1. Thyroid Roger L. Bertholf, Ph.D. Associate Professor of Pathology
Director of Clinical Chemistry & Toxicology

2. Thyroid hormones Tetraiodothyronine (T4, Thyroxine)
3,5,3´ Triiodothyronine
(T3)
3,3´,5´ Triiodothyronine
(reverse T3)

3. 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

4. Regulation of thyroid hormones
TRH
TSH T4
(T3) T3
(rT3)

5. Thyroid hormone production
Follicle
Colloid
TPO T1 T2
Thyroglobulin
Iodide (I-)
NIS* I-
(40X) T4
TBG
Alb
TBPA T3 T4
Thyroglobulin T4 T3
Thyroglobulin
TSH
*Sodium/Iodide Symporter protein

6. Thyroid hormone synthesis
Thyroglobulin
Free
thyroxine

7. Peripheral T4 metabolism

8. 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

9. Circulating thyroid hormones
TBG
Alb
TBPA T3
fT4 (0.03%)
fT3 (0. 3%)
Only free hormone is active!
99.7% T3

10. Affinities of thyroid binding proteins
TBG
>>>
TBPA
>>
Alb
68% of T4
80% of T3
Low conc. (0.27 M)
High affinity (K=1010)
54 kDa
11% of T4
9% of T3
Low conc. (4.6 M)
Low affinity (K=107)
15.5 kDa
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

11. Increased protein binding
 TBG
Genetic, NTI (HIV, hepatitis, estrogen-producing tumors, AIP), pregnancy, drugs
 Prealbumin (TBPA) (euthyroid thyroxine excess)
Albumin variant (familial dysalbuminemia hyperthyroxinemia)
T4 autoantibodies

12. Decreased protein binding
 TBG
Genetic, NTI (NS), drugs, nephrosis
 Prealbumin (TBPA)
 TBG binding capacity (competing drugs such as salicylate and phenytoin)

13. 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

14. 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

15. Sick Euthyroid
Healthy
Sick T3 T3
Peripheral T4
rT3
rT3

16. Sick Euthyroid rT3 TSH Concentration  fT4 T4 T3 Phase of illness
Normal
range
fT4
Concentration  T4 T3
Mild
Moderate
Severe
Recovery
Phase of illness

17. 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°”

18. 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)

19. 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

20. Stages of Hypothyroidism
Stage of disease
TSH
fT4 T3
Sub-clinical  nl
Early 
Mature

21. 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

22. Stages of Hyperthyroidism
Stage of disease
TSH
fT4 T3
Sub-clinical  nl
T3 toxicosis 
Classic pattern

23. Summary of thyroid autoantibodies
Autoantibody
Target antigen HT GD
Thyroid microsomal autoantibody (TMA)
Thyroperoxidase (TPO) 
Thyroglobulin autoantibody (TGA)
Thyroglobulin (TG)
TSH receptor autoantibody (TRAb)
TSH receptor
Thyroid-stimulating immunoglobulin (TSI)
TSH receptor (agonist)
Thyrotropin-binding inhibitory immunoglobulin (TBII)
TSH receptor (inhibitory)

24. Effects of Drugs on Thyroid Hormones
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

25. Laboratory Evaluation of Thyroid Functionnl
TSH
Euthyroid ND  
Hyperthyroid?
Hypothyroid?
Borderline
fT4
if N, T3
fT4, T3
TRH?
fT4