Thyroid - Bertholf Home Page
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Thyroid
Roger L. Bertholf, Ph.D.
Associate Professor of Pathology
Director of Clinical Chemistry & Toxicology
Thyroid hormones
HC
COO-
HC
I
I
HC
I
I
OH
Tetraiodothyronine
(T4, Thyroxine)
I
I
O
I
OH
COO-
CH2
O
O
I
COO-
CH2
CH2
I
NH3+
NH3+
NH3+
I
OH
3,5,3´ Triiodothyronine 3,3´,5´ Triiodothyronine
(T3)
(reverse T3)
Effects of thyroid hormones
• Calorigenic ( O2 consumption)
• Growth, development, sexual maturation, CNS
maturation
• HR and contraction
• Protein synthesis, C(H2O)n metabolism, lipid
turnover
• Sensitivity of -adrenergic receptors to
catecholamines
• Brain, retina, lungs, spleen, testes appear to be
unaffected by thyroid hormones
Regulation of thyroid hormones
TRH
TSH
T4
(T3)
T3
(rT3)
Thyroid hormone production
TPO
Iodide
(I-)
NIS*
I(40X)
Follicle
T1
Colloid
T2
Thyroglobulin
T3
T4
TBG
T4
T4
Alb
Thyroglobulin
T3
Thyroglobulin
T4
TSH
TBPA
*Sodium/Iodide
Symporter protein
T4
Thyroid hormone synthesis
OH
OH
I
OH
OH
I
I
Tyrosyl
residue
TPO
TPO
CH2
CH2
I
I
Thyroglobulin
protease
I
I
CH2
CH2
HOOC
Thyroglobulin
I
O
O
I
-
I
I
NH2
Free
thyroxine
Peripheral T4 metabolism
OH
I
I
O
I
I
5'-(3'-) Deiodinase
OH
5-(3-) Deiodinase
Three types
CH2
Type I or II
I
OH
I
HOOC
NH2
40%
I
45%
T4
O
O
I
I
I
CH2
HOOC
CH2
NH2
T3
HOOC
NH2
reverse T3
Peripheral thyroxine metabolism
•
•
•
•
•
T4 production is exclusively thyroidal
70-90% of T3 is produced extrathyroidally
95-98% of rT3 is produced extrathyroidally
Most peripheral de-iodination occurs in the liver
T3 accounts for most of the thyroid hormone
activity in peripheral tissues
– 3-4 times more potent than T4
– Some researchers have questioned whether T4 has any
intrinsic biological activity
– rT3 is biologically inactive
Circulating thyroid hormones
99.97% T4
T3
T4
TBG
T3
T4
Alb
T3
fT4 (0.03%)
fT3 (0. 3%)
T4
TBPA
99.7% T3
Only free hormone is active!
Affinities of thyroid binding proteins
TBG
68% of T4
80% of T3
>>>
Low conc. (0.27 M)
High affinity (K=1010)
54 kDa
TBPA
11% of T4
9% of T3
Low conc. (4.6 M)
Low affinity (K=107)
15.5 kDa
>>
Alb
20% of T4
11% of T3
High conc. (640 M)
Low affinity (K=105)
66 kDa
A small fraction of thyroid hormones is bound to lipoproteins
Increased protein binding
• TBG
– Genetic, NTI (HIV, hepatitis, estrogenproducing tumors, AIP), pregnancy, drugs
• Prealbumin (TBPA) (euthyroid thyroxine
excess)
• Albumin variant (familial dysalbuminemia
hyperthyroxinemia)
• T4 autoantibodies
Decreased protein binding
• TBG
– Genetic, NTI (NS), drugs, nephrosis
• Prealbumin (TBPA)
• TBG binding capacity (competing drugs
such as salicylate and phenytoin)
Thyroglobulin (Tg)
• 660 kd protein that is the intra-thyroidal
carrier of thyroid hormones
• Synthesized in the thyroid follicular cells;
secreted into the lumen
• Stored mostly in the colloid
• Synthesis, colloidal uptake, and proteolysis
(to release T4 and T3) regulated by TSH
Thyrotropin (TSH)
• One of several hormones synthesized in the
anterior pituitary
– Others are LH, FSH, Prolactin, ACTH, GH
– (common with LH, FSH, hCG) and subunits
• MW=30 kDa
• Binds to a TSH receptor on the thyroid
follicular cells to activate adenylyl
cyclase/cAMP protein kinase A and Ca++
protein kinase C pathways
Sick Euthyroid
Healthy
Sick
T3
T3
Peripheral T4
rT3
rT3
Sick Euthyroid
Concentration
rT3
TSH
Normal
range
T4
fT4
T3
Mild
Moderate
Severe
Phase of illness
Recovery
Hypothyroidism
• A deficiency in thyroid hormone activity
– Occurrence as high as 15%, with ♀preference
– Myxedema is severe form
– Untreated congenital hypothyroidism results in
severe developmental deficits
• Can be structural or functional
– 1° = deficiency in thyroid hormone production
– 2° (or “central) = pituitary or hypothalamic failure
• Hypothalamic failure sometimes called “3°”
Primary Hypothyroidism
• Iodine deficiency (most common worldwide)
• Hashimoto’s thyroiditis (most common in
developed countries)
– Autoimmune (α-TG or α-TPO)
• Non-goitrous causes
– Radioactive I2 therapy/exposure; surgical ablation
– Congenital (1 per 3500 to 4000 live births)
Secondary Hypothyroidism
• Pituitary (TSH) or hypothalamic (TRH)
failure.
• Isolated TSH deficiency is rare; usually
associated with panhypopituitarism.
– Sheehan’s Syndrome
– Endocrine-inactive adenomas
– Other space-occupying lesions
Stages of Hypothyroidism
Stage of disease
TSH
fT4
T3
Sub-clinical
nl
nl
Early
nl
Mature
Hyperthyroidism (thyrotoxicosis)
• Increased thyroid hormone production
– Graves’ Disease (most common; α-TSH receptor)
– Toxic multi-nodular goiter
– Solitary toxic adenoma or pituitary adenoma
• Normal thyroid hormone production
– Thyroiditis (thyroid hormone leakage)
– Thyrotoxicosis facticia
– Metastatic thyroid carcinoma or struma ovarii
Stages of Hyperthyroidism
Stage of disease
TSH
fT4
T3
Sub-clinical
nl
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T3 toxicosis
nl
Classic pattern
Summary of thyroid autoantibodies
Autoantibody
Target antigen
Thyroid microsomal
autoantibody (TMA)
Thyroglobulin autoantibody
(TGA)
TSH receptor autoantibody
(TRAb)
Thyroid-stimulating
immunoglobulin (TSI)
Thyrotropin-binding inhibitory
immunoglobulin (TBII)
Thyroperoxidase
(TPO)
Thyroglobulin
(TG)
TSH receptor
TSH receptor
(agonist)
TSH receptor
(inhibitory)
HT GD
Effects of Drugs on Thyroid
Hormones
Effect
Drugs
TSH fT4 T3
Inhibit TSH secretion
dopamine, glucocorticoids
Inhibit synthesis
iodine, lithium
Inhibit T4 T3
amiodarone, propranolol
glucocorticoids
Inhibit protein binding
salicylate, NSAIDs
phenytoin, carbamazepine
nl
Laboratory Evaluation of Thyroid
Function
nl
ND
TSH
Hyperthyroid?
Euthyroid
Hypothyroid?
Borderline
fT4
if N, T3
fT4, T3
TRH?
fT4