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Thyroid. Roger L. Bertholf, Ph.D. Associate Professor of Pathology Director of Clinical Chemistry & Toxicology. Thyroid hormones. Tetraiodothyronine (T 4 , Thyroxine). 3,5,3 ´ Triiodothyronine (T 3 ). 3,3 ´,5´ Triiodothyronine (reverse T 3 ). Effects of thyroid hormones.

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thyroid

Thyroid

Roger L. Bertholf, Ph.D.

Associate Professor of Pathology

Director of Clinical Chemistry & Toxicology

thyroid hormones
Thyroid hormones

Tetraiodothyronine

(T4, Thyroxine)

3,5,3´ Triiodothyronine

(T3)

3,3´,5´ Triiodothyronine

(reverse T3)

effects of thyroid hormones
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
thyroid hormone production

T1

T2

T4

T3

T3

T4

Thyroglobulin

Thyroglobulin

T4

T4

T4

TBG

Alb

TBPA

Thyroid hormone production

Follicle

Colloid

TPO

Iodide (I-)

NIS*

I-

(40X)

Thyroglobulin

TSH

*Sodium/Iodide Symporter protein

thyroid hormone synthesis
Thyroid hormone synthesis

Thyroglobulin

Free

thyroxine

peripheral thyroxine metabolism
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

T3

T4

TBG

T3

Alb

T4

T4

T3

TBPA

Circulating thyroid hormones

99.97% T4

fT4 (0.03%)

fT3 (0. 3%)

Only free hormone is active!

99.7% T3

affinities of thyroid binding proteins
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

increased protein binding
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
decreased protein binding
Decreased protein binding
  •  TBG
    • Genetic, NTI (NS), drugs, nephrosis
  •  Prealbumin (TBPA)
  •  TBG binding capacity (competing drugs such as salicylate and phenytoin)
thyroglobulin tg
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
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
Sick Euthyroid

Healthy

Sick

T3

T3

Peripheral T4

rT3

rT3

sick euthyroid1
Sick Euthyroid

rT3

TSH

Normal

range

fT4

Concentration 

T4

T3

Mild

Moderate

Severe

Recovery

Phase of illness

hypothyroidism
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
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
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
hyperthyroidism thyrotoxicosis
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
laboratory evaluation of thyroid function
Laboratory Evaluation of Thyroid Function

nl

TSH

Euthyroid

ND

Hyperthyroid?

Hypothyroid?

Borderline

fT4

if N, T3

fT4, T3

TRH?

fT4