Thyroid Physiology I Flashcards
A bilobed gland attached to the lower ventral surface of the trachea and connected by a band of tissue called the isthmus
The Thyroid
Both lobes receive arterial blood via thyroid arteries and are innervated by the sympathetic nervous system that controls
Blood flow
The thyroid gland contains follicles of epithelial cells that are the site of
Thyroid hormone synthesis
Thyroid hormone is stored in the follicle lumen as a clear viscous substance termed
Colloid
Interspersed among the follicles are parafollicular cells (C ells) which secrete
Calcitonin
A peptide hormone involved in calcium metabolism
Calcitonin
Stimulates the thyroid to secrete thyroid hormone into the blood stream
Thyroid Stimulating Hormone (TSH)
The most important function of thyroid hormone in adults is to regulate the overall rate of
Body metabolism
Are among the most common endocrine disorders in the U.S. affecting an estimated 10% of the population
Hyper and Hypothyroidism
Thyroid hormones are a series of compounds produced by the coupling of iodonated tyrosine molecules called
Iodinated thyronines
About 91% of the thyroid hormone produced and secreted by the thyroid gland is in the form of
Thyroxine (T4)
Has relatively weak biological activity
T4
The most biologically active of the thyroid hormones and constitutes only 7% of the hormone load secreted by the thyroid
Triiodothyronine (T3)
Comprises 2% of the hormone secreted by the thyroid and has no known biological activity
Reverse T3 (rT3)
Thyroid hormone is synthesized by
Thyroid epithelial cells (follicular cells)
Display a pronounced functional polarity from their basal to apical membranes
Follicular cells
Trap inorganic iodide (I-) through an ATP-requiring process involving a basal membrane I- pump (Na/I symporter)
Follicular cells
The efficiency and specificity of follicular iodide trapping results in 90% of the total body iodine being concentrated in the
Thyroid
Once transported into the follicular cell, iodide is incorporated into thyroid hormone precursors through which three processes?
- ) Oxidation
- ) Iodination
- ) Coupling
Inorganic iodide is oxidized into an active intermediate by
Thyroid Peroxidase (TPO)
A membrne bound enzyme located on the apical cell surface of the thyroid
TPO
What does TPO require as an oxidizing agent?
Hydrogen Peroxide
Iodination (or organification) of tyrosine residues is also catalyzed by
TPO
Rather than iodinate free tyrosine amino acids, ‘active iodine’ is added to the approximately 120 140 tyrosine residues found within a 660 kD, thyroid specific glycoprotein termed
Thyroglobulin (TG)
Synthesized on the rough endoplasmic reticulum of
thyroid follicular cells, packaged into endocytotic vesicles, and then extruded into the follicle lumen where it becomes a substrate for TPO
Thyroglobulin (TG)
Iodination results in the incorporation of either one or two iodines per TG-tyrosine residue resulting in
Monoiodotyrosine (MIT) or diiodotyrosine (DIT) respectively
Further catalyzes the coupling of either two DITs to form tetraiodothyronine (T4), or one MIT plus one DIT to form triiodothyronine (either T3 or rT3)
TPO
The iodonated TG protein (containing thyroid hormone molecules) is stored in the lumen of the follicle. This form of TG is termed
Colloid
Pathology where the development of autoimmune antibodies against TPO and/or TG disrupts normal thyroid hormone synthesis and leads to hypothyroidism
Hashimoto’s thyroiditis
Hashimoto’s thyroiditis leads to
Hypothyroidism
For thyroid hormone secretion to occur, colloid must be brought back into the follicular cell by
Endocytosis
Pseudopodia on the lumenal membrane surface engulf colloid droplets and transport them back into the cell upon stimulation by
TSH
Once within the cell, the colloid droplets fuse with lysosomes which degrade the colloid and release the
Iodinated tyrosines and thyronines into the cytoplasm
MITs and DITs are rapidly deiodinated by cytoplasmic enzymes producing free iodine and tyrosine residues, which are recycled into new
Thyroglobulin/colloid synthesis
Although the more biologically potent T3 comprises only 7% of the thyroid gland output (~6 µg per day), the total daily production of T3 is increased almost 6-fold (35 µg) by the conversion of
T4 into T3 in peripheral tissues
The conversion of T4 to T3 (i.e. the removal of an iodine from the 5’-position of outer phenyl ring) is catalyzed by the enzyme
5’-deiodinase
5’-deiodinase is found predominantly in the
Liver and Kidneys
Hence, the majority of circulating T3 (biologically active) is derived from
T4
T4 can also be converted into the biologically inactive rT3 by 5-deiodinase, an enzyme that removes an iodine from the
5-position of inner phenyl ring
Upon secretion into blood, thyroid hormones are predominantly bound to
Plasma proteins
Thus serve as a reservoir of thyroid hormone, preventing renal clearance and providing free hormone as needed
Plasma binding proteins
About 80% of the T4 circulating in blood is bound to
Thyroxine-binding globulin (TBG)
The remaining 20% is bound to
Transthyretin and albumin
The affinity of T4 for the binding proteins is so great that only 0.04% of the total T4 in circulation is
Unbound
Most of the circulating T3 is bound to
TBG
Only trace amounts of T3 is bound to
Transthyretin and albumin
T3 has a slightly lower affinity for the binding proteins. Thus what percentage of T3 remains unbound?
0.4%
What has a longer half-life, T3 or T4?
T4 (because it is more tightly bound to proteins
In view of T4’s long half-life and its ability to be converted into the more biologically potent T3, T4 is considered to be a
Pro-hormone (i.e. circulating precursor) for T3
The major activator of thyroid hormone production is
TSH (aka thyrotropin)
A heterodimeric glycoprotein (composed of an α and β subunit) synthesized and secreted by thyrotrophic cells of the anterior pituitary
TSH (thyrotropin)
TSH production and secretion from pituitary thyrotrophs is in turn, stimulated by the neurohormone
Thyrotropin-Releasing Hormone (TRH)
A three amino acid peptide produced in the hypothalamus
TRH
In response to environmental stimulus, TRH is secreted by the hypothalamus and reaches the anterior pituitary via the
Hypophyseal portal sytem
What stimulates the TRH secretion by the hypothalamus?
Cold temp, increased caloric intake, leptin
TRH-stimulated thyrotrophs secrete TSH into the blood-stream, which ultimately bind specific high affinity TSH receptors on the surface of
Thyroid follicular cells
Members of the G protein-coupled receptor family and stimulate membrane-bound adenylate cyclase when activated by TSH
TSH receptors
The resulting increase in intracellular cAMP concentration subsequently activates the entire
Thyroid hormone biosynthesis pathway
TSH stimulation of thyroid follicular cells induces activation of
TG and TPO expression
TSH stimulation of thyroid follicular cells induces
Activation of Na+/K+ ATPase expression
TSH stimulation of thyroid follicular cells induces enhancement of the enzymatic rate of
Oxidation, iodination, and coupling
TSH stimulation of thyroid follicular cells induces stimulation of the uptake of
Colloid droplets
TSH stimulation of thyroid follicular cells induces the uptake and oxidation of glucose, providing substrate for the
Pentose monophosphate shunt (Leads to NADPH and H2O2 production)
TSH stimulation of thyroid follicular cells induces stimulation of the fusion of colloid droplets with lysosomes, which ultimately leads to the release of
T3 and T4
Additionally, TSH exerts a ‘tonic maintenance’ effect on the thyroid gland by increasing the size and number of follicular cells and increasing the
Vascularity of the gland
Pathological hyperstimulation of the thyroid gland by TSH can lead to an abnormal enlargement or swelling of the gland termed
Goiter
Elevated serum levels of T3 and T4 (the result of TSH stimulation) produce a negative feedback both at the
Hypothalamus and pituitary gland
This in turn inhibits the
TRH- and TSH-signaling pathways
In both cases, elevated T3/T4 is thought to inhibit TRH and TSH production at the level of
Gene expression
Quantitation of both TSH and T4/T3 serum concentrations provides the basis for accurate diagnosis of
Thyroid disorders
When the primary disorder stems from the thyroid gland itself, there is typically an inverse correlation between
T3/T4 levels and TSH levles
Elevated T4/T3 concentrations with suppressed TSH levels reveals
Hyperthyroidism
Abnormally low T4/T3 concentrations together with high TSH levels reveals
Hypothyroidism
A HYPERthyroid condition where autoantibodies recognize and pathologically activate thyroid TSH receptors
Grave’s disease
The result of Grave’s disease is
Abnormally high T3/T4 and low to immeasurable TSH
As discussed above, the circulating concentration of biologically active T3 is determined not only by its production and secretion from the thyroid gland, but also by the activity of
5’ deiodinase
Can result in decreased serum T3 levels and increased (inactive) rT3 levels
Increased 5’-deiodinase activity
For instance, during fasting or a severe debilitating illness, serum T3 levels will decrease while
rT3 levels rise
In such cases, TSH levels paradoxically remain in a
normal to low range, presumably due to decreased TRH secretion and the inhibiting action of other hormones and factors at the
Pituitary gland
What is the purpose of decreasing T3 levels in this way (called euthyroid sick syndrome)?
To conserve energy and body tissue during a depleted state
