Download Thyroid Hormones

Thyroid Hormones
I.
II.
Functional anatomy
a. In mammals, thyroid hormones are essential for normal growth and
maturation. Therefore, thyroid hormones are major anabolic hormones.
b. Iodine is gathered by dietary intake in the form of iodide. The ion form is
absorbed from the small intestine
c. Thyroid consists for two lobes attached to either side of the trachea
i. Butterfly
d. They are connected to each other by the isthmus (a band of thyroid tissue)
e. It consists of an aggregate of follicles, which contain a thick, gel-like
substance called colloid. Colloid is a solution of one large protein,
thyroglobulin, which is the storage form of the thyroid hormones
f. In between follicles are the parafollicular cells (C cells) which are the
source of calcitonin.
Thyroid Hormones
a. Secreted by the thyroid gland
b. Required for growth and maturation
c. T4 (thyroxine), T3 (triiodothyronine--most active) and Calcitonin
(decreases serum calcium)
d. Inadequate hormones leads to hypothyroidism
i. Signs and symptoms
1. bradycardia
2. poor resistance to cold
3. mental and physical retardation
e. Excess hormones leads to hyperthyroidism
i. Signs and symptoms
1. tachycardia
2. cardiac arrhythmia
3. body wasting
4. nervousness
5. tremor
6. excess heat production
f. These hormones have an effect on every cell in the body except for the
adult brain, spleen, testes, uterus and the thyroid gland itself
g. To form normal quantities of thyroid hormone, about 50mg of iodine is
required each year or about 1mg/wk. Iodine is absorbed from the GI and
excreted by the kidney, but some is absorbed by the thyroid.
h. Iodide transports actively transport iodide from the basal membrane of
follicular cells (called an iodide trap) to the apical membrane where they
are used for iodination of thyroglobulin in the thyroid
i. An active transport mechanism (pump) on the basal surface of the
thyroid follicle can raise the concentration of iodine within the cell
to as much as 250x that of the plasma. The pump can be blocked by
anions like percholate and thiocynate, which compete with iodine.
Large amounts of iodide with also inhibit the pump and thyroid
hormone synthesis (Wolff-Chaikoff effect).
i. Iodine ions are oxidized to iodine by peroxidase located on the apical
membrane. Iodine is capable of combining with the amino acid tyrosine.
This peroxidase also catalyzes iodination and coupling of tyrosine
residues within thyroglobulin.
j. Binding Mechanism
i. Binds to a receptor located in the nucleus or cytoplasm
ii. Causes transformation of the receptor to an exposed DNA binding
domain
iii. Binds to an enhancer like element in DNA and causes the
transcription of genes for a new protein leading to a physiologic
response
1. the need for gene transcription and protein synthesis delays
the onset of action of these hormones
k. Synthesis and Secretion
i. It involves six interrelated processes that begin when TSH binds to
follicular cell receptors
ii. Formation and storage of thyroglobulin
1. Thyroglobulin is synthesized on the ribosomes then sugar
residues are attached (glycosylated) in the ER, and
molecules are packed into vesicles and then transport to the
Golgi. These transport vesicles move to the apex of the
follicle cell where their contents are discharged into the
lumen and become part of the stored colloid.
iii. Iodide trapping and oxidation to iodine
1. To produce the functional iodinated hormones the follicle
cells must accumulate iodide (anions of iodide) from the
blood. Since their intracellular concentration of iodides is
over 30x higher than that in blood, iodide trapping depends
on active transport. Upon entry, iodides are oxidized by
removal of electrons and converted to iodine. The enzyme
peroxidase, which is located at the apical border of the
follicle cell, catalyzes oxidation and coupling
iv. Ionidation
1. blocked by propylthiouracil (PTU) and methmazole
2. Once formed, iodine is attached to the tyrosine amino acids
forming part of the thyroglobulin colloid. This iodination
reaction occurs at the apical follicle cell colloid junction and
is mediated by peroxidase enzymes
v. Coupling of T2 and T1
1. Attachment of one iodine to a tyrosine produces
monoiodotyrosine (MIT or T1)
2. Attachment of two iodines produces diiodotyrosine (DIT or
T2)
3. Then enzymes within the colloid link T1 and T2 together
a. Tow linked DITs result in T4 and a coupling of MIT
and DIT produces T3.
4. At this point, however, the hormones are still part of the
thyroglobulin colloid. When iodine is abundant mainly T4 is
formed but when iodine becomes scarce, the production of
T3 increases.
vi. Colloid endocytosis
1. Hormone secretion requires that the follicle cells reclaim
iodinated thyroglobulin by endocytosis and combine the
vesicles with lysosomes
vii. Cleavage of the hormones for release
1. With in the lysosomes, the hormones are cleaved out of the
colloid by lysosomal enzymes. The hormones then diffuse
from the follicle cells into the bloodstream. The main
hormonal product secreted is T4 (20 T4 to 1 T3). Some T4 is
converted to T3 before secretion (blocked by PTU), but most
T3 is generated in the peripheral tissues. When iodide
availability is restricted, the formation of T3 is favored.
Because T3 is 3x as potent as T4, this response provides more
active hormone per molecule of organified iodide. The
proportion of T3 is also increased when the gland is
hyperstimulated by TSH or other activators.
viii. Peripheral conversion of Thyroid hormones
1. More than 99% of the T4 and T3 molecules in the blood are
bound to serum proteins. About 80% bind to thyroxine
binding globulin (TBG) and most of the rest is bound either
to albumin or thyroxine binding prealbumin (TBPA). Less
than 1% of the T4 and T3 is in a free and active form.
2. The protein bound fraction serves as a reservoir of
preformed hormone. T4 binds more tightly to serum
binding proteins than T3 resulting in a lower clearance rate
and longer half life. (6-7 days for T4 vs. 1 day for T3).
3. T4 is the major hormone. About 40% of the T4 is converted
to T3 by a 5’-deiodinase present in many tissues of the body,
especially liver, kidney and the anterior pituitary. T3 is
more potent. This deiodination reaction is the major
pathway for metabolic inactivation or disposal of T4.
III.
ix. PTU can also block the condensation of thyroglobulins as well as
the deiodinase enzyme that converts T4 to T3
x. Elevated iodide levels can competitively inhibit the iodination of
tyrosine residues
l. Function and Regulation
i. Bone growth (synergizes with GH)
1. it is required for normal synthesis and secretion of GH
ii. CNS maturation (during fetal life and for the first few years of
postnatal life)
1. includes neuronal proliferation, differentiation,
myelinogenesis, neuronal outgrowth and synapse formation
iii. Beta adrenergic effects
1. increase the number and affinity of beta adrenergic receptors
(heart)
iv. Increases basal metabolic rate via sodium-potasium ATPase
activity
1. increases oxygen consumption and body temperature
2. calorigenic action
v. Increased glycogenolysis, gluconeogenesis and lipolysis
1. accelerates cholesterol clearance from the plasma
vi. Increases cardiac output, heart rate, stroke volume, contractility
and respiratory rate
vii. T4 functions: 4 Bs
1. brain maturation
2. bone growth
3. beta adrenergic effects
4. BMR increase
viii. Regulation
1. TRH (thyroid regulatory hormone) form the hypothalamus
stimulates TSH from the pituitary which stimulates follicular
cells
2. Negative feedback by T3 to the anterior pituitary decreases
sensitivity to TRH.
3. TSI, like TSH, stimulates follicular cells (seen is Graves’
disease)
Thyroid Disorders
a. Hypothyroidism
i. Signs and Symptoms:
1. Cold intolerance, hypoactivity, weight gain, fatigue,
lethargy, decreased appetite, constipation, weakness,
decreased reflexes, myxedema (facial or periorbital) dry cool
skin and coarse brittle hair
2. Increased TSH (primary), decreased total T4, decreased free
T4 and Decreased T3 uptake
3. Total T4 will increase in pregnancy and with the use of oral
contraceptives. It will will decrease in such disorders as
nephritic syndrom and with the use of androgens.
Therefore, total T4 is often a poor index of thyroid function
4. Decreased mental capacity: thought and speed are slow and
memory is poor
5. Lack of thyroid hormone is likely to cause loss of libido,
while great excesses can cause impotence. In women, lack of
thyroid hormone often causes excessive a frequent bleedings
in some women.
6. A complex of protein, hyaluronic acid and chondroitin
sulfate (mucopolysaccharide) accumulates in the
extracellular space of the skin. Its oncotic action holds water
giving rise to a nonpitting edema (myxedema).
7. Cretinism
a. Endemic cretinism occurs where ever endemic goiter
is prevalent (lack of dietary iodine)
b. Sporadic cretinism is caused by a defect in T4
formation or developmental failure in thyroid
formation
c. Symptoms: pot-bellied, pale, puffy faced child with
protruding umbilicus and protuberant tongue
ii. The most common cause of low thyroid production is an
autoimmune disease called Hashimoto’s thyroiditis in which your
lymphocytes make antibodies, which slowly and gradually disable
the hormone producing cells in your thyroid gland.
iii. In severe cases, hyaluronic acid and chondroitin sulfate complexes
with protein and is deposited in the extracellular spaces of the skin
causing water to accumulate osmotically (myxedema)
iv. Drug: Levothyroxine (T4)
1. adverse effects:
a. nervousness
b. heart palpitations
c. tachycardia
d. intolerance to heat
e. unexplained weight loss
2. Metabolized by the P 450 enzyme system
a. Drug interaction with anything that induces the p450
enzyme
i. Phenytoin
ii. Rifampin
iii. Phenobarbital
b. Hyperthyroidism
i. Also known as Graves’ disease, toxic adenoma and goiter
ii. Symptoms:
1. Heat intolerance, hyperactivity, weight loss, chest pain and
palpitations, arrhythmias, diarrhea and increased reflexes
iii. Signs:
1. Decrease TSH (if primary) increased total T4, increased free
T4 and increased T3 uptake, tremor and difficulty sleeping
2. Hyperthyroid women often exhibit greatly reduced bleeding
or none at all
3. Increased metabolic rate and oxygen consumption
4. In spite of increased appetite, there is generally weight loss,
protein wasting and muscle weakness (thyrotoxic
myopathy)
5. Excitability, irritability and restlessness
6. Tachycardia and increased cardiac output (increased beta
adrenergic stimulation)
7. Exophthalmos (Graves’ disease)
iv. Graves’ Disease
1. thyrotoxicosis
2. ophthalmopathy (proptosis, EOM swelling), pretibial
myxedema, diffuse goiter
3. And autoimmune hyperthyroidism with thyroid stimulating
TSH receptor antibodies over stimulate the whole gland to
make too much hormone.
4. About 5% of patients with Graves’ disease also have some
involvement with their eyes in which the eyes may become
inflamed and appear enlarged.
5. Autoantibodies called LATS long acting thyroid stimulator)
interact with the TSH receptor on the follicular cell and
mimic the stimulator actions of TSH.
6. The thyroid gland enlarges and forms a diffuse toxic goiter
with synthesizes thyroid hormones at an accelerated rate
v. This most commonly (70-80% of US cases) results from a
generalized over activity of the entire thyroid gland, a condition
also know as diffuse toxic goiter or Graves’ disease. 10% of hyper
thyroid patients have one or more small benign tumors in their
gland (hot nodules), which make hormone at too high a rate. This
is called toxic nodular goiter or plummer’s disease.
vi. Treatment:
1. In the short term it may focus on making the body less
responsive to the stimulus given by the thyroid hormone
(beta blockers).
2. removal of part or all of the thyroid glad by surgery or
radioactive iodide (beta particle radiation with I131)
a. the active accumulation of iodide into the thyroid
gland is the basis for selective cell destruction by
radioactive iodide
b. avoid radiation therapy during pregnancy and in
children and in Graves’ disease if characterized by
prominent exopthalmia
c. useful in patients in which antithyroid drugs are not
effective or not tolerated
3. inhibition of thyroid hormone synthesis by PTU and
methimazole (short half life)
a. used in uncomplicated hyperthyroid conditions
b. inhibits the iodination of tyrosyl residues on the
thyrogobulin
c. inhibits the coupling reactions to form DIT, T3 and T4
d. slow onset
e. not effective in the case of thyroid storm
f. adverse effects are rare and include agranulocytosis,
rash and edema, maculopapular rash,
hypersensitivity and immune based arthralagia,
jaundice, lupis and vasculitis
g. both drugs cross the placental barrier but PTU is safer
in pregnancy because it is extensively protein bound
4. blockade of proteolytic hormone release from thyroglobulin
a. also done by ipodate
b. iodide inhibits iodination of tyrosine and the release
of the hormone by an unknown mechanism
i. inhibits coupling to form DIT, T3 and T4
c. good for short term therapy
d. reduces thyroid vascularity
e. given PO
f. adverse effects
i. sore throat
ii. rashes
iii. ulceration of mucous membrane
iv. metallic taste
5. use of beta blockers such as propanolol to block the
sympathetic stimulation
6. The conversion of T4 to T3 by 5’-deiodinase in the peripheral
tissues is inhibited by ipodate, propanolol and a high dose of
PTU
7. Iodide
a. Usually given as KI (lugol’s solution)
b. Possible use in thyrotoxicosis and preoperatively
c. Decreases gland size and fragility and vascularity
d. Not good for long term use as the thyroid gland
escapes from its effects after 10-14 days
8. Block-replace regimen means that a thioamide plus Lthyroxine is given