprises follicles surrounded by cuboidal epithelial cells
Follicles filled with colloid – mostly comprises thyroglobulin
Highly vascular
Thyroid Hormones
-Thyroid follicles responsible for synthesis of thyroid hormones:
- Thyroxine (T4)
- Triiodothyronine (T3)
- T3 is four fold more potent than T4
-Thyroid hormones profoundly increase metabolic rate in body
- Parafollicular cells are responsible for synthesis of calcitonin
- plays an important role in calcium metabolism
Synthesis and Secretion of Thyroid Hormones
-Thyroglobulin synthesized in follicular cells
- Large glycoprotein with numerous tyrosine residues
- Secreted into & stored in thyroid follicles
-Iodine is required for thyroid hormone synthesis
- Iodide transported into thyroid follicular cells by sodium–iodide symporter (NIS)
- Iodide conc in follicular cells typically 30× greater than in plasma
- Iodide transported across apical membrane by chloride–iodide counter transporter
¢Iodination of Tyrosine and Formation of the Thyroid Hormones
Thyroperoxidase (TPO) catalyzes the conversion of idodide to iodine.
The iodine binds to tyrosine molecules on TG forming either monoiodotyrosine (MIT) or diiodotyrosine (DIT).
2 DIT → “coupling reaction” to form one T4 molecule.
MIT + DIT → T3
¢The thyroid secretes about 80 μg of T4 and 4 μg of T3 per day
-one-third of circulating T4 is converted to T3 by Dio2 and 45% is converted to the metabolically inert reverse triiodothyronine (rT3)
-About 87% of circulating T3 derives from peripheral conversion of T4 to T3and only 13% from thyroid secretion
Role of TSH in Thyroid Hormone Synthesis
¢TSH receptor – GPCR
¢TSH upon binding to TSHR ↑ses cAMP → expression of Sodium Idodide Symported (NIS) upregulated
- NIS: Transports two Na+ for each Iodide ion
- NIS also expressed in other tissues
- Expression in mammary gland relevant for idodide uptake in newborns
Thyroid Hormone Transport
¢Thyroid hormones are bound to …..
-plasma proteins
- albumin
- transthyretin
- thyroxine-binding globulin (TBG)
- Binding proteins serve mainly to transport and facilitate distribution
- ¢Free T3 & T4 levels usually maintained even when [TBG] changed
……. are active and inhibit TSH secretion from pituitary
ANSWER: ¢Free T3 and T4
half-life of T4 is long (about 6–7 days) compared to that of T3 (1 day)
-T3 is more potent and acts more rapidly than T4
Mechanism of Action of Thyroid Hormones
- Thyroid hormones (THs) – modified amino acids
- Nuclear receptors – present in nucleus of essentially all tissues
- TH receptor is typically heterodimer with retinoid X receptor (RXR)
- Associated with thyroid hormone response element (TRE) on DNA
- Many different genes regulated
¢T3 binds to receptor with much higher affinity than T4
What is the role of thyroxine binding globulin?
hyroxine-binding globulin (TBG) is one of three major transport proteins, which are primarily responsible for binding to and transporting thyroid hormones to the necessary tissues
What is the role of thyroglobulin?
Thyroglobulin is the other major component needed for synthesis of thyroxine and triiodothyronine. Thyroglobulin is the matrix for thyroid hormone synthesis and is the form in which hormone is stored in the gland. It is a large glycoprotein that forms a stable dimer with a molecular mass of about 660,000 daltons.
effects of thyroid hormone on energy metabolsim
growth development
Thyroid hormones play major role in regulation of energy metabolism
↑ metabolic activity
↑ oxygen consumption
↑ number & activity of mitochondria
↑ activity of Na+/K+- ATPase
Thyroid hormones essential for physical growth & for development of CNS
Critically important in fetus & neonate
↑synthesis & catabolism of proteins
↑metabolism of carbohydrates & fats
Net hyperglycemic effects and promotes lipolysis
↑free fatty acids
lower cholesterol
prolonged hypothyroidism leads to severe atherosclerosis
Effects of Thyroid Hormones on basal metabolic rate
↑ BMR by 50% with large excess of thyroid hormones
↓ BMR to 50% of normal in absence of thyroid hormones
Effects of Thyroid Hormones on cardiovascular
Cardiovascular System
↑ cardiac output & heart rate
¢Increased expression of beta adrenergic receptors
↑ strength of cardiac muscle with modest ↑ in thyroid hormones
Excess may lead to myocardial failure
Mean arterial pressure usually unaffected (but pulse pressure often increased)
Effects of Thyroid Hormones on respiration and gastrointestinal
↑ respiration & gastrointestinal motility typical
Excess of thyroid hormones causes nervousness & anxiety
Excess also causes rapid muscle tremor
- key indicator of hyperthyroidism
- Lack of thyroid hormones leads to decreased libido in men & women
Regulation of Thyroid Hormone Secretion
- TRH from hypothalamus – stimulates anterior pituitary
- TRH receptor is GPCR and triggers ↑ Ca2+ in thyrotropes in anterior pituitary
TSH from anterior pituitary binds to TSHR (GPCR) and stimulates adenylyl cyclase
- ↑ cAMP stimulates T3 & T4 synthesis & secretion
Free T3 & T4 suppress TRH & TSH release
Exposure to cold triggers TRH secretion by hypothalamus
- Resulting ↑ thyroid hormones helps to maintain body temperature
Describe the symptoms & causes of hyperthyroidism.
Describe the symptoms & causes of hyperthyroidism.
-Most often due to Graves’ disease/thyrotoxicosis
- Autoimmune disease – thyroid stimulating immunoglobulins bind to TSH receptor and induce continual activation of the cAMP (prolonged stimulatory effect than TSH)
- Stimulates growth of thyroid gland called goiter & excess secretion of T3 + T4
- Often associated with exophthalmos
¢Toxic thyroid adenoma (localized portion of thyroid gland)
secretory function in the remainder of the thyroid gland is inhibited due to suppressed TSH
Secondary hyperthyroidism
TSH secreting pituitary adenoma
Tertiary hyperthyroidism:
¢TRH secreting hypothalamic disease
In both 2o and 3o hyperthyroidism, TSH level is high or high normal
primary hyperthyroidism
Primary hyperparathyroidism is a condition in which one or more of the parathyroid glands makes too much PTH.
Approaches to treat hyperthyroidism
Diagnosis: The most accurate diagnostic test is direct measurement of the concentration of “free” thyroxine & triiodothyronine and TSH in the plasma
- ↓ in TSH; ↑ in Free T3 and T4
- In secondary hyperthyroidism you may see ↑ in Free T3 and T4; high or normal TSH
Therapy:
Thyroidectomy
131Iodine therapy
TPO Inhibitors (PTU)
Methimazole
Propranolol (Beta blockers)
Symptoms of hyperthyroidism
¢Mostly predictable from physiological effects of thyroid hormones
- Intolerance to heat & increased sweating
- Weight loss
- Nervousness & excitability
- Muscle weakness
- Extreme fatigue, but inability to sleep
- Diarrhea
- Tremor of hands
¢Protrusion of eyeballs (exophthalmos) often occurs
- May damage optic nerve and/or prevent closure of eyelids
Hypothyroidism causes
¢Hashimoto’s thyroiditis
Autoimmune disease that causes destruction of thyroid gland
- Can be caused by dietary iodide deficiency (common in past, rare nowadays)
- Thyroid gland enlarged (goiter) in attempt to trap more iodide
- Occasionally arises from genetic defect in iodide trapping or metabolism
- Secondary hypothyroidism – damage to pituitary gland - reduced TSH (accounts for < 10%)
- Tertiary hypothryroidism – hypothalamus lacks the ability to secrete TRH
- In both cases suppressed TSH levels will be seen unlike primary hypothyroidism where elevated TSH is seen
Hypothyroidism symptoms
¢Generally predictable & opposite to those of hyperthyroidism
- fatigue and extreme somnolence
- cold intolerance
- muscular sluggishness
- slowed heart rate, ↓ cardiac output, ↓blood volume
- ↑ body weight, ↑ blood cholesterol - atherosclerosis
- mental retardation due to impaired development of CNS
Mixedema
¢Develops in the patient with almost total lack of thyroid hormone function
¢Hyaluronic acid and chondroitin sulfate bound with protein form excessive tissue gel in the interstitial spaces
¢Non-pitting edema
Hypothyroidism treatment and diagnostic test
Diagnostic tests
- ↓ free thyroxine and ↑ TSH levels in the blood
- ¢In 2o and 3o hypothyroidism: ↓ free thyroxine and ↓ or normal TSH
- ↓ basal metabolic rate
- TRH response test (↑ TSH levels with TRH injection)
¢Treatment
Thyroid hormone replacement therapy
¢Daily oral ingestion of thyroxine
¢T4 replacement standard treatment
Levothyroxine
Cretinism
¢Extreme hypothyroidism during fetal life, infancy, or childhood
¢Characterized by failure of body growth and mental retardation
¢Should be treated within a few weeks after birth with thyroxine to prevent permanent retardation
¢Skeletal growth more inhibited than soft tissues – obese, stocky appearance
