Endo 1.08 The thyroid gland

• Gross anatomy and histology of the thyroid gland

• Thyroid hormone synthesis

• Thyroid hormone secretion, peripheral conversion and metabolism

• Measurement of free T4 and TSH

• Actions of thyroid hormones, hyper-and hypothyroidism

Blood supply

Superior and inferior thyroid arteries from external carotids and subclavian arteries respectively

Superior, middle and inferior thyroid veins

More blood per unit weight than kidney - goitre bruit

20 grams

4 cm

Histology of the thyroid gland

Thyroid hormones derived from two iodinated tyrosine molecules

Synthesis of thyroid hormones

• Active uptake of iodide into follicular cell

• Iodide iodine - H2O 2 (catalysed by TPO)

• Active uptake of iodine at follicular/ colloid interface

• Incorporation of iodine onto tyrosine residues of thyroglobulin

• Coupling of iodinated tyrosines

• Storeage of T3 and T4

Active transport of iodine (ATPase dependent) against electrical and chemical gradient - concentration of

iodine 30-50 times that of the circulation

• Active uptake of iodine by a sodium iodide symporter

• Oxidation of iodide to iodine

• Iodination of tyrosine residues at apical/colloid interface to form MIT and DIT

• Uptake of thyroglobulin into the lumen of the follicle

Incorporation of iodine onto tyrosine residues on the thyroglobulin molecule

4) Release of T4 and T3 into circulation -

100g T4 & 10g T3/day

3) ~ 10% T4 undergoes mono-deiodination to T3 before secretion

2) Fusion of colloid droplets with lysosomes --> hydrolysis and release of thyroid hormones

1) Stimulated by TSH colloid droplets with the bound thyroid hormones are taken back into follicular cells by pinocytosis

Daily production of thyroid hormone

secretion and serum

concentrations

5’ 5

3’ 3

5’

5Thyroid hormone

metabolism

Metabolism of thyroid hormones

Series of deiodinations by deiodinasesType 1 - liver, kidney, thyroid, pituitary gland,

CNS: 5’ and 5 positions

Type 2 - brain, brown fat, placenta, pituitary gland: 5’ position only: T4 T3 only: intracellular concentrations of T3

Type 3 - brain, placenta: 5 position only

T4 T3

Other metabolic pathways: sulphation, decarboxylation, conjugated with glucuronide

Thyroxine (T4)

T3rT3

T3 S

TRIAC

T2T2

other pathways

T1 T1

thyronine

1 & 2 1 & 3

3,5,3’ 3,5’,3’

Type 1 - 5’ and 5

Type 2 - 5’ only

Type 3 - 5 only

Control of thyroid hormone synthesis

and release and feedback control

TSH Receptors

TSH

G protein linked receptor

cAMP IP3 + DAG

Protein Ca2+ Protein Kinase A CM Kinase

C(high concentrations)

Actions of TSH

• Active uptake of iodine*

• Stimulates other reactions involved in thyroid hormone synthesis

• Stimulates the uptake of colloid

• Induces growth of the thyroid gland

Thyroid hormone receptors

Thyroid hormone receptors

• Type 2 receptors in nucleus - high affinity for T3

• Dimerize with another T3 receptor (homodimer) or retinoic acid receptor (heterodimer)

• Dimerized receptor + other transcription factors gene transcription

• Membrane receptors? Ion movements

Isoforms of the thyroid hormone receptor

DBD

DBD

DBD

DBD

T3

Dimerization of thyroid hormone receptors and gene activation/inactivation

Functions of thyroid hormonesStimulate metabolic rate: increasing number and

size of mitochondria, increasing enzymes in the

metabolic chain, increasing Na+/K+ ATPase activity.

Resting metabolic rate may increase 100% with

excess thyroid hormones or decrease by 50% with a

deficiency

Positive inotropic and chronotropic effects on

the heartImportant in growth and development -

particularly skeleton and nervous system

Feedback control of

thyroid hormone

synthesis and secretion

Radioisotopic (technetium) scanning of the thyroid gland - regional function of the gland

No left lobe hyperthyroidism

hypothyroidism

Hot noduleCold nodule

Measuring ‘free’ T4

1) Add serum sample or standard (T4 ) to latex beads coated with Abs

2) Add T4 labelled with alkaline phosphatase. This will bind to any unoccupied Ab binding sites

3) Add a substrate that will fluoresce when the alkaline phosphatase removes a phosphate group

4) Fluorescent intensity will be inversely proportional to the concentration of T4

Phosphate

Assay of antibodies to the human TSH receptors

Patients serum Add Precipitate Count + TSH 125I-TSH

receptors (bovine) (porcine)

Circulating concentrations of TSH and pituitary function test in normal and primary hyperthyroidism

Saggital MR scans of a) normal and b) a patient with a craniopharyngioma causing bitemporal hemianopia and

hypopituitarism

Primary hyperthyroidism Hypothyroidism

Grave’s disease (10)

• Autoimmune - activating AB’s to TSH receptor

• High concentrations of circulating thyroid hormones, low TSH

• Weight loss, tachycardia, tiredness

• Diffuse goitre - TSH stimulating growth

• Opthalmompathy and dermopathy

Symptoms and signs of hyperthyroidism

Hashimoto’s (1o)

• Autoimmune - AB’s destruction of thyroid gland

• Low concentrations of thyroid hormones, high TSH

• Lethargy, intolerance to cold

• Lack of growth and development

• Diffuse goitre - lymphocytic infiltration of gland + TSH stimulated growth

Symptoms and signs of hypothyroidism