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181

(Thyroid Gland)
- Scattered among follicular cells and in spaces between the spherical follicles which secrete calcitonin

Parafollicular Cells

182

(PARATHYROID GLAND)

– Produce PTH
– Small, polygonal, darkly staining, abundant cells
– Contain lakes of glycogen giving them a water clear appearance

Chief Cells

183

(PARATHYROID GLAND)

– Function unknown
– Large, light staining, fewer in numbers
– Only present at age 6 onwards

Oxyntic cells

184

Percentage synthesized: 93%
Half-life: More (6 days)
Affinity for binding plasma protein: More
Binding to nuclear receptor: Less (10% of the receptors)
Onset of Action: 4x slower (2 days)

T4

185

Percentage synthesized: 7%
Half-life: Less (1 day)
Affinity for binding plasma protein: Less
Binding to nuclear receptor: More (90% of the receptors)
Onset of Action: 4x faster (12 hours)

T3

186

Steps in Synthesis of Thyroid Hormones

1. Iodide trapping
2. Formation and secretion of thyroglobulin
3. Oxidation of iodine
4. Organification of thyroglobulin
5. Storage and secretion

187

- Basal membrane of the thyroid actively pumps iodide to the cell interior (Na-I symporter)
- Concentrates the iodide to about 30 - 250 times its concentration in the blood
- Stimulated by TSH

Iodide Trapping

188

- Thyroid cell endoplasmic reticulum and Golgi apparatus synthesize the glycoprotein thyroglobulin and secrete to the follicle colloid

Formation of Thyroglobulin

189

- Conversion of iodide to nascent iodine I0 or I3
- Promoted by PEROXIDASE and its accompanying hydrogen peroxide
- Peroxidase is located in the apical membrane of the cell or attached to it, so the iodine will be readily available
- When peroxidase is blocked or hereditarily absent, the rate of synthesis of thyroid hormone falls to zero

Oxidation of Iodine

190

- Binding of iodine to thyroglobulin
- Oxidized iodine is associated with IODINASE, which speeds up the binding
- Iodine binds with about 1/6 of the tyrosine molecules in thyroglobulin

“Organification” of Thyroglobulin

191

- successive stages of iodination of tyrosine
- COUPLING of iodotyrosine molecules
- may occur in a matter of minutes or even days

Final Formation of Thyroxine (T4) and Triiodothyronine (T3)

192

Release of Hormones from Thyroid Gland

- Apical surface of the cell sends out pseudopods to form pinocytic vesicles that engulf some colloid
- Lysozymes fuse with the vesicles which have proteases that digest thyroglobulin
- T4 and T3 will be in free form then diffuse to basal membrane into surrounding capillaries
- T4 and T3 now enter circulation

193

Fate of Thyroglobulin

- About ¾ of iodinated tyrosine will not become T3 or T4 and remain only as mono- or diiodotyrosine that are cleaved from thyroglobulin as well
- Iodine is cleaved from these through the DEIODINASE ENZYME, which makes all the iodine available again for hormone synthesis
- Congenital absence of deiodinase enzyme causes iodine deficiency due to failure of recycling

194

Daily Secretion of T4 and T3

- 93% of hormone released from thyroid is T4, only 7% is T3
- During ensuing days, T4 is slowly deiodinated to T3 which is more readily available in the tissues
- Delivery is about 35 micrograms of T3 per day

195

Transport of T4 and T3 to Tissues

1. Upon entering the blood, 99% of T4 and T3 bind to transport proteins secreted by the liver:
– Main: Thyroxine-binding globulin
– Less: Thyroxine-binding prealbumin and albumin
– Half of T4 is released to tissues in 6 days

2. Half of T3 is released to tissues in 1 day (due to lower affinity to binding proteins)
3. Upon entering tissues, T4 and T3 bind with intracellular proteins (T4 > T3 binding)
4. Hormones are stored and used slowly in the next few days or weeks

196

• Unique: can produce and store hormones for up to 3 months
↓TBG: liver & kidney disease
↑TBG: estrogen or pregnancy

Thyroid Hormone

197

FORMS OF THYROID HORMONE IN PLASMA

– Thyroxine Binding Globulin :70%
– Transthyretin or Thyroxine Binding Prealbumin : 20%
– Thyroxine Binding Albumin: 10%
– Free Thyroxine : 0.03%

198

Latency of Thyroid Hormones

- After injection of thyroxine to the blood, the basal metabolic rate only increases after 2 to 3 days
- Once activity begins, it lasts for 10-12 days then decreases with a half-life of 15 days
- Triiodothyronine has a latency of 6-12 hours
- Maximal cellular activity happens in 2-3 days
- Latency is due to binding to protein and their slow release and from how these are used in the cell

199

- Thyroid hormone receptors are located in the DNA
- Forms a heterodimer with retinoid X receptor (RXR) on DNA
- On binding with thyroid hormones, they initiate transcription and eventual translation into intracellular proteins
- Whole process takes about minutes to hours (explains latency)

Thyroid Hormones Activate Nuclear Receptors

200

Actions of Thyroid Hormones

- Increases O2 consumption and Basal Metabolic Rate (BMR) >> Increases mitochondria and Na-K-ATPase pump activity
- Stimulates carbohydrate, fat and protein metabolism
- Increases requirements for vitamins
- Increases blood flow, Cardiac Output, Heart Rate, Heart Strength

201

How does Thyroid Hormone stimulate carbohydrate, fat and protein metabolism?

- Increases glucose uptake, gluconeogenesis, glycogenolysis
Decreases cholesterol, phospholipids and triglycerides but increases fatty acids
- Increases cholesterol secretion to bile and number of liver LDL receptors
- Increase protein synthesis
- Needed for Growth

202

Actions of Thyroid Hormones

- Increases respiration
- Increases gastrointestinal motility
- Increases cerebration
- Increases muscle vigor (reason for Fine Muscle Tremors)
- Increases risk for somnolence
- Loss may cause loss of libido, impotence, menstrual changes

203

- Hyperthyroidism following administration of iodine or iodide, either as a dietary supplement or as contrast medium
- Typically occurs with comparatively small increases in iodine intake, in people who have thyroid abnormalities that cause the gland to function without the control of the pituitary

Jod-Basedow Effect

204

- Reduction in thyroid hormone levels caused by ingestion of a large amount of iodine
- Autoregulatory phenomenon that inhibits organification in the thyroid gland (inhibition of peroxidase), the formation of thyroid hormones inside the thyroid follicle, and the release of thyroid hormones into the bloodstream
- Lasts several days (around 10 days), after which it is followed by an "escape phenomenon“

Wolff-Chaikoff Effect

205

– Resumption of normal organification of iodine and normal thyroid peroxidase function
– Due to decreased inorganic iodine concentration secondary to down-regulation of sodium-iodide symporter (NIS) on the basolateral membrane of the thyroid follicular cell

Escape phenomenon

206

- Increased metabolic rate
- Excitability, restlessness
- Exophthalmos (sometimes but not always)
- Increased appetite but with weight loss, protein wasting and muscle weakness (thyrotoxic myopathy)
- Pre-tibial Myxedema (20% of patients)
- Tachycardia, increased Cardiac output
- Fine Tremors
- Diarrhea

Hyperthyroidism

207

- Decreased metabolic rate
- Slow thought process, poor memory
- Elevated plasma cholesterol and other lipids (atherosclerosis)
- Fatigue, increased somnolence, weight gain
- Whole body myxedema
- Prolonged relaxation phase of Deep Tendon Reflexes (DTRs)
- Hoarse voice
- Constipation

Hypothyroidism

208

– Autoimmune disease, anti-TSH receptor antibodies
– Classic Triad:
• Exophthalmos
• Goiter
• Pre-Tibial Myxedema

Graves Disease

209

– Plummer’s Disease
– Most common cause of hyperthyroidism in those >50 y.o.

Toxic Multinodular Goiter

210

– Results from congenital lack of thyroid gland, genetic defect of the thyroid gland or lack of iodine in the diet
– Skeletal growth

Cretinism