Thyroid Physiology Flashcards Preview

MS 1 Unit VI Physiology > Thyroid Physiology > Flashcards

Flashcards in Thyroid Physiology Deck (19):
1

Basal metabolic rate

-energy expenditure at rest (kcal/hr/sq meter body surface area)
-is the largest proportion of our daily energy usage (-60% in sedentary individuals)
-is 5% higher in adult males vs. females mainly due to increased muscle mass and body size (at rest skeletal muscle accounts for 20-30% BMR)
-is increased by several hormones, thyroid hormones in particular
-is profoundly increased by strenuous exercise

2

Body's metabolism

-all chemical processes involved in energy production, energy release, and growth.
-these processes can be anabolic (formation of substances) or catabolic (breakdown)
-ultimately all energy contained in ingested nutrients manifests as heat, work done on the environment, or growth
-healthy young man requires ~30kcal/kg body weight to sustain resting metabolism for 1 day
-thus, a 70 kg human requires 2100 kcal/day, an amount known as the resting metabolic rate (RMR)
-the number of calories rises with increased activity, illness, or other stress
-BMR is less than RMR

3

Thyroid gland

-regulates vertebrate growth, development and metabolism
-it is bilobulated, large (10-25 gms) and stores large amounts of hormones
-it is the only endocrine gland that can be easily palpated during a routine exam
-it has tremendous potential for growth (goiters can weigh hundreds of grams)
-it is highly vascularized (blood flow 4-6 ml/min/gm)
-it is attached to the trachea by lose CT
-composed of numerous follicles (100-300 um in diameter, the functional units
-follicular epithelial cells (aka thyrocytes) are the sites of thyroid hormone synthesis/release
-stored form of TH is in association with thyroglobulin (TG) in the colloid (gelatinous inner area of follicles)
-it contains scattered parafollicular C cells- the sites of calcitonin synthesis/release
-it also contains fibroblasts, lymphocytes, adipocytes, and endothelial cells lining the capillaries providing the blood supply to the follicles

4

Thyroid hormones

-T3 and T4 are synthesized from amino acid tyrosine on thyroglobulin and require iodide provided in the diet
-thyroxine and triiodothyronine (T4 and T3)
-they are synthesized from tyrosine residues on thyroglobulin, a large protein dimer (660 kDa thus accounting for the gelatinous nature of colloid inside the follicles)
-there is preferential synthesis of T4
-reverse T3 is also produced, but is biologically inactive
-thyroid hormones are the only hormones that require an essential trace element, iodine, which normally exists as a salt, iodide

5

Iodide and the thyroid gland

-to remain in thyroid balance, it is necessary to ingest adequate quantities of dietary iodide: 70-300 ug/day
-Iodide is concentraetd in the thyroid gland by a specific transport protein (2Na+/I- symporter) that uses the inwardly-directed electrochemical Na+ gradient as a driving force. It is not a pump and thus does not use ATP directly
-the gland has some capacity to autoregulate iodide transport according to its needs (if dietary iodide is somewhat low, it will concentrate more, and vice versa)
-however, chronic iodide defiency can lead to a form of hypothyroidism that can be corrected by providing adequate dietary iodide. This is especially true in land locked mountainous areas outside the USA
-the majority of organic iodide in the body resides in the thyroid gland in association with colloidal TG
-the remainder is present in target tissues or circulation as organic and inorganic iodide
-ultimately, TH is metabolized and iodide is excreted in the urine and feces

6

Synthesis and storage of thyroid hormones

-in the ER, thyroglobulin molecules are produced, packaged in vesicles by the Golgi, and exocytosed into the lumen of the follicle
-Iodide enters the thyrocyte via basolateral Na+/I+ cotransporters (aka the I trap). The iodide exits the cell on the apical side into the lumen via I-/Cl- antiporters
-in the follicular lumen, I- is oxidized to iodine by thyroid peroxidase and substituted for H+ on the benzene ring of tyrosine residues of thyroglobulin
-binding of one iodine will form monoiodotyrosine, and binding of two iodine moieties will form diiodotyrosine (DIT). This reaction is termed organification. Thyroid peroxidase also catalyzes the coupling of DIT to another DIT, forming T4. Some DIT will also couple to an MIT, forming T3. These products remain attached to TG
-the mature TG, containing MIT, DIT, T4, and T3 (in order of less abundance) is endocytosed back into the follicle cell and can be stored as colloid unit secreted
-colloid proteolysis is stimulated by TSH and constituent molecules released. MIT and DIT reenter the synthetic pool; T3 and T4 exit the basolateral membrane into the blood

7

Thryocyte response to TSH

-the thyroid gland secretes primarily T4 (93%) compared to T3 and reverse T3 (7%)
-the majority of circulating or tissue T3 (and biologically inactive reverse T3) is derived from T4 (often referred to as a prohormone)
-most circulating TH is bound to thyroid-binding globulin (70% TBG)
-other TH binding proteins are transthyretin and albumin
-a small amount of TH circulates in the free form (0.03% of T4 and 0.3 of T3). This free/bioavailible form is able to enter target tissues and bind to TH receptors in the nucleus

8

T4 metabolism

-THs are metabolized in tissues such as liver and kidney through the action of 5' peripheral deiodinases
-conversion of T4 to T3 produces a more biologically active/potent form
-T4 is often referred to as a prohormone
-some pharmacological agents inhibits conversion of T4 to T3 (propylthiourcail/PTU) thereby acting as antithyroid agents in the treatment of hyperthyroidism

9

T3 and T4 levels

-T3 and T4 differ with regard to biological potencies, half-lives, distributions, etc
-T4 is typically used to treat hypothyroidism because of its longer half-life (7 days vs 1) and greater stability (tighter binding/lower metabolic clearance)
-in essence, it is a prohormone for the more biologically active T3 (4 vs the 1)

10

TH entry into cells

-the majority of TH is bound to thyroxine-binding globulin (TBG)
-unbound hormone enters target tissues to activate intracellular receptors in the cell nucleus
-the mode entry of TH into cells is under active investigation
-typically, TR heterodimerizes with RXR to regulate genes containing TREs
-TH receptors are expressed in virtually all tissues in the body
-TH regulates the metabolism of carbohydrates, proteins and lipids

11

Action of thyroid hormones on target cells

-free extracellular T4 and T3 enter the target cell
-once T4 is inside, a cytoplasmic 5'/3'-monodeiodinase converts much of the T4 to T3 so cytoplasmic levels of T4 to T3 are about equal
-TR binds to nuclear DNA at thyroid response elements in the promoter region of genes regulated by thyroid hormones
-the binding of T3 or T4 to the receptor regulates the transcriptions of these genes
-of the total thyroid hormone bound to receptor, is T3
-the receptor that binds to the DNA is preferentially a heterodimer of the TR and RXR

12

Onset and duration of action of thyroid hormones

-THs have slow onsetes and long duration of actions
-Thyroxine injected graph looks like it increases basal metabolic rate up to ten days and then gradually decreases to 40 days
-T3 acts 4x as rapidly as T4 (latency 6-12 hrs and max effect 2-3 days)

13

TH transcriptional effect

-T4 is converted to active T3 at target tissue by 5'-deiodinase actions
-the T3 binds to nuclear receptors, initiating transcription of a variety of proteins and enzymes
-the overall effects of thyroid hormone are to increase metabolic rate and O2 consumption, and the general effects in target organs
-THs act synergistically with GH and somatomedins to promote bone formation
-THs promote ossification and fusion of bone plates and bone maturation
-in hypothyroidism, bone age is less than chronological age
-in hypothyroidism excessive replacement therapy with thyroxine can lead to bone loss/osteoporosis
-THs have multiple effects on the CNS and are essential for CNS development in the perinatal period
-increase CO2 and increase ventilation
-increase cardiac output
-increase urea and increase renal function

14

TH deficiency in infants

-mental retardation (cretinism) and growth retardation
-the growth retardation can be attenuated by treatment with thyroxine/T4
-the mental retardation can be attenuated only if treatment is initiated shortly after birth

15

TH exerts major effects

-thyroxine (T4) is converted to triiodothyronine (T3) in target tissues by 5' iodinase
-growth- growth formation, bone maturation
-CNS- maturation of CNS
-BMR- increase Na+-K+ ATPase, increase O2 consumption, increase heat production, increase BMR
-metabolism- increase glucose absorption, increase glycogenolysis, increase gluconeogenesis, increase lipolysis, increase protein synthesis and degredation (net catabolic)
-cardiovascular- increase cardiac output

16

Effects of thyroid hormone on BMR

-graph shows the dependence of BMR on the daily rate of thyroid hormone secretion (T4 + T3)
-we use the secretion rate because it is difficult to know where to use fre T4 or free T3
-thus the secretion rate is a crude measure of effective thyroid hormone levels
-complete lack of TH secretion causes BMR to fall 40-50% below normal
-extreme excess secretion causes BMR to rise 60-100% above normal

17

Anabolic and catabolic effects

-hypothyroid everything is lowered except for increased serum cholesterol (LDL receptor expression and cholesterol excretion in bile are decreased in hypothyroidism)
-hypothyroid women who take thyroxine must be carefully monitored as they approach the menopause to prevent osteoporosis
-hyperthyroid everything is raised except for decreased serum cholesterol
-THs have both anabolic and catabolic effects on multiple tissues
-in hyperthyroidism, muscle wasting occurs bc proteolysis outweighs synthesis
-in hyperthyroidism, increased expression of beta-adrenergic receptors leads to enhanced sensitivity to circulating epi and norepi. THs interact with sympathetic nervous system in ways that are not well understood. Thus, beta adrenergic antagonists (propranolol) are effective in treating many of the symptoms of hyperthyroidism

18

Thyroid function regulation

-regulated by thyrotropin-releasing hormone (TRH), a tripeptide hypothalamic releasing factor, thyroid stimulating hormone aka thyrotropin (TSH), an anterior pituitary thyroid-stimulating hormone, and negative feedback by circulating T3 (especially) and T4
-TRH stimulates TSH release by activating a GPCR linked to PLC, leading to generation of IP3 and mobilization of intracellular calcium
-TSH stimulates TH synthesis/release by activating a GPCR linked to adenylate cyclase, generating intracellular cAMP
-T3 (especially) and T4 act on target tissues and also exert negative feedback at the level of the anterior pituitary and hypothalamus
-dopamine and somatostatin also exert inhibitory effects on TSH release

19

TSH immunoassay

-determination of serum TSH is commonly used to diagnose primary thyroid disease
-TSH is significantly elevated in primary hypothyroidism (due to lack of negative feedback by low circulating T3 and T4) and reduced in primary hyperthyroidism (due to excessive negative feedback by high circulating T3 and T4)