Download Thyroid

Thyroid
Roger L. Bertholf, Ph.D.
Associate Professor of Pathology
Director of Clinical Chemistry & Toxicology
Thyroid hormones
NH3+
NH3+
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+
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
5'-(3'-) Deiodinase
Type I or II
OH
I
5-(3-) Deiodinase
Three types
CH2
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
nl
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