PBL 9 Flashcards
What is the structure of a thyroid follicle?
Thyroid epithelial cells surrounding a colloid cavity
Each thyroid follicle is surrounded by a network of capillaries
What are the 3 main hormones released by the thyroid gland?
Thyroxine (T4)
Triidothyronine (T3)
Calcitonin
Which is the major protein secreted into the colloid of follicle cells?
Thyroglobulin
How do iodine ions enter thyroid epithelial cells
They are actively transported on a Na+/I- transporter
This is stimulated by TSH
What is the function of pendrin?
Transporter which moves I- ions into the colloid
How are iodine ions converted into their active form in the colloid?
By thyroid peroxidase
How is thyroglobulin converted into thyroid hormones
Thyroglobulin tyrosine resides bind to I+ ions in colloid by covalent bonds Addition of 1 iodine to tyrosine = MIT Addition of 2 iodine to tyrosine = DIT MIT + DIT = T3 DIT + DIT +T4
How is thyroglobulin taken up back again by epithelial cells and broken down into thyroid hormones?
Taken up by endocytosis into epithelial cells
Lysosome enzymes break down thyroglobulin into the different thyroid hormones
What is the majority of thyroid hormone released into the blood?
What is the percentage?
T4
90%
Which is the more active thyroid hormone?
T3 (triiodothyronine)
What is the majority of thyroid hormones bound to once they enter circulation?
Thyroid binding globulins (TBGs)
Apart from TBG, what other carrier plasma proteins can thyroid hormones bind to?
Transthyretin
Albumin
What is the half life of T4 and T3?
T4: 5-7 days
T3: 1-3 days
Why is the half life of T4 longer than T3?
Because T4 has a much higher affinity to plasma binding proteins, therefore it is released much more slowly into the tissues
How do thyroid hormones affect the transcription of genes?
Thyroxine is deionised to T3 in target cells
T3 binds to nuclear hormone receptor which makes heterodimer with RXR on DNA
This initiates transcription of genes
How is thyroid hormone production controlled by the hypothalamus?
Hypothalamus secretes thyrotropin releasing hormone (TRH)
TRH acts on anterior pituitary gland to stimulate secretion of thyroid stimulating hormone (TSH)
TSH binds to TSH receptors on basal membrane of thyroid cell
This increases production of cAMP which has intrasignalling effects causing production of thyroid hormones
What intracellular effects does TSH have on thyroid cells?
Increased proteolytic action of thyroglobulin to release thyroid hormones
Increased activity of iodine pump
Increased iodination of tyrosine
Increase size and secretion of thyroid cells
Increased number of thyroid cells
What is the HPT axis
Hypothalamus
Pituitary
Thyroid
How is the HPT axis negatively controlled
Increased levels of T3 in the blood lead to:
- inhibition of TRH from hypothalamus
- inhibition of TSH from anterior pituitary gland
What do the C cells of the thyroid secrete?
Calcitonin
How are calcium levels controlled by calcitonin and parathyroid hormone?
Calcitonin - decreases Ca2+ plasma concentration
Parathyroid hormone - increases Ca2+ plasma concentration
How does Calcitonin decrease plasma calcium levels?
Inhibits osteoclasts - slows the rate of calcium release from bone
Stimulates kidney excretion of calcium
How does parathyroid hormone increase the plasma levels of calcium?
Inhibits osteoblasts - reduces calcium deposition in bone
Trigger RANK L - increases osteoclasts numbers to increase calcium release from bones
Enhance calcium reabsorption in kidney
Increases calcitrol levels - which help to enhance calcium reabsorption
What is the most common cause of autoimmune hypothyroidism?
What happens in it?
Hashimoto disease
Where antithyroid antibodies lead to lymphoid infiltration and destruction of the gland
What is postpartum thyroiditis?
Where you get transient hypothyroidism following pregnancy due to modifications in the immune system
What are the major signs and symptoms of hypothyroidism?
Weight gain Fatigue Cold intolerance Mentally slowed Dry, brittle thinning hair
What results in a thyroid function test are indicative of hypothyroidism?
Raised TSH
Low free T4
What kind of anaemia is associated with hypothyroidism?
Normochromatic and normocytic (normal colour and normal size)
How is hypothyroidism treated?
With levothyroxine (T4 supplements)
Why is T4 given instead of the more active T3 in treatment for hypothyroidism?
T4 has a longer half life so only need to be taken once a day
What are the main causes of hyperthyroidism?
Graves' disease - autoimmune disease Toxic nodule Pituitary adenoma Excess iodine Medication De Quervain's thyroiditis
What is the pathophysiology of Graves’ disease
TSH receptor autoantibody’s are produced
These stimulate the Thyroid hormone receptor
This stimulates production of thyroid hormone even in the absence of TSH
What are the consequences of Graves’ disease in pregnancy?
Fetal hyperthyroidism
Due Placental crossing of the TSHR
Even if mother has been treated, IgG may still be present to stimulate the fetal thyroid
What are the major signs and symptoms of hyperthyroidism?
Weight loss Heat intolerance, sweating Irritability Increased appetite Palpitations Fatigue, weakness
How can Grave’s Disease lead to orbitopathy (thyroid eye disease)?
The same TSH receptor autoantibodies can cross react with things in the eye
This leads to inflammation of the extraocular muscles, causing increased retrorbital pressure
What are the results of a thyroid function test that suggest hyperthyroidism?
Low TSH - due to negative feedback
Raised T4
Raised T3 (sometimes)
TPO and thyroglobulin antibodies
How is carbimazole used to treat Graves’ disease?
Inhibits the action of TPO autoantibody
Inhibits the formation of thyroid hormone
Why does it take 10-20 days to see a clinical benefit from carbimazole?
High half lives of existing T4/T3
It reduces the hormone production
What drug can be taken to rapidly relieve the symptoms of Graves’ disease?
Beta blocker
How is radioiodine used to treat Grave’s Disease?
Radioactive iodine is taken orally
131 Iodine destroys the surrounding Thryoid tissue
This decreases thyroid hormone production
What are the major risks in thyroidectomy
Damage to the laryngeal nerves
What are all steroid hormones derived from?
Cholesterol
Which enzyme is present in the Zona glomerulosa to determine production of aldosterone?
3B-hydroysteroid dehydrogenase (HSDB2)
Which enzyme is present in the Zona fasciculosa to determine production of cortisol?
11B-hydroxylase (CYP11B1)
Which enzyme is present in the Zona reticulosa to determine production of sex steroid precursors?
CYP17A1
How does the HPA axis control cortisol release?
Hypothalamus releases corticotrophin releasing hormone (CRH)
CRH acts on anterior pituitary causing it to release adrenocorticotrophin hormone (ACTH)
ACTH acts on the adrenal cortex in the Zona fasciculosa causing it to release cortisol
What is cortisol converted to in peripheral tissues and how?
Cortisone
By the enzyme HBD11B2
What is Conn Syndrome?
This is hyperaldosteronism (too much aldosterone produced) due to a tumour in the adrenal cortex
What is the major symptom of Conn syndrome and why?
Hypertension due to excess aldosterone
This causes retention of sodium in the kidneys, leading to water retention and increased blood volume
What is Cushing syndrome?
Excessive cortisol secretion
What are the major causes of Cushing syndrome?
Medication - steroids
Adrenal tumour
Pituitary tumour (Cushing syndrome)
Ectopic tumour (small cell lung cancer)
What are the main symptoms of Cushing syndrome?
Round face with purple plethora Central obesity Weight gain Purple stretch marks on abdomen (abdominal striae) Muscle waisting and thin extremities Diabetes
Why would taking cortisol levels at night help to diagnose Cushing syndrome?
In Cushing syndrome there is loss of circadian rhythm
Control levels should be low at night, if high this is suggestive of cortisol disease
Why would you give an overnight dexamethasone dose to help diagnose Cushing syndrome?
Dexamethasone is similar to cortisol and so suppresses ACTH release by negative feedback
This should inhibit cortisol production
In the morning cortisol should be low - if not then this is suggestive of cushing syndrome
How would ACTH levels help to distinguish the cause of endogenous cushing syndrome?
Adrenal tumour - low ACTH
Cushing disease (pituitary tumour) - slightly high ACTH
Ectopic ACTH secreting tumour (lung) - very high ACTH
How would a high dose dexamethasone suppression test help to distinguish between a pituitary tumour and an ectopic ACTH secreting tumour?
High dose of Dexamethasone would:
- turn off pituitary tumour slightly to lower ACTH
- have no effect on ectopic lung cancer which would still continue to pour out ACTH
How do you treat Cushing syndrome?
Exogenous - reduce steroid medication dose
Endogenous - remove tumour by surgery
What is Addison’s disease?
Primary adrenal insufficiency
Where the adrenal gland isn’t able to produce as much hormones as the body requires - particularly aldosterone and cortisol
What is the most common cause of hypoadrenalism in developing countries?
TB
Spreads from the lungs to the adrenal cortex
What are the symptoms of Addison’s disease?
Nausea and vomiting
Feeling weak and tired
Hyperpigmentation of the skin - due to raised melanocytes stimulating hormone (MSH), which is produced by the ACTH precursor
How is Addison’s disease diagnosed?
ACTH stimulation test (short synachten test) - synthetic ACTH is given and the cortisol and aldosterone levels are measured to see how the adrenal glands are working
What is pheochromocytoma?
A rare neuroendocrine tumour of the medulla of the adrenal glands (within chromaffin cells)
What are the symptoms of pheochromocytoma?
Hypertension
Throbbing bilateral headaches
Palpitations
What is the calorigenic effect?
The role of thyroid hormone to increase basal metabolic rate and heat production, by turning on genes concerned with glucose oxidation
What are the sides effects of carbimazole?
Greanylocytopenia
Headaches, nausea
Jaundice
Joint pain & rashes
What are the cells called that secrete parathyroid hormone?
Chief Cells
What is the function of thyroid peroxidase (TPO) enzyme?
To convert iodine to iodine in the follicular lumen
