Lecture 22 - Thyroid Disorders Flashcards
What are the second most common endocrine disorder?
thyroid disorders
What has the use of iodine salt done?
eliminated iodine deficiencies in most countries
Levels of thyroid hormones in the body?
show little variation in plasma levels and are steady
Where does the thyroid gland sit?
within the neck, straddling the trachea
it is a butterfly shape with 2 lateral lobes connected by the isthmus
When does the thyroid gland become functional?
early in foetal life
What does the thyroid gland contain?
lots of follicles composed of epithelial cells and arranged in spheres
What are follicles filled with?
colloid
What do the follicles participate in?
all phases of thyroid hormone synthesis
What is a colloid?
proteinaceous depot of thyroid hormone precursors
stains pink
When does synthesis of thyroid hormones begin?
when circulatory iodide is actively cotransported with sodium ions across the basolateral membrane of the epithelial cells
What happens to the sodium once in the cell?
it is pumped out of the basolateral membrane by the sodium potassium pump
What happens to the iodide?
the negatively charged iodide diffuses across the epithelial to the apical membrane and is transported into the colloid
How is iodide transported into the colloid?
by a mechanism that is believed to require an integral membrane protein called pedrin
What does the colloid contain?
large amounts of a protein called thyroglobulin
What happens to the iodide once inside the colloid?
it is rapidly oxidised to iodine, which is then attached to the phenolic rings of tyrosine residues within the thyroglobulin molecule
Where is thyroglobulin synthesised?
within the thyroid epithelial cells and is secreted into the colloid by exocytosis
What is the enzyme which oxidises and attaches the iodide?
thyroid peroxidase, which is synthesised by thyroid epthelial cells and secreted into the colloid
What is a tyrosine with one iodine attached?
monoiodotyrosine
What is a tyrosine with two iodine attached?
diiodotyrosine
What then happens to the mono or diiodotyrosine?
the phenolic ring of it is removed from the remainder of the thyroglobulin molcule
If two diiodotyrosine molcules are coupled it becomes?
Thyroxine (T4)
If a mono and a diiodotyrosine are coupled it becomes?
Triiodothyronine (T3)
What happens for the hormones to be secreted into the blood?
there are extensions of the thyroid epithelial membrane which engulf portions of the colloid which contain the iodinated thyroglobulin by endoytosis
What happens to the thyroglobulin with its coupled mono or diiodotyrosine in the cell interior?
it is brought into contact with lysosomes, so there is proteolysis of the thyroglobulin which releases T3 and T4, which can diffuse into the blood
How much iodinated thyroglobulins are stored in the body?
enough to provide thyroid hormones for several weeks
What makes the thyroid gland unique?
its storage capacity - which is needed because of the unpredictable intake of iodine
What is the active thyroid hormone?
T3
What is most circulating T3 derived from?
~80% is derived from deiodination of T4
Where does the remaining T3 come from?
the thyroid gland itself
Solubility of thyroid hormones?
poorly soluble in water
Thyroid hormones in the plasma?
99.9% are extensively protein bound in the plasma
What are thyroid hormones bound to in the plasma?
thyroxine binding globulin (TBG) and transthyretin (TTR) thyroxine binding prealbumin
What are plasma proteins responsible for?
the maintenance of the large extra thyroidal pull of thyroid hormones present in our blood
What is thyroxine binding globulin (TBG)?
a glycoprotein that is synthesised in the liver
What synthesises and secretes thyrotropin releasing hormone (TRH)?
the hypothalamus
What does TRH do?
it is transported along the blood vessels to the anterior pituitary and acts on pituitary cells to stimulate secretion of thyrotropin (TSH)
What does TSH do?
is transported in the blood to the thyroid gland where is stimulates secretion of T3 and T4
What happens when levels of T4 in the blood increases?
the pituitary gland detects the increase and reduces amount of TSH is releases
What does this decreased amount of TSH cause?
less stimulation of the thyroid gland itself so a reduction in the secretion of thyroid hormones
What else does a high level of T4 inhibit?
the hypothalamus, but to a lesser extent
What is negative feedback due to?
T4 being taken up and converted to T3 by the deiodinase enzymes
Euthyroid state?
thyroid hormone secretion is normal
Hypothyroid state?
thyroid hormone secretion is subnormal (myxoedema)
Hyperthyroid state?
thyroid hormone secretion is excessive (thyrotoxicosis)
What does TSH do?
stimulate T3 and T4 production
ALSO
increases protein synthesis in follicular epithelial cells, increases DNA replication and cell division
increases rough endoplasmic reticulum and cell machinery required for protein synthesis
When exposed to greater TSH concentration what happens to the thyroid?
thyroid will undergo hypertrophy
this results in goitre
What is a goitre?
an enlarged thyroid gland
When can a goitre occur?
in hypothyroidism, hyperthyroidism and euthyroidism
Where can a goitre extend to?
into the retrosternal space with or without substantial interior enlargement
What can a goitre cause??
a variety of compressive syndromes
e.g. local compression causing dysphagia and strider
Non toxic goitre?
when thyroid stimulation is normal
Toxic goitre?
when thyroid is overactive
Hypothyroid goitre?
when thyroid is underactive
How do thyroid hormones get into cells?
they are lipophilic and can easily cross cell membranes
Where are receptors for T3 and T4?
present in the nuclei of most cells
How does T3 induce effects?
by inducing gene transcription and protein synthesis
How long to thyroid hormones take to have an effect?
hours to days, but once effect is established it will last for days
Tissue action of T3?
increase basal metabolic rate
increase heat production
responsiveness to sympathetic input
permits normal growth and development
Nervous system effects of T3?
permits normal growth and development
permits maintenance of normal activity
What are the primary actions of thyroid hormones?
to increase the bodies metabolic rate
How do thyroid hormones increase heat production?
increased oxygen consumption and energy expenditure at rest
e.g. increase activity of Na+/K+ pump, as ATP is hydrolysed heat is generated
How do thyroid hormones promote energy utilisation?
by promoting glycogenolysis and lipolysis
What are the effects of the thyroid hormones described as?
permissive - they promote the synthesis of beta adrenoceptors this permitting the tissues to respond to sympathetic input and circulating adrenaline
Why are developmental aspects of the nervous system important?
deficiency can lead to a form of irreversible brain damage called cretinism
What is cretinism?
the most extreme manifestation of thyroid deficiency
What does cretinism cause?
mental retardation, reduction in physical growth, deaf mutism
What can cretinism be caused by?
inadequate dietary intake, maternal iodine deficiency during pregnancy
What has been done to prevent cretinism?
salt is now fortified with iodine (iodide), 70mcg/g
How many thyroid function tests are there in the UK per year?
10 million (~£30 million)
What are thyroid function tests used for?
to establish if there is a thyroid disorder and also monitor the response to therapy
What are the thyroid function tests?
TSH
free T4
free T3
Normal TSH levels?
0.27-4.2mU/L
Normal free T4?
12-22pmol/L
Normal free T3?
3.1-6.8pmol/L
What are free thyroid hormones?
the biologically active fraction of the total circulating thyroid hormone pool and are unaffected by changes in the concentration and affinity of the thyroid hormone binding proteins
Signs of hypothyroidism?
cold intolerance
modest weight gain
bradycardia
tiredness for no reason
constipation
forgetfulness and personality changes (depression)
pale, dry, coarse skin
puffiness of face
What can hypothyroidism be thought of?
by bringing about a reduction of particular systems within the body e.g. in intestine where it causes constipation by reducing GI motility
What is primary hypothyroidism?
any condition characterised by plasma T3 or T4 below normal and increased TSH
Cause of primary hypothyroidism?
95% due to damage or loss of thyroid tissue
can also be due to inadequate iodine consumption
What does primary mean?
the thyroid gland itself is unable to produce sufficient amounts of the thyroid hormones
Why does T3 usually remain normal in primary hypothyroidism?
due to the sustained TSH resulting in preferential synthesis and secretion of T3
Most common cause of primary hypothyroidism?
Hashimoto’s thyroiditis
What is Hashimoto’s thyroiditis?
an autoimmune disease where there is antibodies to thyroid peroxidase
thyroid is attacked by a variety of cell and antibody mediated immune processes
What happens in Hashimoto’s thyroiditis?
Immune cells mistakenly attack healthy thyroid tissue causing inflammation of the thyroid and lead to its destruction
Who is primary hypothyroidism more prevalent in?
women
What may occur in primary hypothyroidism?
a goitre due to constant stimulatory effects of TSH
Treatment for primary hypothyroidism?
levothyroxine
synthetic thyroid hormone that is identical to thyroxine (T4)
How often should patients on levothyroxine be monitored?
annually
How often should pregnant patients on levothyroxine be monitored?
monthly and should have a 50-100% dose increase
How is the dose of levothyroxine adjusted?
until TSH levels are in mid range
Why is early treatment of primary hypothyroidism important in neonates?
to prevent mental defect and serious complications
When should primary hypothyroidism be treated?
if there is overt clinical hypothyroidism and the TSH is above reference range
Adverse effects of levothyroxine?
hair loss during first few months
headaches
sleep problems (insomnia)
nervousness
fever, hot flashes, sweating
pounding heart beat or fluttering in chest
appetite changes, weight loss
How long do side effects of levothyroxine last?
usually temporary as the body adjusts to medication and should resolve after first few months
What is another treatment for primary hypothyroidism?
Liothyronine
synthetic form of T3
What is different around liothyronine?
it is not supported in The Royal College of Physicians Consensus Statement on the diagnosis and management of primary hypothyroidism
What are the risks of T3 therapy?
on bone (osteoporosis) and heart (arrhythmia)
When can patients be given T3 therapy?
at discretion of endocrinologist - clinical evidence supports use of levothyroxine alone
Levothyroxine effects?
single dose reaches maximum effect in ~10 days and passes off in 2-3 weeks
Why is levothyroxine considered the ideal drug?
the conversion from T4 to T3 is constant and stable
What is the half life of levothyroxine?
7 days in euthyroid and 14 days in hypothyroidism
Liothyronine effects?
~5 times as biologically potent as T4
single dose reaches its maximum effect in ~24 hours and passes off within 1 week
Half life of liothyronine?
2 days in euthyroid
Binding of liothyronine to plasma proteins?
weak which is why it passes off so quickly
How long can TSH levels take to return to normal?
3-6 months
What effects dosage of these drugs?
age, pregnancy and weight
Secondary hypothyroidism?
uncommon
pituitary doesn’t produce TSH
Levels of T3, T4 and TSH in secondary hypothyroidism?
all below normal
Tertiary hypothyroidism?
hypothalamus doesn’t produce sufficient TRH
Symptoms and treatment of secondary hypothyroidism?
same as primary hypothyroidism
What is myxoedema coma?
the end result of untreated hypothyroidism
progressive weakness leading to a loss of conciousness
Symptoms of myxoedema coma?
extreme hypothermia (24-32 degrees)
areflexia, seizures, respiratory depression
Precipitating factors of myxoedema coma?
Illness, infection, trauma, drugs that suppress the CNS, exposure to cold
Who does myxoedema coma usually occur in?
patients who have a long history of hypothyroidism
Why is rapid diagnosis of myxoedema coma important?
it is a medical emergency, the mortality rate is ~80% without rapid treatment
How can corticosteroids affect thyroid function?
can decrease basal production of TRH and TSH, consequently decreasing thyroid hormone levels
high doses of these e.g. dexamethasone
How does lithium affect thyroid function?
used for manic depression
inhibits the release of thyroid hormones and interfered with their peripheral deiodination
How does amiodarone affect thyroid function?
an antiarrhythmic
contains iodine and can cause both hypothyroidism and hyperthyroidism
How does cholestyramine affect thyroid function?
reduces blood cholesterol
reduces the absorption of thyroxine from the GI tract
Symptoms of hyperthyroidism?
Heat intolerance
palpitations
weight loss (despite increased appetite)
restlessness and nervousness
fatigue
increased sweating
frequent bowel movements
goitre may be present
What is hyperthyroidism?
thyroid produces an excess of T4, reduction in TSH due to negative feedback loop
T3, T4 & TSH levels in hyperthyroidism?
T4 elevated
T3 usually elevated
TSH decreased
What is the most common cause of hyperthyroidism?
Grave’s disease (85% of cases)
Two characteristics of grave’s disease?
goitre
exopthalmos (protruding eyeballs)
What is Grave’s disease?
an autoimmune disease caused by thyroid stimulation immunoglobulin (TSI)
What does TSI do?
activates TSH receptor on thyroid follicular cells and causes increased secretion of thyroid hormones
How does TSI function?
just like TSH, is stimulatory so produces a goitre
When can Grave’s disease sometimes occur?
with other autoimmune disorders like diabetes, pernicious anaemia and connective tissue disorders
What increases risk of grave’s disease?
hereditory
Treatment for hyperthyroidism?
Surgery to remove the thyroid gland
radioactive iodine (131Iodine)
How is radioactive iodine administered?
orally
how does radioactive iodine work?
it is taken up by the thyroid gland and emmits gamma and beta radiation (T1/2 8.1 days), this leads to destruction of cells in the thyroid gland, causing it to shrink and reducing hormone production
How long does radioactive iodine take to work?
usually has its maximum effect around 3 months but may be as long as 6 months
Antithyroid drugs?
Thioamides e.g. carbimazole and propylthiouracil
How do antithyroid drugs work?
accumulated by the thyroid and inhibit thyroid peroxidase, and prevent hormone synthesis
What does propylthiouracil inhibit as well?
peripheral deiodination
Onset of antithyroid drugs?
slow (4-6 weeks)
Side effects of antithyroid drugs?
generally safe but may cause agranulocytosis, increasing the risk of infection (esp carbimazole)
