thyroid Flashcards
hypothyroidism: list the causes of hypothyroidism, recall the clinical features, explain diagnosis, recall types of thyroid hormone replacement and their limitations
what 2 things does the healthy adult thyroid gland secrete
T3 and T4
what is T4 (thyroxine; tetraiodothyronine) and what is its fate
prohormone converted by deiodinase enzyme into more active metabolite tri-iodothyronine (T3)
relative proportions of T3 in circulation
80% from T4 deiodination, 20% from direct thyroidal secretion
what does T3 provide in target cells compared to other thyroid secretions
almost all thyroid hormone activity which increased basal metabolic rate
how do T3 and T4 cause altered gene expression in target cells
T3 and T4 enter target cells via channels -> any T4 that has entered is converted to T3 by deiodinase -> T3 binds to a retinoid x receptor (RXR) and thyroid hormone receptor (TR) -> this complex binds to a thyroid response element (TRE) on DNA -> altered gene expression
2 drugs used in thyroid hormone replacement therapy
levothyroxine sodium, liothyronine sodium
what does levothyroxine sodium mimic
T4 (drug of choice); converted in target cells to T3
what does liothyronine sodium mimic
T3 (less commonly used)
when is levothyroxine sodium (T4) used clinically
primary hypothyroidism, secondary hypothyroidism
when treating primary hypothyroidism, how is levothyroxine sodium (T4) administered and and what is used as a dose guide
by oral administration, suppressing TSH into reference range through negative feedback (TSH used as guidance for dose)
2 causes of primary hypothyroidism (myxoedema), and effect on thyroxine and TSH levels
autoimmune damage to thyroid or iatrogenic (post-thyroidectomy, post-radioactive iodine); thyroxine levels decline, TSH levels climb (used to diagnose)
hypothalamic pituitary thyroid axis
TRH released from hypothalamus -> TSH released from anterior pituitary -> causes thyroid to make T3 and T4 -> both have direct negative feedback on pituitary and indirect negative feedback on hypothalamus
3 causes of secondary hypothyroidism and effect on TSH
pituitary tumour, post-pituitary surgery, radiotherapy; low TSH as effect upstream of thryoid
when treating secondary hypothyroidism, how is levothyroxine sodium (T4) administered and what is used as a dose guide
by oral administration; as TSH is low to due anterior pituitary failure, can’t use TSH as dose guide so must aim for fT4 (free T4) in middle of reference range
what is a very rare complication of hypothyroidism
myxoedema coma
what is used to treat myxoedema coma
initially i.v. liothyronine sodium (T3) as onset of action is much faster than T4, then oral when possible
significance of T3 replacement vs T4 replacement
T4 converted to T3 by deiodinase enzyme which then has effect, so T4 administered normally as less expensive and same effect
outcomes of combined thyroid hormone replacement (combination of T4 and T3; very expensive)
some reported improvement in well-being, but complicated by symptoms of ‘toxicity’ as too much thyroid hormone: palpitations, tremor, anxiety (often combination treatment suppresses TSH)
2 pharmacokinetic features of thyroid hormone replacement therapy drugs
active orally, long half-life
plasma half-life of levothyroxine (T4) and liothyronine (T3)
levothyroxine (T4): 6 days; liothyronine (T3): 2.5 days
what is 99.97% of circulating T4 and 99.7% of circulating T3 bound to
plasma proteins, mainly thyroxine binding globulin (TBG)
what version of thyroid hormone is available to tissues (biologically active)
free, unbound fraction
when do plasma binding proteins increase (3)
in pregnancy, on prolonged treatment with oestrogens and phenothiazines
when does thyroxine binding globulin fall (2)
malnutrition and liver disease
what co-administered drugs compete with thyroid hormone replacement therapy drugs for protein binding sites, increasing concentration of fT4
phenytoin, salicylates
T3 and T4 synthesis pathway: what 3 things does TSH stimulate thyroid follicles to do
synthesis and release of protein hormone thyroglobulin and enzyme thyroporoxidase into the colloid from apical membrane; iodide uptake from blood and release into colloid; uptake and transport of T3 and T4 by lysozymes from the colloid into the blood (appears as a white dot in colloid in histology)
T3 and T4 synthesis pathway: how is iodide taken up from blood into follicular cells
through NIS (sodium/iodide active cotransporter), then oxidated to I2
T3 and T4 synthesis pathway: in the nucleus what is incorporated into thyroglobulin
tyrosyl residues
T3 and T4 synthesis pathway: what happens within the colloid
iodination of tyrosine in thyroglobulin to form mono/di-iodotyrosine, catalysed by thyroporoxidase and H2O2
T3 and T4 synthesis pathway: what is the coupling reaction
where mono/di-iodotyrosine are coupled to form T3/T4, catalysed by thyroporoxidase and H2O2
clinical signs and symptoms of hypothyroidism
dry and brittle hair; lethargy and depression; memory impairment; oedema of face and eyelids; thick tongue and slow speech; deep coarse voice; feel cold; diminished perspiration; enlarged heart (cardiomegaly) so poor heart sounds and precordial pain; bradycardia; hypertension; coarse, dry, scalin, cold, yellowish skin; slow pulse; ascites; menorrhagia; weight gain with reduced appetite; constipation; eventual myxoedema coma
