Thyroid Flashcards
What is the structure of the thyroid gland?
follicular. cells create follicles that are filled with thyroglobulin. cells secrete t3 and t4
What do parafollicular cells secrete?
calcitonin
What does thyroglobulin contain?
iodide - approx enough for 90 day supply
What is the HPA pathway for thyroid regulation?
Hypothalamus releases thyrotropin releasing hormone (TRH)
A. pituitary (pituitary thyrotropes) releases Thyroid stimulating hormone (TSH)
thyroid gland produces more T3 and T4
What are the negative feedback loops in thyroid regulation?
sufficient T3 and T4 inhibit production of TRH and TSH (only T3 acts on hypothalamus)
What is the difference between T3 and T4?
T4 is far more abdundant, but T3 is more active - T4 is a storage facility and is readily converted to T3 when required
T4 has a much longer half life
What effect does TSH have directly on the thyroid gland?
enlargement of thyroid to increase activity
What types of hormones at T3 and T4?
thyronine hormones
TSH action on thyroid gland receptors?
TSH receptors on follicular cells are GPCRs
- activation of adenylyl cyclase which produces cAMP
- cAMP activates all functional aspects of thyroid cell -
What are the functional aspects of the thyroid cells?
thyroglobulin synthesis, iodide pumping, iodination by peroxidase, endocytosis, proteolysis and hormone release
What are the steps of iodide transport in follicular cells?
Na+ and I- symporter actively transports iodide across basolateral membrane from blood into cells
(Na+ then pumped out by Na+/K+ pump)
Iodide then transported from cells into follicle lumen via pendrin transporter (exchanges chloride for iodide)
iodide then oxidised to Iodine
How is thyroglobulin made?
synethsised in endoplasmic reticulum of follicular cells, then secreted (exodytosis) into follicle
Why is thyroglubulin made up of?
A Tg backbone and tyrosine molecules
What makes up the thyroid peroxidase complex (TPO)?
Tyrosine peroxidase enzyme and iodine
What does the TPO complex do?
covalently bind iodine to the tyrosine residues
produces mono- or di-iodotyrosine
How are T3 and T4 produced?
conjugating two molecules of MIT / DIT
2 x DIT makes `t4, DIT then MIT makes T3
THe order of steps of thyronines production?
- iodination of tyrosine
- conjugation
- endocytosis into follicular cell
- proteolysis - cleavage from thyroglobulin
- released into bloodstream
Another name for T4?
thyroxine
What is reverse T3?
inactive. reverse tri-iododothyronine
less than 1% of all thyronines
What drugs are used to treat hypothyroidism?
levothyroxine (T4) - tablets and oral solution
liothyronine (T3) - tablets and slow iv injection
What anti-thyroid drugs are available?
carbimazole (brand name neo-mercazole) - tablets
propylthyrouracil - tablets
block synthesis of thyroid hormones
How is T4 transported in the blood and why?
insoluble in serum, so travels bound to proteins
How can liver disease lead to thyroid related problems?
transport proteins are synthesised in liver, so not enough can lead to loss of effective T4 transport to peripheral tissues
How much thyroid hormone does Thyroxine binding globulin (TBG) bind, and what is the half life?
70-75% of plasma T4, as well as T3
T1/2 = 5 days
large circulating T4 resevoir, and prevents loss of T4 in urine
How much thyroid hormone does Transthyretin bind, and what is the half life?
20% of plasma T4, no T3
half life 2-3 days
important for CNS delivery
How much thyroid hormone does albumin bind?
5-10% of plasma T4, and 30% of T3
What are the benefits of protein bound thyroid hormones?
- transport
- prolongs availability of T4 to tissues
- buffer effects of altered T4 secretion from thyroid
- can control delivery of T4 to tissues (rate etc)
How do the thyroid hormones enter cells?
must be unbound
through specific transporters (e.g. MCT8, MCT10, OATP1c1)
How is T4 converted to T3 to become more active?
intracellular iodothyronine deiodinases
What are iodothyronine deiodinases made of?
seleno-cysteine containing enzymes, selenium accepts iodine
How many iodothyronine deiodinases are there?
3 - DIO1, DIO2 and DIO3
What is DIO1?
found mostly in liver, kidney and muscle (as well as thyroid)
produces most of the circulating T3
What is DIO2?
found mostly in CNS areas and pituitary thyrotropes
controls intracellular T3, important for feedback regulation
What is DIO3?
produces inactive (reverse) T3
prevents thyroid hormone access to certain tissues
How do the thyroid hormones exert an effect once inside a cell?
- bind to thyroid hormone receptors (A or B) found in the nucleus, heterodimered with retinoid X receptor (RXR)
- binds to thyroid responsive element (DNA sequences)
- transcription factor, or can inhibit
thyroid receptors have 15x higher affiniy for T3 than T4
What effects can T3 exert on the pituitary?
gene that codes for growth hormone is T3 responsive, as is the one that codes for decreased prolactin and less TSH (feedback loop)
What is the importance of maintaining calcium levels in tthe body?
- growth/maintenance of skeletal system
- neurotransmitter release
- muscle contraction
- hormone secretion
- blood clotting
- intracellular signalling
- apoptosis
What are examples of calcium rich foods?
dairy, broccoli, almonds, flax, sesame, kale etc
avoid alcohol and smoking as these can inhibit absorption
What regulates calcium levels?
Calcitonin and parathyroid hormone
vitamin D and extracellular calcium concentration are also important factors
Which parts of the body play a large role in the calcium in the body?
Bone, gut and kidneys
What is the role of the kidneys in the body’s calcium levels?
filtration and reabsorption
the kidneys excrete around 200mg calcium every day
What is the role of the gut in the bodys calcium levels?
adsorption of calcium into blood, or secretion.
gut is responsible for uptake of calcium from external sources
What happens when calcium regulation is abnormal?
disease
What do osteoblasts do?
BUILD BONE
use plasma Ca and other minerals
What do osteoblasts do?
BUILD BONE
use plasma Ca and other minerals
What do osteoclasts do?
break down bone (crush) by demineralising
critical for maintenance and repair of bones
What diseases are related to defective calcium homeostasis?
- primary/secondary (renal failure) hyperparathyroidism
- osteoporosis
- rickets
- calcium stones
- receptor mutations (PTH receptor, calcium receptors etc)
what type of hormone is calcitonin?
protein (32 amino acids)
Where is calcitonin produced?
parafollicular cells in the thyroid
found between the follicles
What is the half life of calcitonin?
5 minutes
What is the function of calcitonin?
Reduce blood calcium levels
- opposes effects of parathyroid hormone
Where is the parathyroid?
glands attached to the back of the thyroid - 4 of them
What are the two types of cells in the parathyroid glands?
chief cells (few in number) oxyphil cells (many, unknown function)
What do chief cells in the parathyroid do?
produce parathyroid hormone
What is the structure of parathyroid hormone? half life?
helical protein, 84 amino acids
half life 20 mins
What is the function of parathyroid hormone?
increase blood calcium levels
How are low blood calcium levels detected?
the calcium sensing receptors (CaSR) - a GPCR
What effect does parathyroid hormone have on the body?
- stimulate osteoclasts to release more calcium from bones (indirectly), resorption (PTH + Vit D)
- increase renal calcium reabsorption (PTH + Vit D)
- PTH also stimulates vit D activation in kidneys
- increase production of vitamin D, which helps improve intestinal absorption of calcium
What is the parathyroid hormone feedback loop?
INcrease in blood calcium reduces secretion of PTH
What is important to note about impact of PTH on bones?
Intermittent PTH causes bone formation
What effect does calcitonin have on the body?
Reduce osteoclast acitivity (reduced bone resorption), allows rapid bone deposition by osteoclasts
What is the calcitonin feedback loop?
decreased blood calcium decreases calcitonin secretion, and reduces bone formation
Connection between calcitonin levels and disease?
Effects of calcitonin are minor, and high or low levels do not cause disease
Which cells are responsible for the action of PTH on bone resorption?
A substance released from osteoblasts in response to PTH causes osteoclasts to release calcium from bone
In which gland does primary thyroid disease occur?
Thyroid
In which gland does secondary thyroid disease occur?
Pituitary
In which gland does tertiary thyroid disease occur?
Hypothalamus
What are the causes of primary hypothyroidism?
- Autoimmune (Hashimoto’s thyroiditis)
- previous treatment for hyperthyroidism
- iodine imbalance (uncommon in UK)
- congenital hypothyroidism
Symptoms of hypothyroidism?
lethargy, cold, memory loss, weight gain, gruff voice, depression, constipation, hair loss, dry skin
What markers can be tested to look for primary hypothyroidism?
TSH and unbound T4 - also thyroid peroxidase antibody but rarely measured outside secondary care
primary hypothyroidism has high TSH and low T4
Treatment options for someone symptomatic with high (5-10) TSH and normal T4?
trial 3-6 months thyroxine
if symptoms resolved: lifelong treatment
if symptoms not resolved, consider alternate diagnoses (thyroid peroxidase antibody check)
Treatment options for someone asymptomatic with high (5-10) TSH and normal T4?
check thyroid peroxidase antibody
positive: check thyroid hormones annually
negative: check thyroid hormones every 3 years
Treatment options for someone with high (5-10) TSH and low T4?
treat with lifelong thyroxine
Treatment options for someone with v high (10+) TSH, with or without low T4
treat with lifelong thyroxine
Half life of T4?
7 days
Initial dose of thyroxine treatment in adults under 50?
initially 50-100 mcg thyroxine daily, adjusted 25–50mcg every 3–4 weeks according to response
Initial dose of thyroxine treatment in adults over 50, or in heart disease?
initially 25mcg once daily, adjusted 25mcg every 3–4 weeks according to response
Initial doses of thyorxine treatment for congenital hypothyroidism?
initially 10-15 mcg/kg for neonates (max 50 mcg), adjusted 5 mcg/kg
How soon after starting treatment should TSH be re-measured?
8-12 weeks
What is the usual maintenance dose for thyroxine treatment for adults?
100-200mcg
What is the usual maintenance dose for thyroxine treatment for children?
50-200mcg
age dependent
What should be monitored during ongoing thyroxine treatment?
TSH - should be in lower half of reference range
lack of symptoms
also monitor for angina
When is liothyronine used in combination with thyroxine?
rarely - only by endocrinologist. meta-analysis shows no obvious benefit
What counselling points are important for patients taking thyroxine?
single daily dose, taken for life
don’t take at the same time as calcium or iron preps
there are three strengths of tablet - do not confuse
importance of regular monitoring
medical exemption
What causes most cases of hyperthyroidism?
Grave’s disease (autoimmune)
How does grave’s disease cause hyperthyroidism?
The body produces antibodies to the TSH receptor, which stimulate the gland
What is the prevalence of Grave’s disease?
2% of women, 0.2% of men
causes 3 of 4 hyperthyroidism cases
What are symptoms of hyperthyroidism?
- anxious, tremor
- tachycardia, palpitations
- weight loss
- goitre
- prefers cold weather
- warm clammy skin
What tests are done to diagnose hyperthyroidism?
TSH and unbound T4
low TSH and high T4 indicate hyperthyroidism
What are the treatment options for hyperthyroidism?
drug treatment, radioactive iodine, surgery
none are ideal - patient choice where possible
What patient groups is drug therapy for hyperthyroidism preferred for?
children, pregnancy/breastfeeding, uncomplicated disease in young adults, acute phase before surgery
How do thionamide drugs work?
e.g. carbimazole , propythiouracil
inhibit coupling of iodotyrosines etc
What is the normal regimen for carbimazole?
15-40mg daily (severity depending, can be higher)
maintain 4-8 weeks until TFTs normal
maintenance for 12-18 months: reduce by 20-30% each month until 5-15mg daily
What is the blocking replacement regimen for carbimaole
40-60mg for 4 weeks
then add thyroxine 50-100mcg (makes patient hypothyroid temporarily)
continue for -18 months ish
thyroid function returns to normal when stop medication
What is important with carbimazole in pregnancy?
Blocking replacement regimen is not suitable - high doses can be dangerous for fetus
- crosses placenta
What is the equivalent of carbimazole and propythiouracil?
1mg carbimazole = 10mg propythiouracil
What are the inital and maintenance doses and regimens of propythiouracil ?
200-400mg daily initially, divided doses
maintenance 50mg three times a day
What is important with propythiouracil in pregnancy?
potentially slightly safer but unknown
When is propythiouracil used?
carbimazole not tolerated/agranulocytosis
What is drug induced agranulocytosis?
carbimazole and propythiouracil can both cause bone marrow suppression
reduced white cell count leads to infection
occurs in 0.3-0.5% of cases, not dose dependent
What counselling points are important for hyperthyroid patients?
- frequency of dosing difference
- tapering to maintenance dose
- signs of agranulocytosis (sore throat, bruising, mouth ulcers, any infection sign)
- signs of hepatic dysfunction
- need for regular tests
- management of relapse
When is radioactive iodine treatment indicated for hyperthyroidism?
failure of treatment, relapse or toxic nodular goitre
When is surgery indicated for hyperthyroidism?
oesophageal obstruction, intolerance to drugs, young age
Why should radioiodine and surgery not be used in the acute stage of disease?
can cause thyrotoxic crisis (thyroid storm) - excessive release of thyroid hormones when damaging the gland, can be fatal
What adjuvant therapies are used in hyperthyroidism treatment?
beta-blockers to reduce CNS symptoms
multiple daily dosing due to increased metabolism
usually only needed in initial stages when still symptomatic
What drugs can cause drug-induced thyroid disease?
iodine, amiodarone, lithium
How can iodine cause drug-induced thyroid disease?
overdose from radiographic media
acute phase- inhibit release
prolonged- suppression of production
can cause thyrotoxicosis if problem with autoregulation
iodine deficiency can cause hypothyroidism
How does amiodarone cause hypothyroidism?
can cause inhibition of release of T3 and 4
usually continue amiodarone and use T4 replacement therapy if needed
How does amiodarone cause hyperthyroidism?
contains iodine
MILD: blocks conversion of T4 to T3, so increase of TSH and T4
usually resolves itself in a few months after starting treatment
SEVERE: increased T4 production (due to iodine) - direct thyroiditis.
should withdraw therapy if possible, or use carbimazole
How does lithium cause hypothyroidism?
inhibits iodine uptake and prevetns release of T3 and 4
can be transient and sub-clinical, so monitor TSH and start therapy if it becomes clinical
How can lithium cause hyperthyroidism?
rare, paradoxical effect
