Transcript Thyroid - VCOMcc

Thyroid I and II
Cindy McKinney, Ph.D.
Cell Biology and Physiology
Block 5, 2012
Gastroenterology and
Endocrinology
Learning Objectives
 Identify the steps in the biosynthesis, storage, and secretion of triiodothyronine (T3) and thyroxine (T4) and their regulation.
 Describe the absorption, uptake, distribution, and excretion of iodide.
 Explain the importance of thyroid hormone binding in blood on free and total
thyroid hormone levels.
 Understand the significance of the conversion of T4 to T3 and reverse T3
(rT3) in extra-thyroidal tissues.
 Describe the physiologic effects and mechanisms of action of thyroid
hormones.
 Explain what conditions can cause an enlargement of the thyroid gland.
 Understand the causes and consequences of
a) over secretion of thyroid hormones
b) under secretion of thyroid hormones
Location of Thyroid Gland
Thyroid
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canine
Located in the neck over the first part of the trachea
Humans-”butterfly” –two lateral lobes connect by an isthmus
Nodules on thyroid=parathyroid glands (2 superior/2 inferior)
Parafollicular (C cells)—major source for hormone calcitonin
Chemistry of Thyroid Hormone
Thyroid hormones are derivatives of the amino acid tyrosine covalently bound to
iodine
-Iodine bound at either 3 or 4 positions on two linked tyrosines
Other iodinated molecules can be generated (example: rT3 but are inactive)
T3 and T4 are poorly soluble in water (blood) so are carried bound to proteins
- principle binding protein is thyroid-binding globulin
- other important carrier proteins are albumin and transthyrein
Carriers allow a stable pool of hormone in blood that can release free hormone
to tissues (sites of action)
Steps in Biosynthesis, Storage
and Secretion of T3/T4
Raw materials:
1: Tyrosine-sourced from thyroglobulin in colloid
thyroglobulin secreted by thyroid epithelial cells
2: Iodide (I-)-uptake from blood by thyroid
epithelial cells (outer plasma membrane has a
Na+/I- symporter) once in cell transported to
colloid with thryoglobulin
Steps in Biosynthesis, Storage
and Secretion of T3/T4
1. Thyroid peroxidase adds the (iodide) I- to tyrosines on thyroglobulin (organifaction of
iodide).
2. Synthesis of thyroxine (T4) or tri-iodotyrosine (T3) from two iodotryosines
Remember that the hormone is still tied to the thyroglobulin ---needs to be liberated into
the circulation as needed
Thyroid hormone cycle
Steps in Biosynthesis, Storage
and Secretion of T3/T4
Release of T3/T4 from colloid:
1. Thyroid epithelial cells ingest iodinated thyroglubulin
from apical surface (endocytosis)
2. Colloid filled endosomes fuse with lysosomes that contain
hydrolytic enzymes that digest the iodinated thyroglobulin
---release of active thyroid hormone
3. Free thyroid hormone diffuses across the basolateral
epithelial membrane into ECF (blood)
4. Free thyroid hormone quickly bound to carrier proteins
to be transported and release at target cells.
Transport of Thyroid Hormone
• T3/T4 are highly bound to plasma protein carriers
– Major carrier is thyroxine–binding globulin (TBG)
– Secondary carriers are albumin and thyroxine-binding
prealbumin
– Approximately 99.9% of T4 bound and <0.1% is free hormone
– [T3]free in plasma <1%
– Because of tight binding to plasma proteins –long half life (T4=7
days)
Free hormone is what is captured by target cells and
exerts its biological effect before degradation
Transport of T4/T3 to peripheral tissues
Increases(pregnancy) and Decreases (liver diseases) in circulating
plasma TBG levels change the amount of TBG bound hormone
However, They only transiently effect the amount of biologically active
FREE hormone because the
 negative feedback of free hormone on TSH levels
(remember: TSH stimulates release of free hormone
Example: in pregnancy, a fall in T3 levels, causes a compensatory
increase in TSH levels that in turn will increase production of free
hormone in the circulation. Increased thyroid hromone shuts off TSH
But total [free hormone] may be higher
Thyroxine (T4) conversion to T3
T4 is the dominant secreted/circulated form from the thyroid
However:
Most of the T4 secreted by thyroid is metabolized to T3
(de-iodinated at the 5’ or 5 position in peripheral tissues to
either T3 or rT3 (inactive)
Since T4 is primarily converted to T3 that has a higher affinity for
thyroid hormone receptors ---sometimes T4 is considered a
prohormone for T3
Ratio of T4 to T3 is 5:1 in circulation (meaning it’s bound up)
Potency of T4 to T3 is 1:10 (affinity)
Mechanism of Action and of T3/T4
Receptors for thyroid hormone action are:INTRACELLUAR DNA –BINDING PROTEINS
function as hormone responsive transcription (HRE) factors
mode of action is similar to steroid hormones
• T3 binds to short repetitive sequences of DNA called Thyroid Response Elements (TRE)
• TRE DNA sequence= AGGTCA
• Can be arranged as direct repeats, pallindromes or inverted repeats.
• Can be monomer (AGGTCA) homodimer (AGGTCANNNNAGGTCA)or a heterodimer
(T3+another protein in complex) with the retinoic acid recepter (RXR) another member
of the nuclear receptor subfamily
• Heterodimer is the high affinity form and thought to be the major functional entity
Mechanism of Action and of T3/T4
• Thyroid hormone receptors bind to the TRE DNA with and without T3
• Biological effects of T3 bound vs. T3 unbound receptor are dramatically different
Generally:
1: binding of receptor w/o T3 to DNA transcriptional repression
results in compacted “turned off” chromatin
HDA=histone deactelyase
2: binding of T3+receptor complex transcriptional activation
complex recruits different co-activators proteins –conformational change
leads to gene activation
HAT=histone transacetylase
Thyroid Hormone Receptors
Structure
Mammalian Thyroid Receptors are encoded by two genes α and β
Three Functional Domains:
1. Transactivation
-amino terminus---interacts with other transcription factors
2. DNA Binding
-Recognition of HRE for binding
3. Ligand-Binding and dimerization
-T3 ligand binding at carboxy terminus
Primary gene transcript for both forms can be alternately spliced to form
multiple α and β isoforms.
Thyroid Receptors
The different isoforms of thyroid receptor have patterns of expression that differ
by tissue and developmental stage.
Examples:
α1, α2 and β1 isoforms are expressed in virtually all tissues
β2 found predominantly in hypothalamus, anterior pituitary and developing ear
α1 first to be expressed in fetus
and β1, β2 up-regulated in developing brain after birth
-they activate several genes known to important in brain development
such as myelin basic protein
Regulation of Thyroid Hormone Secretion
Hypothalamic-pituitary-thyroid axis
Control of thyroid hormone secretion is a NEGATIVE
FEEDBACK LOOP
- Binding of TSH on thyroid epithelia enhances all the processes
for hormone synthesis of
1. iodide transporter
2. thyroid peroxidase
3. thyroglobulin
-magnitude of the TSH signal sets the rate for endocytosis of colloid
 TSH faster rates of colloid synthesis hence more
hormone in circulation
 TSH decrease in colloid synthesis hence less
hormone in circulation
COLD Exposure can increase TRH release  enhanced thyroid hormone release
Degradation of Thyroid Hormone
• Degradation occurs in peripheral tissues
STEP 1: Deiodination and decarboxylation
STEP 2: Glucuronidation/Sulfonation in liver
STEP 3: Excretion into bile ducts
STEP 4: Excretion of glucuronide conjugate in
urine
Thyroid Hormone and Cellular
Metabolic Rate
Many of the effects of T3 are secondary to increased BMR
•  sweating and thermogenesis—heat elimination from skin
• rate and depth of breathing –need for O2
•  cardiac output from increases in SV and HR and changes
in contractile force
• Improve memory and learning capacity
• Most tissues
– Increase in O2 consumption
– Increase in heat production
• Mitochondria increase in size and number
• Key respiratory enzymes increase
Physiological Effects of Thyroid
Hormone
Metabolism:
Thyroid hormone stimulates most tissues of the body resulting in an increase of
Basal metabolic rate
1. increases body temperature---O2 consumption and ATP hydrolysis
2. stimulates fat mobilization leading to increases of [FA] in plasma,
FA oxidation is also increased
3. increases in carbohydrate metabolism ---increased insulin dependent
glucose entry into cells, gluconeogenesis ,glycogenolysis
Growth:
Thyroid hormone synergistically combines with growth hormone to enhance
grow processes
Physiological Effects of Thyroid
Hormone
Development:
Critical for development of fetal and neonatal brain
Cardiovascular:
Promotes vasodilation ---increased vascular flow in organs
Increases cardiac output, cardiac rate, and cardiac contractility
CNS:
Decreased hormone sluggish mental activity
Increased hormone related to anxiety
Reproduction:
Low hormone levels frequently associated with infertility (female) (male?)
Thyroid and Bone
Bone cells have receptors for Thyroid hormone:
 necessary for growth and maturation of the skeleton
 if thyroid hormone levels are too high ---osteoporosis and bone loss
Thyroid and the heart:
T3 responsive genes for important cardiac proteins
Positive regulation-increased gene expression
Sarcoplasmic reticulum calcium adenosine triphosphatase
Myosin heavy chain α
β1-Adrenergic receptors
Guanine-nucleotide-regulatory proteins
Sodium/potassium adenosine triphosphatase
Voltage-gated potassium channels
Negative regulation-decreased gene expression
T3 nuclear receptor α1
Myosin heavy chain β
Phospholamban
Sodium/calcium exchanger
Adenylyl cyclase types V and VI
Thyroid: Pregnancy and Fetal
Development
Maternal Thyroid Function in Pregnancy:
Normal changes in thyroid function during pregnancy include:
1a) 2 fold increase T4 (thyroxine) binding globulin (TBG) stimulated by increases
in estrogen
1b) Increased levels of TBG decrease amount of free T4 therefore more TSH is
made, in turn, increasing T3 and T4
1c) increased amounts of thyroid hormone balance reached at 20 weeks and
maintained until parturition
2. Increased demand for iodine—significant increase in pregnancy clearance of
I- by kidney and siphoning of I- by fetus from maternal circulation
3. Thyroid stimulation by hCG—TSH and hCG similar enough that hCG can
increase mimics TSH at gland receptor—stimulates T3 release while TSH maybe
suppressed (graph)
some women may develop transient hyperthryoiddis in
pregnancy or if a woman as subclinical hypothryoidism
demand of fetus can precipitate hypothyroidism.
Thyroid and Fetal Brain
Thyroid receptors present in brain tissue before fetus is synthesizing its own hormone
During fetal brain development thyroid hormone assists in activation of genes (HRE)
Involved with terminal stages of brain differentiation
1. synaptogenesis
2. growth of dendrites and axons
3. myelination
4. neuronal migration
Disorders of the Thyroid
• Thyroid hormone resistance
– Mutations in β receptor gene that abolish ligand-binding
– In most families transmitted as dominant trait
– Clinic: hypothyroidism with goiter, elevated serum [T3] and [thyroxine] and
normal or elevated serum [TSH], significant number of pediatric patients
show attention deficit disorder,
Disorders of Thyroid
•
Grave’s Disease
– Most common form of hyperthyroidism
– Antibodies Thyroid stimulating immunoglobulins (TSIs)
form against the TSH receptor of the thyroid gland
-TSI’s bind to TSH receptor and mimic action of TSH
-results in Goiter and increases thyroid hormone and decreases in TSH
because of negative feedback due to increased thyroid hormone in plasma
-Predicted changes:
1) increased metabolic rate
2) heat intolerance and sweating
3) increased appetite but weight loss
4) palpitations and tachycardia
5) nervousness and emotional swings
6) muscle weakness
7) tiredness but inability to sleep
-Many patient’s develop protruding eyeballs (exopthalmos)
degenerative changes in extraocular muscles resulting from autoimmune
reaction
Disorders of Thyroid
• Hypothyroidism
– Hashimoto’s disease—autoimmune destruction of gland
– Also called Autoimmune Thyroiditis
– Predicted changes
1) decreased metabolic rate
2) cold intolerance and decreased sweating
3) weight gain w/o increased appetite
4) bradycardia
5) slowness of speech, thought and movement
6) lethargy and sleepiness
-accummulation of mucoplysacchrides in interstial spaces----”puffiness” of
skin myxedema
Decreased Thyroid hormone  increased TSH levels (may lead to
compensatory goiter)
Thyroid Deficiency in Fetus and
Neonate
Maternal
Fetus has two potential sources of thyroid hormone
Fetal
Fetus begins to make T3/T4 at approximately 12 weeks gestation
Substantial transfer of hormone across the placenta
placenta has a deiodinases that converts T4 to T3
Three forms of hypothyroidism in Pregnancy:
1.Isolated Fetal Hypothyroidism
2. Isolated Maternal Hypothyroidism
3. Iodide Deficiency (combined maternal and fetal hypothyroidism)
Disorders of Thyroid
• Cretinism
-severe hypothyroidism resulting stunted
growth and mental retardation
Athyrotic cretinsim—thyroid aplasia or
Iodine deficiency in utero
Endemic cretinism---iodine deficiency
Spasticity, deaf-mutism, motor dysfunction
Puffy face, short stature, protruding abdomen and swollen tongue, slow
reflexes
Iodide Deficiency
• Combined maternal-fetal hypothyroidism
• Most common cause of preventable mental
retardation world-wide
• Results in cretinism, mental retardation,
deaf mutism and spasticity
• Supplement with iodine in 1st and 2nd
trimester (later will not prevent defects)
• Endemic Goiter---high plasma TSH
stimulates gland
Hyperthyroidism in Pregnancy
Gestational hyperthyroidism
(increased T3 levels)
• Increased risk for
– Preeclampsia
– Premature labor
– Fetal or perinatal death
– Low birth weight
May be caused by Grave’s Disease (that was
undiagnosed)
auto-antibodies against TSH receptor
Fetal Hypothyroidism
• Sporadic congenital hypothyroidism
fetal gland doesn’t produce enough hormone
normal at birth (maternal compensation)
Needs rapid diagnosis shortly after birth or risk
child having permanent mental and growth
retardation
Maternal Hypothyroidism
• Female hypothyroidism frequently associated
with infertility
• If pregnancy does occur –increased risk of fetal
death and gestational hypertension
• Subclinical maternal hypothyroidism
– Diagnosed retrospectively
– Auto-antibodies to thyroid that can cross placenta
– Children with lower IQ scores
Hamburger Thyrotoxicosis
In the ODD
BUT TRUE category:
A 61 yr. old woman in Canada presented to physicians with intermittent hyperthyroidism
that would resolve on its own over 2-3 months. They saw rapid weight loss, increased
sweating and palpitations, tremor in her hands and a heart rate of 112 beats/minute.
Diagnosis was confirmed by and elevated free T4 (46 compared to 9-23) and a very low TSH.
Within 2 months her symptoms disappeared on their own and her T4 returned to normal
range. She did not have thyroid antibodies. The woman had 5 such episodes over an
11 year period. The physicians were left puzzled.
Resolution:
1) Patient indicated she did not take herbal supplements or thyroid supplements
2) Additional questioning about her dietary habits revealed the cause. She lived on a farm
And every year a cow was slaughtered and the butcher packaged the meat for use. It was
discovered that the butcher did not know that “gullet trimming” was prohibited. Hence,
Muscles from the larynx and thyroid were trimmed and used to make hamburger patties.
The woman consumed these (her husband did not) patties and had exposure to cow thyroid
gland. !984-85—similar cases seen in Minnesota, South Dakota and Iowa.
Key Concepts
• How is thyroid hormone regulated ?
• Why is mode of action like a steroid hormone?
• Over secretion of thyroid hormone has what
consequences?
• Under secretion of thyroid hormone has what
consequences?
• What is the active form of the hormone?
• How does hormone reach tissues?
• What are the actions at tissue level?
• What amino acid forms the backbone of thyroid
hormone?
Sample Board Question
• Blood levels of ________would be
decreased in Grave’s Disease.
a) Tri-iodothyronine (T3)
b) Thyroxine (T4)
c) Diiodothyrosiine (DIT)
d) Thyroid Stimulating Hormone (TSH)
e) Iodide (I-)
Answer
• Recognize that Grave’s Disease is a form of
hyperthyroidism. What’s happening? autoantibodies (TSIs) are stimulating large
increases in hormone by acting at the TSH
receptors. Increased [hormone] is circulating
and accessed in the CNS (anterior pituitary
and hypothalamus) where TSH is decreased
by the negative feedback loop (review
regulation of thyroid).