MEH session 7 Flashcards
Where is the thyroid gland?
In the neck just above the suprasternal notch
Anterior to the lower larynx and upper trachea
Is the thyroid gland visible and palpable under normal conditions?
No - only visible or palpable when enlarged (goitre)
Describe the structure of the thyroid?
Butterfly shape with two lateral lobes jointed by a central isthmus
Size varies
Which nerves lie in close proximity to the gland?
Recurrent laryngeal nerve
External branch of the super laryngeal nerve
Are the parathyroid glands and thyroid glands district structures?
Yes
Which endocrine gland is the first to develop?
Thyroid gland
Describe embryonic development of the thyroid gland.
- 3-4 weeks gestation —> appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue
- Descends through thyroglossal duct and migrates downwards passing in front of hyoid bone
- During migration it remains connected with the thyroglossal duct which degenerates
- Detached thyroid then continues to its final position over the following two weeks
What cells are present in the thyroid gland? Describe the histological structure of the thyroid gland.
• Two major cell types:
◦ Follicular cells- arranged in numerous spherical functional units called follicles seperated by connective tissue. PRODUCES THYROID HORMONE
◦ Parafollicular cells (c-cells)- found in the connective tissue. PRODUCES CALCITONIN
• Follicles are spherical and are lined with epithelial follicular cells surrounding a central space (lumen) containing colloid which is rich in the protein THYROGLOBULIN
Which cells produce thyroid hormone?
Thyroid follicular cells
Which cells produce calcitonin?
Thyroid parafollicular cells
What stores thyroglobulin?
Colloid
Which cells in the parathyroid gland produce parathyroid hormone?
Principal cells/ chief cells
Describe the chemical structure of T3 and T4
Small molecules derived from the amino acid tyrosine with the addition of atoms of iodine.
What is MIT and DIT?
MIT is tyrosine with one iodine attached to the aromatic ring.
DIT is tyrosine with 2 iodines attached to the aromatic ring.
Describe the basic steps in the synthesis of T3 and T4.
- Transport of iodine into the epithelial cells against a concentration gradient
- Synthesis of a tyrosine rich protein (thyroglobulin) in the epithelial cells
- Exocytosis of thyroglobulin into the lumen of the follicle
- Oxidation of iodide to produce an iodinating species
- Iodination of the side chains of tyrosine residues in thyroglobulin to form MIT (mono-iodotyrosine) and DIT (di-iodotyrosine)
- Coupling of DIT with MIT or DIT to form T3 and T4 respectively within the thyroglobulin.
- T3 and T4 residues are produced in the ratio of 1:10
What is the roll of thyroglobulin?
Acts as a scaffold on which thyroid hormones are formed.
T3 and T4 is stored extracellularly in the lumen of the follicles as part of the thyroglobulin molecules. The amounts normally stored are considerable and would last for several months at normal rates of secretion.
What is the role of thyroid peroxidase?
Regulates 3 separate reactions involving iodide.
1) oxidation of iodide to iodine (requires the presence of hydrogen peroxide)
2) addition of iodine to tyrosine acceptor residues on the protein thyroglobulin
3) coupling of MIT or DIT to generate thyroid hormones within the thyroglobulin protein
How is dietary iodine absorbed?
Dietary iodine is reduced to iodide before absorption principally in the small intestine.
Where is iodine found in the body?
Thyroid hormones and precursors are the only molecules in the human body that contain iodine. The thyroid gland contains 90-95% of iodine in the body
How is iodide taken up by thyroid epithelial cells?
Sodium-iodide transporter
What are rich sources of iodine?
Dairy products
Grains
Meat
How is T3 and T4 secreted?
- Thyroglobulin is taken into the epithelial cells from the lumen of the follicles by the process of endocytosis
- Proteolytic cleavage of the thyroglobulin occurs to release T3 and T4
- These diffuse from the epithelial cells into the circulation
Why and how is T4 converted to T3?
90% of thyroid hormone is secreted is T4
T3 is more biologically active than T4
Most T4 is converted to T3 in the liver and kidneys
T4 can be converted to T3 in tissues by removal of the 5’-iodide
Which releasing hormone is released from cells in the hypothalamus to stimulate the release of TSH from the anterior pituitary?
What is it released in response to?
TRH
Release is stimulated by:
Low levels of T3 and T4 (long loop)
Low levels of TSH (short loop)
Which tropic hormone is released from the anterior pituitary gland?
What is its release stimulated by?
TSH
Release is stimulated by:
- effects of TRH
- low levels of T3 and T4 (long loop)
What are the general effects of the thyroid hormones?
They affect virtually every cell in the body and have effects on:
- cellular differentiation and development
- metabolic pathways
Describe the structure of TSH.
glycoprotein hormone
consists of two non-covalently linked subunits (alpha and beta)
The alpha subunit in TSH is the same as the alpha subunit in which other hormones?
LH
FSH
How does TSH trigger thyroid hormone release?
TSH binds to TSH receptor on epithelial follicular cells of thyroid gland.
TSH receptor is a GPCR and when activated can recruit a Gs or Gq protein (Gq at higher concentrations)
This stimulates thyroid hormone synthesis and release
What specific reactions does TSH stimulate in the thyroid gland?
Iodide uptake Iodide oxidation Thyroglobulin synthesis Thyroglobulin iodination Colloid pinocytosis into cell Proteolysis of thyroglobulin Cell metabolism and growth
What are the major physiological actions of T3 and T4?
Increase in basal metabolic rate and heat production
Stimulation of metabolic pathways
Sympathomimemetic effects - increases target cell response to catecholamines by increasing receptor number on target cells
How does thyroid hormone increase BMR and heat production?
Increasing the number and size of mitochondria
Stimulating synthesis of enzymes in the respiratory chain
Which catabolic pathways does thyroid hormone stimulate?
Lipid metabolism -
stimulates lipolysis and beta oxidation of fatty acids
Carbohydrate metabolism -
stimulates insulin-dependent entry of glucose into cells (promotes GLUT4 translocation to cell membrane)
increases gluconeogenesis
Increases glycogenolysis
How does thyroid hormone increase the effect of adrenaline and noradrenaline?
Increases the number of catecholamine receptors
What effect does thyroid hormone have on the cardiovascular system?
Increases the hearts responsiveness to catecholamines
—>This increases cardiac output due to an increase in:
Inotropy
Chronotropy
—> This increases peripheral vasodilation to carry extra heat to body surface
What effect do the thyroid hormones have on the nervous system?
Increases myelination of nerves
Increases the development of neurones
This is essential for both development and adult function
What is cretinism?
Mental and physical retardation. Irreversible damage occurs if not corrected within a few weeks of birth
Caused by absence of thyroid hormones from birth to puberty.
A lack of thyroid hormones in children causes…
Cretinism
A lack of thyroid hormones in female adults causes…
Ovulation to fail as thyroid hormones have a permissive role in the actions of hormones such as FSH and LH
What class of receptors does thyroid hormone act on?
Nuclear receptors
What is the mechanism of action of T3 and T4?
Function as hormone-activated transcription factors
Act by modulating gene expression
Thyroid hormones receptors bind DNA in the absence of hormone, usually leading to transcriptional repression.
Hormone binding is associated with a conformational change in the receptor which causes it to function as a transcriptional activator.
What does the thyroid hormone receptor do in the absence of T3 and T4?
Binds to DNA and represses transcription of specific genes
How does thyroid hormone enter cells?
Thyroid hormone transporters
(Even though it is lipophilic, transporters are required to regulate which cells thyroid hormone affects otherwise a very high concentration of thyroid hormone would have to be present int he blood)
How is thyroid hormone transported in the bloodstream?
Thyroxine binding globulin (TBG)
Oestrogens increase the synthesis of TBG during pregnancy. This produces a decrease in the amount of T3 and T4 in the circulation as more is bound. How does the level of free T3 and T4 return to normal?
Inhibitory feedback of T3 and T4 on the pituitary and hypothalamus is removed
More TRH and TSH is produced so the thyroid gland secretes more T3 and T4.
As a result, the amount of free T3 and T4 returns to normal but the total amount in the blood is increased
Give some examples of genes that are activated by thyroid hormone.
PEPCK
Ca2+ ATPase
Na+/K+ ATPase
Cytochrome oxidase
Do goitres occur in hyperthyroidism or hypothyroidism?
Either
What clinical significance does a goitre have?
It shows that the thyroid gland is being overstimulated
Give some symptoms of hypothyroidism.
Obesity but decreased appetite Lethargy Intolerance to cold Bradycardia Dry skin Alopecia Hoarse voice Constipation Slow reflexes
What would the levels of T3, T4 and TSH be in hypothyroidism?
Low T3
Low T4
Elevated TSH
What is the most common form of hypothyroidism?
Hashimotos disease
What is Hashimotos disease?
Autoimmune disease where antibodies for thyroglobulin and thyroid peroxidase are present in the blood. Hashimoto’s disease may be associated in the early stages with a small diffuse goitre (due to inlammation) or the thyroid may never enlarge and shrink in size from the beginning of the disease
Most common disease of the thyroid gland
Goitre may or may not be present.
Low T3 and T4. Elevated TSH
What is the treatment of Hashimotos disease?
Oral thyroid hormone- dose is adjusted depending on patients signs and symptoms
T4 used as it has a longer half life
What are the symptoms of hyperthyroidism?
Weight loss but increased appetite Irritability Heat intolerance, warm sweaty hands Tachycardia- heart beat is often irregular Fatigue Possible tremor of outstretched hand Hyper-reflexive Breathlessness Loss of libodo
What is grave’s disease?
Antibodies (thyroid stimulating immunoglobulin TSI) are produced which stimulate the TSH receptors on follicle cells
- This results in increased production and release of T3 and T4
- TSH levels fall due to negative feedback exerted by T3 and T4 on the anterior pituitary gland
- This does not affect thyroid hormone secretion since the stimulus for thyroid hormone release is from TSI rather than TSH
What is the treatment for graves disease?
Carbimazole - inhibits the enzyme thyroid peroxidase so prevents coupling and iodination of tyrosine residues on thyroglobulin
What are the levels of T3, T4 and TSH in Graves’ disease?
High T3
High T4
Low TSH
Can thyroid hormone be administered orally?
Yes
What is the most common way for the thyroid gland to be imaged?
Technetium-99m is used for isotope scanning of the thyroid with a gamma camera
It has a biological half-life of approximately 1 day so radiation exposure is low
What is carbimazole converted to in the body?
What does it do?
It is a pro-drug which is converted to methimazole in the body.
Prevents thyroid peroxidase from coupling and iodinating tyrosines on thyroglobulin.
Does carbimazole have a delayed or immediate effect? Why?
Delayed because there are stores of T3 and T4 present bound to TBG in the blood and attached to thyroglobulin in the thyroid colloids
The two lobes of the thyroid gland are joined by a structure called the…
Isthmus
The parafollicular cells within the thyroid gland secrete which substance?
Calcitonin
What is thyroxine?
T4
Tetraiodothyronine
Thyroid hormone secreted from the thyroid gland is mostly in what form?
T4
The release of thyroid hormone from the thyroid gland is triggered by which hormone?
TSH
Where is TSH released from?
Anterior pituitary gland
Which form of thyroid hormone has the longest half life?
T4
In what molar range is thyroxine found in the plasma?
Picomolar (10-12)
What attaches the thyroid gland to the trachea and larynx?
Pre-tracheal fascia
How does the thyroid gland move on swallowing?
Moves up
When someone’s airway is blocked, where in the trachea can a hole be made in order to get air into the trachea?
Between the thyroid cartilage and cricoid cartilage
What is a lingual thyroid?
Part of the thyroid gland remains at the floor of the pharynx during development and does not descend through the thyroglossal duct.
When does a thyroglossal duct cyst move up?
On tongue protrusion
Where would you find a thyroglossal duct cyst?
It would appear as a swelling in the anterior neck directly in the midline of the neck because the thyroid descends through the thyroglossal duct in the midline during development.
It is usually near or within the body of the hyoid.
What causes a thyroglossal duct cyst?
The thyroglossal duct normally disappears but remnants of epithelium may remain and form a thyroglossal duct cyst.
What is a pituitary adenoma?
A benign tumour of glandular epithelial tissue
Hypothetically, a problem with the hypothalamus, anterior pituitary gland or thyroid gland could cause metabolic thyroid disease as all of these tissues produce hormones that influence the release of T3 or T4.
What is usually the cause of metabolic thyroid disease?
Primary abnormality of the thyroid gland itself
It is very rare for a pituitary adenoma to produce TSH and lead to thyrotoxicosis.
True or false
True
Pituitary failure nearly always presents with isolated hypothyroidism.
True or false.
False.
It very rarely does.
What is the difference between thyrotoxicosis and hyperthyroidism?
Thyrotoxicosis is where there is excess T3 and T4 whereas hyperthyroidism is where there is over activity of the thyroid gland. Hyperthyroidism can lead to thyrotoxicosis.
Why can TSH level be used as a screening test for hyperthyroidism or hypothyroidism?
98% of cases of hyper/hypothyroidism are caused by a primary abnormality of the thyroid gland.
This leads to increased or decreased levels of plasma T3/T4 which has a negative feedback effect on secretion of TSH from the normally functioning anterior pituitary gland.
In hyperthyroidism, there are elevated plasma levels of T3/T4 and low plasma levels of TSH.
In hypothyroidism, there are low plasma levels of T3/T4 and elevated plasma levels of TSH.
Levels of which hormone are used as a screening test for hyperthyroidism and hypothyroidism?
TSH
Why does the thyroid gland move up on swallowing?
It is invested by the pre-tracheal fascia
An autoimmune disease affecting the islet of Langerhans causes which disease?
Type 1 diabetes
Which autoimmune disease causes hypothyroidism?
Hashimoto’s disease
Which autoimmune disease causes hyperthyroidism?
Grave’s disease
Which autoimmune disease affects the adrenal glands?
Addison’s disease
Is goitre more common in males or females?
Females
When is it possible to get a physiological goitre?
Menarche - first occurrence of menstruation
Pregnancy
Menopause
What is the most commonest causes of a goitre?
Iodine deficiency
Multinodular goitre - most common in UK
Why does iodine deficiency cause a goitre?
Reduced thyroxine levels lead to increased TSH which leads to generalised thyroid enlargement. This is usually nodular.
Severe cases may develop hypothyroidism
What is a Derbyshire neck?
Goitre caused by iodine deficiency
Multinodular goitre causes hyperthyroidism.
True or false.
False.
Normal thyroid function.
although after many years, a small number may develop hyperthyroidism (toxic multinodular goitre). Aetiology unknown.
Why is iodine deficiency a particular concern during pregnancy?
If a mother is iodine deficient and hyperthyroid then the foetus is also iodine deficient. This leads to a child with: • Mental retardation • Abnormal gait • Deaf-mutism • Short stature • Goitre • Hypothyroidism
What happens if a multinodular goitre enlarges inferiorly into the superior mediastinum?
Retrosternal multinodular goitre. This may cause tracheal compression.
Menorrhagia is a symptom of hyperthyroidism or hypothyroidism?
Hypothyroidism
Carpal tunnel syndrome and loss of outer third of eyebrows is seen in hyperthyroidism or hypothyroidism?
Hypothyroidism
Myxoedema is a sign of…
Hypothyroidism
Peaches and cream face is a sign of…
Hypothyroidism
How is hypothyroidism treated?
Oral thyroid hormone - dose is adjusted depending on the patient’s signs and symptoms. T4 used as it has a longer half life. Adjust dose to normalise serum TSH.
How can you differentiate between anxiety and hyperthyroidism?
Anxiety = cold sweaty hands Hyperthyroidism = warm sweaty hands
What would proximal myopathy present as?
Patient struggles to get out of chair
What is lid lag and staring eyes a sign of?
Thyrotoxicosis
Why do people with hyperthyroidism have staring eyes and lid lag?
Levator palpebrae superioris muscle is 90% skeletal and 10% smooth. The smooth muscle portion is supplied by the sympathetic nervous system. Over stimulation of this leads to staring eyes and lid lag
What are the signs of Grave’s disease in addition to the signs of thyrotoxicosis?
Exophthalmos - staring eyes alone
Pre-tibial myxoedema
What are the treatment options for hyperthyroidism?
- Carbimazole - inhibits the enzyme thyroid peroxidase so prevents coupling and iodination of tyrosine residues on thyroglobulin, reducing the production of T4
- Thyroidectomy- Surgical excision of thyroid
- Ablative dose of radioactive iodine to kill thyroid off
What are the causes for hypothyroidism?
- hashimoto’s disease
- severe iodine deficiency
- post surgical removal of thyroid with inadequate thyroxine replacement
What are the causes for hyperthyroidism?
- grave’s disease
- toxic multinodular goitre
- toxic adenoma
How does thyroid cancer present?
Thyroid nodule
Do thyroid cancers cause hypothyroidism or hyperthyroidism?
Neither
Which thyroid abnormality can cause metabolic dysfunction without a goitre?
Hashimoto’s disease
What thyroid abnormalities can cause metabolic dysfunction and a goitre?
Grave’s disease
Toxic multinodular goitre
Toxic adenoma
Hashimoto’s disease
Which thyroid abnormalities only present with a goitre and no metabolic dysfunction?
Multinodular goitre
Iodine deficiency
Thyroid cancer
What proportion of plasma thyroid hormone (T3 and T4) is free in plasma?
Approximately 1%
A 44 year old female patient is shown to have normal plasma T3 and T4 but undetectable TSH. Which condition best describes this scenario?
Subclinical hyperthyroidism is characterised by a low or undetectable concentration of serum with T3 and T4 within normal range
What would the levels of T4 and TSH be in someone with dietary iodine deficiency?
Low T4
High TSH
What would the levels of T4 and TSH be in a patient with Graves’ disease?
High T4
Low TSH
Which drug is commonly associated with side effects that disrupt thyroid function?
Amiodarone - it is structurally similar to thyroxine so can disrupt thyroid function
What is the half life of T3 and T4 in plasma?
T3 = approx 1 day T4 = approx 5-7 days
