B8.058 Prework 1: Thyroid Gland Flashcards
describe the H-P-T axis
hypothalamus > TRH anterior pituitary (thyrotropes) > TSH thyroid gland (thyrocytes) > thyroid hormones
importance of iodide
necessary for synthesis of thyroid hormones
minimum - 75 ug/day
recommended - 150 ug/day
where is iodide stored in the body
thyroid (8000 ug)
hormone pool, in circulation within T3 and T4 (600 ug)
primary steps in thyroid hormone synthesis and secretion
- stimulated by TSH
- uptake of iodide
- thyroglobulin: iodination, organification, and coupling
- secretion
composition of thyroid tissue
numerous follicles
- lined by thyrocytes (functional cells that make hormone)
- filled with colloid containing thyroglobulin
description and regulation of iodide uptake
active process: -achieved via Na/I symporter -requires energy regulation: -internal autoregulatory mechanisms -TSH drives iodide from blood into lumen of thyroid follicle
where is TPO found
membrane bound in lumen of follicle
TPO requirements for function
Tg (substrate)
iodide
H2O2 (NADPH oxidase)
what is thyroglobulin (Tg)
660 kD homodimer
regulated by TSH
contains 120-140 tyrosine residues
iodinated by TPO
function of TPO
responsible for iodination/organification and coupling of Tyr in Tg molecules
result of TPO
20-30 Tyr become iodinated
20-25% (6-8) of the MIT/DIT become coupled
stored in this form
secretion of thyroid hormone
stimulated by TSH
- pinocytosis
- lysosome fusion
- hydrolysis
- secretion
- deiodination
* *hormone is cleaved out of the Tg before moving into circulation
thyroid hormone in circulation
exist both in free and bound form
70-75% is bound to thyroid binding globulin (TBG)
<1% is free, but this amt is biologically important
describe TBG
made in the liver
high affinity for T4/T3
70-75% of T4/T3 is bound to TBG
increased expression of TBG
pregnancy
newborns
oral contraceptives (due to E)
decreased expression of TBG
androgens (anabolic steroids) large doses of glucocorticoids chronic liver disease severe systemic illness active acromegaly kidney disease with proteinuria
other thyroid binding proteins in circulation (not TBG)
transthyretin/thyroxine binding pre-albumin (TBPA) -10% of T4 albumin -low affinity -15% of T4/T3
T4 half life
8 d
T3 half life
1-3 d
conversion of T4
40% of secreted T4 is converted to T3 in the periphery (majority of what is secreted is T4)
30% of secreted T4 is converted to rT3 in the periphery
5’ Deiodinase
converts T4 to T3
type 1: thyroid, kidney, liver
type 2: pituitary, brain, brown adipos
5 Deiodinase
converts T3 to T2
converts T4 to rT3
inactivates hormone at target tissues
found in kidney, liver, skin, and placents
mechanism of propylthiouracil
inhibits type 1 5’ Deiodinase and TPO
used in hyperthyroidism to maintain T4 state (less potent)
potency of thyroid hormones
T3 > T4 (10x)
negative feedback of T4/T3 on HPT axis
- hypothalamus
- decreased TRH - pituitary
- predominant mechanism
- T4 conversion to T3 by type 2 5’DI
- decreases response to TRH by decreasing TRH-R expression
- decreases synthesis and secretion of TSH
why does a goiter form
iodide deficiency
leads to low thyroid hormone synthesis/secretion
increased activity in gland to attempt to stimulate production > larger gland
thyroid hormone receptors
nuclear; alter gene expression (slow)
- at least 6 types
- number is regulated (decreased by fasting)
- bind T3 with higher affinity than T4
- expressed in most tissues/cells
primary roles of thyroid hormone
regulate protein metabolism regulate glucose metabolism regulate lipid metabolism regulate basal metabolic rate (BMR) important during CNS fetal development
TH and protein metabolism
growth permissive effects
- stimulates GH expression (and IGF)
- stimulates metabolic proteins and enzymes (mitochondria)
- promotes calcification within cartilage
effect of EXCESS TH on protein metabolism
protein catabolism
TH and glucose metabolism
potentiated actions of insulin
-stimulates glycogen synthesis and glucose utilization
effect of EXCESS TH on glucose metabolism
reverse of normal effect
- increases glycogenolysis
- altered glucose utilization
- enhances actions of epinephrine via induction of B-AR expression
TH and lipid metabolism
stimulates cholesterol synthesis and also its conversion to bile (decreases cholesterol levels)
effect of EXCESS TH on lipid metabolism
increases lipolytic actions of other hormones
results in increased fat metabolism
effect of LOW TH on lipid metabolism
can lead to hypercholesterolemia
-regulates hepatic LDL-R
TH and basal metabolic rate (BMR)
regulates oxidative phosphorylation (Na+/K+ATPase)
- transcription and activity
- altered oxygen consumption and heat production
effect of LOW TH on BMR
can lead to a 50% decrease
effect of EXCESS TH on BMR
can increase BMR 80%
effect of TH on bone
stimulates linear growth and development and bone maturation (via GH)
effect of TH on skin & hair
required for normal follicle development and epidermis renewal
effect of TH on GI tract
can increase GI motility
effect of TH on the heart
regulates sensitivity of B1 receptors
increased CO by increasing HR and SV
excess TH will cause vasodilation
effect of TH on brain development
promotes dendritic branching
promotes proliferation of axons
promotes formation of synpases
regulates myelinization within the cortex
symptoms of hypothyroidism
weight gain cold intolerance decreased perspiration constipation bradycardia fatigue muscle stiffness depression dry skin and hair menstrual disturbances
symptoms of hyperthyroidism
weight loss heat intolerance increased sweating frequent BMs tachycardia and palpitations fatigue muscle weakness and hypotrophy increased excitability and nervousness moist skin and hair menstrual disturbances
assessment of thyroid hormone levels
TSH assay
total T4 or T3 assays
free T4
rT3 assay
other assessments of thyroid function
anti-thyroid Abs -TPO -thyroglobulin -TSI TBG assay (carrying capacity) RAIU and thyroid scans fine needle aspiration cytology
TRH test process
assess the responsiveness of pituitary thyrotropes to exogenous administration of TRH
outcomes:
1. excess TH > reduced response due to downregulation of the TSH receptor by TH
2. deficient TH > increased response due to upregulation of the TSH receptor from reduced TH negative feedback
characterize thyroid disorders in general
very common
women are affected more often than men (10:1)
causes of hypothyroidism
iodide deficiency congenital/cretinism non-thyroidal illness thyroiditis endemic goiter sporadic goiter
congenital hypothyroidism
deficiency in utero
mental and growth retardation (can be treated)
non-thyroidal illness (euthyroid sick syndrome)
shift in conversion of T4 from T3 to rT3 (inactive)
types of thyroiditis
- subacute - granulomatous (deQuervain)
- Reidel
- Hashimoto
subacute, granulomatous (deQuervain) thyroiditis
viral infection, URI
typically resolve over time
reidel thyroiditis
rare
fibrosis, calcification of gland
hashimoto thyroiditis
autoimmune disease that attacks/ destroys the thyroid gland
autoreactive T cells and Abs to thyroid antigens (TPO or Tg)
sporadic goiter
due to mutations in Tg or TPO
treatment of hypothyroidism
exogenous T4 (levothyroxine) -better than T3 because it has a longer half life and is less potent so there's not as much of a risk of overdose
etiologies of hyperthyroidism
Graves disease
adenomas of the thyroid gland
pituitary adenomas
thyrotoxicosis
what is Graves disease
autoimmune disease
thyroid stimulating immunoglobulins (TSI) directed against the TSH-R, inducing function
no negative feedback on TSH production
epidemiology of Graves
5:1 , F:M
60-80% of hyperthyroidism
most prevalent autoimmune disorder in the US
predisposing factors for Graves
sex (female)
stress
smoking
symptoms of graves
nervousness fatigue rapid heartbeat or palpitations weight loss 50% get ophthalmopathy (exophthalmos)
treatment of hyperthyroidism
radioactive iodine to destroy gland thyroidectomy (avoid parathyroid glands) antithyroid drugs -PTU -carbimazole/ methimazole
carbimazole/ methimazole mechanisms
TPO inhibition
hot thyroid nodules
functional - take up radiotracer
secrete thyroid hormone
-hyperthyroidism
ablate w radiotracer
cold thyroid nodules
nonfunctional- do not take up radiotracer
non-secretory
increased association with malignancy
-FNA cytology > surgery
primary hypothyroidism findings
T4 low
TSH high
secondary hypothyroidism findings
T4 low
TSH normal or low
