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

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Presentation on theme: "Thyroid Roger L. Bertholf, Ph.D. Associate Professor of Pathology Director of Clinical Chemistry & Toxicology Roger L. Bertholf, Ph.D. Associate Professor."— Presentation transcript:

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

2 Thyroid hormones Tetraiodothyronine (T 4, Thyroxine) 3,5,3´ Triiodothyronine (T 3 ) 3,3´,5´ Triiodothyronine (reverse T 3 )

3 Effects of thyroid hormones Calorigenic (  O 2 consumption) Growth, development, sexual maturation, CNS maturation  HR and contraction  Protein synthesis, C(H 2 O) n metabolism, lipid turnover  Sensitivity of  -adrenergic receptors to catecholamines Brain, retina, lungs, spleen, testes appear to be unaffected by thyroid hormones Calorigenic (  O 2 consumption) Growth, development, sexual maturation, CNS maturation  HR and contraction  Protein synthesis, C(H 2 O) n metabolism, lipid turnover  Sensitivity of  -adrenergic receptors to catecholamines Brain, retina, lungs, spleen, testes appear to be unaffected by thyroid hormones

4 TRH TSH T 4 (T 3 ) T 3 (rT 3 ) Regulation of thyroid hormones

5 Thyroid hormone production T1T1 T2T2 Thyroglobulin T4T4 T3T3 T3T3 T4T4 Iodide ( I - ) NIS * T4T4 T4T4 T4T4 TBG Alb TBPA I-I- ColloidFollicle TPO TSH (40X) * Sodium/Iodide Symporter protein

6 Thyroid hormone synthesis ThyroglobulinFree thyroxine

7 Peripheral T 4 metabolism

8 Peripheral thyroxine metabolism T 4 production is exclusively thyroidal 70-90% of T 3 is produced extrathyroidally 95-98% of rT 3 is produced extrathyroidally Most peripheral de-iodination occurs in the liver T 3 accounts for most of the thyroid hormone activity in peripheral tissues –3-4 times more potent than T 4 –Some researchers have questioned whether T 4 has any intrinsic biological activity –rT 3 is biologically inactive T 4 production is exclusively thyroidal 70-90% of T 3 is produced extrathyroidally 95-98% of rT 3 is produced extrathyroidally Most peripheral de-iodination occurs in the liver T 3 accounts for most of the thyroid hormone activity in peripheral tissues –3-4 times more potent than T 4 –Some researchers have questioned whether T 4 has any intrinsic biological activity –rT 3 is biologically inactive

9 Circulating thyroid hormones T4T4 T4T4 T4T4 TBG Alb TBPA T3T3 T3T3 T3T3 fT 4 (0.03%) fT 3 (0. 3%) 99.97% T % T 3 Only free hormone is active!

10 Affinities of thyroid binding proteins TBGAlb TBPA >>>>> 68% of T 4 80% of T 3 Low conc. (0.27  M) High affinity (K=10 10 ) 54 kDa 20% of T 4 11% of T 3 High conc. (640  M) Low affinity (K=10 5 ) 66 kDa 11% of T 4 9% of T 3 Low conc. (4.6  M) Low affinity (K=10 7 ) 15.5 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) T 4 autoantibodies  TBG –Genetic, NTI (HIV, hepatitis, estrogen- producing tumors, AIP), pregnancy, drugs  Prealbumin (TBPA) (euthyroid thyroxine excess) Albumin variant (familial dysalbuminemia hyperthyroxinemia) T 4 autoantibodies

12 Decreased protein binding  TBG –Genetic, NTI (NS), drugs, nephrosis  Prealbumin (TBPA)  TBG binding capacity (competing drugs such as salicylate and phenytoin)  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 T 4 and T 3 ) regulated by TSH 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 T 4 and T 3 ) 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 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 Peripheral T 4 T3T3 rT 3 T3T3 HealthySick

16 Sick Euthyroid Concentration  Phase of illness MildModerateSevereRecovery Normal range rT 3 TSH T3T3 fT 4 T4T4

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°” 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 I 2 therapy/exposure; surgical ablation –Congenital (1 per 3500 to 4000 live births) Iodine deficiency (most common worldwide) Hashimoto’s thyroiditis (most common in developed countries) –Autoimmune (α-TG or α-TPO) Non-goitrous causes –Radioactive I 2 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 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 diseaseTSHfT 4 T3T3 Sub-clinical  nl Early  nl 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 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 diseaseTSHfT 4 T3T3 Sub-clinical  nl T 3 toxicosis  nl  Classic pattern 

23 Summary of thyroid autoantibodies AutoantibodyTarget antigenHTGD 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 EffectDrugsTSHfT 4 T3T3 Inhibit TSH secretiondopamine, glucocorticoids  Inhibit synthesisiodine, lithium  Inhibit T 4  T 3 amiodarone, propranolol glucocorticoids  Inhibit protein bindingsalicylate, NSAIDs phenytoin, carbamazepine nl 

25 Laboratory Evaluation of Thyroid Function TSHEuthyroid nl ND  Hyperthyroid? Borderline Hypothyroid? fT 4 if N, T 3 fT 4, T 3 TRH? fT 4


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