chapter 9 - thyroid Flashcards
active thyroid hormones
T3 more active than T4 but most output is T4, but target tissues convert T4 to T3
only difference between two structures is iodine atom
also a reverse T3 that has no biological activity
follicular epithelial cells
synthesize thyroid hormones
arranged in circular folicles
have basal membrane facing blood and apical membrane facing follicular lumen
make colloid
colloid
made by thyroid follicular epithelial cells
secreted into lumen
newly synthesized thyroid hormones attached to thyroglobulin
secretion of colloid
when gland stimulated, colloidal thyroid hormone absorbed into follicular cells by endocytosis
features of thyroid hormone synthesis (3)
1: need large amounts of iodine from diet
2: partially intercellular and partially extracellular - completed hormones stored extracellularly until secretion stimulated
3: major secretory product (T4) not most active form of hormone
steps in thyroid hormone biosynthesis
1: thyroglobulin made in rough ER and golgi of thyroid follicular cells
2: thyroglobulin incorporated into secretory vesicles and extruded across follicular lumen
3: I- is pumped into cell by I-/Na+ cotransporters
4: at apical membrane, I- is oxidized to I2 by thyroid peroxidase
5: thyroid peroxidase now catalyzes the combination of I2 with thyroglobulin - makes monoiodotyrosine (MIT) or diiodotyrosine (DIT)
note: MIT and DIT still attached to thyroglobulin
6: thyroid peroxidase now catalyzes either the combination of two DIT molecules to make D4 or one DIT and MIT to make T3 (D4 reaction faster) - stored as colloid
note: some MIT and DIT does not get converted and so remains attached to thyroglobulin as MIT and DIT
7: gland stimulated and iodinated thyroglobulin endocytosed into follicular endothelial cells by pseudopods
8: microtubules transport thyroglobulin to basal membrane
9: thyroglobulin droplets fuse with lysosomal membranes
10: lysosomal proteases hydrolyze peptide bonds to release T3, T4, MIT and DIT
11: T3 and T4 transported across basal membrane into nearby capillaries
12: MIT and DIT remain in cell and are recycled - deiodinationed by thyroid deiodinase - I- added to intercellular pool
thyroid peroxidase
enzyme that catalyzes the oxidation of I- to I2, the combination of I2 with thyroglobulin (formation of MIT and DIT), and the coupling of MIT and DIT to make T3 and T4
inhibited by propylthiouracil (PTU)
propylthiouracil (PTU)
blocks thyroid peroxidase
effective treatment for hyperthyroidism
Wolff-Chaikoff effect
when high levels of I- inhibit organification and synthesis of thyroid hormones
I-trap
the Na/I cotransporter
in blood side membrane of follicular epithelial cells
transports I- and Na+ into cell against both chemical and electrical gradients
regulated by I- levels in the body - low levels stimulate - so if dietary deficiency will work to compensate, but if there’s a severe deficiency won’t be able to keep up and there will be a reduction in thyroid hormone production
competitively inhibited by anions thiocyanate and perchlorate
thyroid deiodinase
removes iodine from MIT and DIT in follicular epithelial cells
allows iodine to be salvaged
deficiency in this enzyme will mimic dietary I- deficiency
perichlorate
inhibits Na/I cotransporter
will reduce iodine uptake and so thyroid hormone production
thiocyanate
inhibits Na/I cotransporter
will reduce iodine uptake and so thyroid hormone production
thyroxine-binding globulin (TBG)
protein that most T3 and T4 binds to in circulation
come circulates unbound and some binds to albumin and prealbumin
changes in blood levels can alter the fraction of free (and so physiologically active) thyroid hormones
hepatic failure and thyroid hormone levels
blood levels of TBG decrease because there’s decreased hepatic protein synthesis
results in a transient increase in level of free thyroid hormones
results in inhibition of synthesis of thyroid hormones
pregnancy and thyroid hormone levels
high level of estrogen inhibits hepatic breakdown of TBG, increases TBG levels
high TBG means that more thyroid hormone is bound to TBG and less is free and unbound
increased level of synthesis and secretion but low levels of active hormone = clinically euthyroid
T3 resin test
way to indirectly assess levels of TBG
measures binding of radioactive T3 to a synthetic resin
add standard amount of radioactive T3 to an assay system that has a sample of patient’s serum and the T3-binding resin
radioactive T3 will bind to unoccupied sites on patient’s TBG and any leftover radioactive T3 will bind to the resin
so T3 resin uptake associated with amount of TBG present and endogenous T3 levels
5’-iodinase
enzyme that converts T4 to T3 by removing one atom of I2
also convert portion of it to reverse T3 (rT3) - inactive
inhibited in starvation in skeletal muscle and other tissue but not in brain
5’-iodinase during starvation
inhibited in most tissues - lowers O2 consumption and basal metabolic rate
but brain 5’ iodinase not inhibited so brain levels of T3 are protected
regulation of thyroid hormone production
hypothalamus releases TRH
activates anterior pituitary release of TSH
activates thyroid gland release of T4 and T3
T4 and T3 have negative feedback effect on anterior pituitary
stimulatory factors for thyroid hormone
TSH
Thyroid stimulating inmmunoglobulins
increases TBG levels (like during pregnancy)
inhibitory factors for thyroid hormone secretion
I- deficiency
deiodinase deficiency
excessive I- intake (Wolff-Chaikoff effect)
Perchlorate, thiocyanate (inhibit Na/I cotransport)
propylthiouracil (inhibits peroxidase enzyme)
decreased TBG levels (liver disease)
TRH
secreted by parventricular nuclei of hypothalamus
acts on thyrotrophs of anterior pituitary to stimulate transcription of TSH gene and secretion of TSH
also stimulates secretion of prolactin by the anterior pituitary
TSH
glycoprotein
secreted by anterior lobe of pituitary in response to stimulation by TRH
regulates growth of thyroid gland and secretion of thyroid hormones
begins being secreted around gestational week 13 - same time that fetal thyroid gland begins secreting thyroid hormones
regulation of TSH secretion
regulated by:
1: TRH from the hypothalamus (stimulates)
2: thyroid hormone, mediated by T3 - anterior lobe contains thyroid deiodinase (inhibit)
actions of TSH on the thyroid gland
binds receptor coupled to adenylyl cyclase via Gs protein
generates cAMP
results in:
1: increased secretion and synthesis of thyroid hormones by stimulating each step of the biosynthetic pathway
2: trophic effect on gland - raised for extended periods of time results in hypertrophy and hyperplasia of thyroid follicular cells and increased thyroidal blood flow
thyroid stimulating immunoglobulins
activate TSH receptor on thyroid cells - antibodies to the receptor
IgG
one example = graves’ disease
Graves’ disease
form of hyperthyroidism
due to increased circulating levels of thyroid-stimulating immunoglobulins
get high circulating levels of thyroid hormones
lower TSH levels than usual because TSH has negative feedback effect on its secretion
get hypertrophy of the thyroid gland
actions of thyroid hormones
growth: growth formation bone maturation CNS: maturation of the CNS BMR: increases Na/K ATPase activity increases O2 consumption increases heat production increases BMR metabolism increases glucose absorption increases glycogenolysis increases gluconeogenesis increases lipolysis increases protein synthesis and degradation (net catabolic) cardiovascular increases cardiac output
rT3 levels
normally tissues make about equal amounts of T3 and rT3
but pregnancy, fasting, stress, hepatic and renal failure, and beta-adrenergic blocking agents all decrease conversion to T3 and increase conversion to rT3 => decrease in amount of active hormone
T3 actions in cell
binds to nuclear receptor in nucleus
T3-receptor complex binds to regulatory element on DNA
stimulates DNA transcription
effects of thyroid hormone on BMR
increases O2 consumption => increase in BMR and body temperature
in all tissues except brain, gonads and spleen
does so by inducing the synthesis of Na/K ATPase
effects of thyroid hormone on metabolism
increase glucose absorption from GI tract and potentiate effects of other hormones on glyconeogenesis, lipolysis, and proteolysis
increase both protein synthesis and degradation but the overall effect is catabolic (degradation) => loss of muscle mass
done via increased synthesis of metabolic enzymes including cytochrome oxidase, NADPH cytochrome C reductase, alpha-glycerophosphate dehydrogenase, malic enzyme, some proteolytic enzymes
thyroid hormone effects on cardiovascular and respiratory systems
increase O2 consumption so create higher demand for O2
to allow for this, also create increase in cardiac output and ventiallation
increase HR and increase contractility (so increase stroke volume) by inducing synthesis of cardiac beta1-adrenergic receptors - mediate effects of sympathetic nervous system
also induce synthesis of cardiac myosin and sarcoplasmic reticulum Ca2+ ATPase
thyroid hormone effect on growth
required for growth to adult stature
act synergistically with growth hormone and somatomedins to promote bone formation
promote ossification and fusion of bone plates and bone maturation
thyroid hormone effects on CNS
age dependent:
- in perinatal period: essential for normal maturation of CNS
hypothyroidism results in irreversible mental retardation, but if detected in newborn can be treated
- in adults:
hypothyroidism causes listlessness, slowed movement, somnolence, impaired memory, decreased mental capacity
hyperthyroidism causes hyperexcitability, hyperreflexia and irritability
thyroid hormone effects on autonomic nervous system
synergistic effects with catecholamines on heat production, cardiac output, lipolysis and gluconeogenesis - beta-adrenergic blocking agents can treat symptoms of hyperthyroidism
effects on BMR, heat production, HR, and SV similar to those produced by catecholamines via beta-adrenergic receptors
symptoms of hyperthyroidism
increased basal metabolic rate weight loss negative nitrogen balance increased heat production sweating increased cardiac output dyspnea (shortness of breath) tremor, muscle weakness exophthalmos goiter
symptoms of hypothyroidism
decreased basal metabolic rate weight gain positive nitrogen balance decreased heat production cold sensitivity decreased cardiac output hypoventilation lethargy, mental slowness drooping eyelids myxedema growth retardation mental retardation (if perinatal) goiter
causes of hyperthyroidism
Graves’ disease
thyroid neoplasm
excess TSH secretion
exogenous T3 or T4
causes of hypothyroidism
thyroiditis (autoimmune or Hashimoto's thyroiditis) surgery for hyperthyroidism I- deficiency congenital (cretinism) decreased TRH or TSH
TSH levels in hyperthyroidism
decreased - due to feedback inhibition of T3 on the anterior lobe
but if defect is in the anterior pituitary, levels will be increased
TSH levels in hyperthyroidism
increased by negative feedback if primary defect is in the thyroid gland
decreased if defect is in hypothalamus or anterior pituitary
treatment for hyperthyroidism
propylthiouracil - inhibits peroxidase enzyme and thyroid hormone synthesis
thyroidectomy
131I- destroys thyroid
beta-adrenergic blocking agents (adjunct therapy)
treatment for hypothyroidism
thyroid replacement therapy
diagnosis of hyperthyroidism
if cause is Graves’ disease, thyroid neoplasm, or exogenous administration of thyroid hormones then TSH levels decreased by negative feedback of T3 on anterior pituitary
if cause is increased secretion of TRH or TSH then TSH levels will be increased
goiter
enlargement of thyroid gland
happens in both hyperthyroidism and hypothyroidism
in hypothyroidism when cause is in the thyroid - due to unrelenting stimulation of the thyroid gland by high levels of TSH
thyroiditis
autoimmune destruction of the thyroid gland
antibodies either destroy gland or block synthesis of thyroid hormone
diagnosis of hyperthyroidism
decreased levels of T3 and T4
if defect is in thyroid gland, will have increased TSH
if defect in hypothalamus or pituitary, TSH levels decreased
myxedema
increased filtration of fluid out of the capillaries and edema due to accumulation of osmotically active mucopolysaccharides in interstitial fluid
cretinism
form of growth and mental retardation caused by hypothyroidism during the perinatal period that is untreated
irreversible but can be treated at birth if detected
