ERS08 Physiology Of Thyroid

Question 1

Thyroid gland

Answer 1

• one of largest endocrine gland
• C5-T1
• behind Sternohyoid + Sternothyroid
• wrap around Cricoid cartilage, superior tracheal ring
• Blood supply: Superior + Inferior thyroid arteries (ECA)
• Venous drainage: Superior + Middle + Inferior thyroid veins
• Highly vascular
• Ductless

Lobules of gland:
- Follicles (structural unit of thyroid)
—> each follicle lined by simple layer epithelium by ***Principal cells surrounding colloid-filled core
—> colloid: Iodinated thyroglobulin (precursor to thyroid hormones)

Principal cells:

• Colloid, thyroid hormones production
• Functionally polarised, each side of membrane has specific function (synthesis of thyroid hormones + release)

Parafollicular cells (C cells):
- Calcitonin production

Blood capillaries:

• deliver Iodine to Principal cell
• carry thyroid hormones away from gland

Question 2

Hormones from Thyroid gland

Answer 2

1. Calcitonin
   - Parafollicular cells
   - ***Peptide hormone (32 a.a.)
   - Regulation of Ca metabolism (esp. blood Ca level)
2. Triiodothyronine (T3)
3. Thyroxine (T4)

• from Thyroglobulin (134 Tyrosine residues)
• Principal cells
• from 2x Tyrosine a.a. —> bind covalently to ***Iodine
• ***Peptide hormone
• ***Poorly water-soluble —> bound to carrier protein in blood
• Growth, development, control of body temp, energy levels through control of basal metabolic processes

Iodine:

• seafood, seaweed, dairy food (min 150 µg / day, higher requirement in pregnancy)
• taking KI with ACE inhibitor, K-sparing diuretics —> ↑ risk of hyperkalaemia

Question 3

***Calcitonin

Answer 3

• Peptide hormone
• Synthesised as large precursor molecules
  —> process to mature peptide hormone
  —> packed into vesicles and stored
  —> released upon stimulation

- Rising / High [Ca] in plasma
—> detected by ***CaSR (Calcium sensing receptor, a ***GPCR)
—> responsible for molecular process of Ca sensing on Parafollicular cells
—> trigger IP3/Ca signaling pathway
—> Phospholipase C activation
—> IP3
—> Ca release from ER
—> Calcitonin secretion

Physiological effects:
- Net ↓ plasma [Ca]

Calcitonin receptors:
- mediated by high affinity Calcitonin receptor (GPCR family)
1. Osteoclasts
—> binding of Calcitonin inhibits osteoclasts motility + induce osteoclasts retraction
—> mediated by cAMP/PKA pathway
—> inhibit bone resorption + allow osteoblasts come in for bone formation/lock Ca in bone
—> ↑ Ca stored
—> ↓ plasma Ca level

2. Kidney
   —> Inhibit renal tubular Ca reabsorption + ↓ Calcitrol
   —> ↑ Ca excretion + ↓ Rate of intestinal absorption
3. Intestinal effect (Indirect)
   —> ↓ Calcitrol from Kidney
   —> ↓ Rate of intestinal absorption

Question 4

Thyroid hormones

Answer 4

Hypothalamic-Pituitary-Thyroid axis

Parvocellular neurons of Paraventricular nucleus (PVN) (Hypothalamus)
—> TRH (Thyrotropin-releasing hormone)
—> Thyrotrophs in Anterior pituitary (bind to GPCR (Gαq))
—> TSH release
—> TSH receptor
—> Stimulate synthesis + secretion of thyroid hormones from Follicular cells

Thyroid hormone synthesis + secretion under -ve feedback (short, long loop) by Hypothalamic-Pituitary-Thyroid axis

(Dopamine, Somatostatin, Glucocorticoid can inhibit TSH from Anterior pituitary)

Question 5

TSH and TSH receptor

Answer 5

TSH:

• Heterodimer (1α, 1β subunit)
• Hypophysiotropic peptide

TSH receptor:

• GPCR
• basolateral membrane of thyroid follicular cells

Binding of TSH to TSH receptor
—> Gαs + Gαq activation
—> Adenyl cyclase + PLC activation
—> cAMP + PLC (IP3, DAG) signalling

cAMP (Gαs):

1. ↑ Differentiation, Growth of Thyroid gland
2. ***Thyroglobulin production and secretion into colloid
3. ***Thyroid peroxidase production
4. **Na/I symporter (NIS) expression on **basolateral membrane of Principal cells
5. **Pendrin (Iodide transporter) translocation to **apical membrane of Principal cells

PLC (Gαq):
1. ***H2O2 generation by Dual oxidase

Question 6

***Synthesis and Secretion of Thyroid hormones (T3, T4)

Answer 6

1. Uptake of Iodide from blood by ***NIS (basolateral membrane)
   - cotransport 2 Na ions + 1 Iodide ion
   - Na gradient: Driving force (created by Na/K ATPase: Na pump back to blood)
2. Efflux of Iodide into follicular lumen via ***Pendrin
3. Iodide **oxidised to Iodine and rapidly organified by incorporation into selected tyrosyl residues of Thyroglobulin
   —> **Organification
   —> form mono-iodotyrosine (MIT) + di-iodotyrosine (DIT) on Thyroglobulin
   —> **catalysed by Thyroid peroxidase (with presence of **H2O2)
4. Coupling reaction
   - T4 formed from 2x DIT
   - T3 formed from MIT + DIT
   —> T3, T4 still attached to Thyroglobulin
   —> stored in follicle as colloid (for ~2-3 months)
5. T3, T4 liberated from Thyroglobulin scaffold before secreted as free hormone in blood
   —> require endocytosis of Iodinated Thyroglobulin from apical membrane (成舊野食翻落Follicular cell)
   —> ***digestion by Lysosomes (remaining MIT, DIT on Thyroglobulin will be deiodinated intracellularly —> Iodide transported back to colloid via Pendrin for reuse)
   —> free T3, T4
   —> T4&raquo_space;> T3 (40 fold in plasma conc)
6. Circulating thyroid hormones bind to carrier protein
   - Thyroxine-binding globulin (~70%)
   - Albumin (~15%)
   - Transthyretin (~10%)
   - unbound (0.05%)
   —> ensure circulating reserve + delay metabolic clearance of hormone
   —> only unbound hormone are bioavailable
   —> clinical measurement: measure total T4 instead of unbound T4 (in absence of protein binding abnormality) + measure binding protein level

Changes in binding protein level:

1. ↑ binding protein —> ↓ free thyroid hormone —> stimulate TSH release
2. ↓ binding protein (chronic liver disease) —> ↑ free thyroid hormone —> suppress TSH release —> ↓ thyroid hormone synthesis and release
3. Active biological half life
   - T4: 7 days
   - T3: 1 day

Question 7

Assessment of Thyroid activity

Answer 7

Radioactive Iodine uptake

Normal Thyroid gland: uptake 10-35% of radioactive iodine through NIS

Abnormal Thyroid gland: higher/lower uptake (Hyperactivation / Hypoactivation of Thyroid gland)

Question 8

MOA of Thyroid hormones

Answer 8

T4: prohormone
T3: active hormone
—> T4 needs to be deiodinated to T3 by ***Deiodinase within target cells before interact with Thyroid hormone receptor (THR)

T4, T3 enters cell via transporter (carrier-mediated)
—> T4 deiodinated into T3 via Deiodinase I / II
—> T3 interact with THR (Nuclear receptor)
—> THR function as transcription factor
—> bind to TRE (Thyroid Hormone Response Element) on target gene
—> transcriptional regulation of target gene

2 THR identified (***Nuclear receptor family):

1. THRα
2. THRβ

THR expressed in all tissues (act on ALL cells / tissues!!!)

• THRα: ***Peripheral tissue + Brain (brain, heart, skeletal muscle, kidney, liver)
• THRβ: ***CNS (brain, pituitary, retina, inner ear, lung)

Question 9

***Function of Thyroid hormones

Answer 9

Primary function:

• 記: Metabolism + Growth + Development
• Maintain normal cellular metabolic activity (transcription of Na/K-ATPase —> oxygen consumption, protein synthesis / degradation, growth, differentiation)

Nervous system:
1. **Promote fetal, post-natal CNS development
—> influence neuronal migration, myelination, axonal growth and development
2. **Enhance SNS activity —> wakefulness, alertness, responsiveness towards stimuli

CVS (mainly T3, no deiodinase in cardiomyocyte):
1. **Regulates genes important for myocardial contraction, electrochemical signalling
—> ↑ SERCA, ↑ β1 receptors, ↓ phospholamban
—> ↑ HR, stroke volume, contractility
—> ↑ CO
2. **Vasodilation —> ↓ systemic vascular resistance

Skeletal muscle:

1. Muscle mass development
2. Differentiation of contractile characteristics of skeletal muscle

Bone:
1. ***↑ Bone growth / turnover rate via activation of osteoblasts + osteoclasts

Gut:

1. ***↑ Glucose absorption
2. ↑ Rate of digestive enzymes secretion
3. ***↑ GI motility

Adipose tissue

1. ***↑ Thermogenesis
2. ***↑ Weight loss in brown adipose tissue
3. ↑ Catecholamine-mediated lipolysis by ↑ β-adrenoceptor expression

Others:

1. Induce O2 utilisation by metabolically active tissue —> ↑ energy expenditure, basal metabolic rate
2. ↓ Cholesterol
3. Regulate epidermal cell proliferation and homeostasis

Question 10

Disorders related to Thyroid hormones

Answer 10

1. Hyperthyroidism (Thyrotoxicosis)
2. Hypothyroidism
3. Resistance to Thyroid hormone (RTH)

Question 11

Hyperthyroidism (Thyrotoxicosis)

Answer 11

1. Can occur during pregnancy: hCG from embryo turn on thyroid function for fetal growth
2. Graves’ disease: autoimmune disease by ***Thyroid-stimulating Ig (TSI)
   —> mimic TSH
   —> continuously stimulate thyroid hormone production

Signs and Symptoms:

1. ***Intolerance to heat, Facial flushing (∵ too much heat production)
2. ***Palpitation (Rapid, Irregular heart beat), Cardiac hypertrophy
3. ***Weight loss (∵ lipolysis)
4. Bulging eyeballs (Graves’ ophthalmopathy) (AutoAb attack fibroblasts in eye muscle —> differentiate into fat cells, muscle —> inflammation —> edema around eye area)
5. Diarrhoea
6. Weakness of bone / muscle (Thyrotoxic periodic paralysis: secondary to hyperthyroidism ∵ ↑GFR, ↑Angiotensin, ↑Aldosterone —> Hypokalaemia —> Respiratory failure, Arrhythmia)
7. ***Tremor
8. **Goitre
   - only occur in Graves’, result of hyperplasia + hypertrophy of gland
   - also occur in **Primary Hypothyroidism —> ∵ High TSH from pituitary

Question 12

Hypothyroidism

Answer 12

1. Autoimmune inflammatory reaction —> Atrophy of glands
   - Hashimoto’s thyroiditis (Goitre)
2. Congenital diseases
   - Cretinism - most severe form of hypothyroidism from poor development of thyroid gland —> associated with severe mental retardation and learning disability (∵ retarded nervous system growth / development)
   - Gene mutation involved in thyroid hormone production
3. Medical treatment
   - surgical removal of Thyroid gland
4. Iodine deficiency

Signs and Symptoms:

1. ***Intolerance to cold, subnormal temperatures
2. ***Extreme fatigue
3. ***Weight gain
4. ***Deep cocky voice (∵ deposition of mucopolysaccharides along vocal cord)
5. Constipation
6. ***Slow heartbeat
7. Dry skin with brittle and thick nails (∵ retarded epidermal proliferation)
8. ***Muscle weakness
9. ***Delayed bone development
10. ***Myxedema (∵ deposition of mucopolysaccharides in dermis —> swelling mucosal membrane, skin)
11. **Goitre (occur in **Primary Hypothyroidism —> ∵ High TSH from pituitary)

Question 13

Resistance to Thyroid hormone (RTH)

Answer 13

Mutation in THR α / β
—> reduction / lack of end-organ responsiveness to Thyroid hormone
—> symptoms of TH excess (in CNS) / deficiency (in periphery)

THRα mutation:
—> Peripheral + Brain
—> Resistance —> ∴ Hypothyroidism symptoms
—> ***Near-normal level of T3, T4 + Normal TSH (∵ not involved)
1. Delayed bone development
2. Chronic constipation
3. Slow heart rate
4. Impaired neural development, abnormal cortical layering, abnormal cerebellum development

THRβ mutation:
—> CNS
—> **Impaired negative feedback (∵ impaired HPT axis)
—> **↑ T3, T4, TSH
1. Goitre (∵ ↑ TSH)
2. Fast heart rate (∵ ↑ T3)
3. Impaired neural development, abnormal cortical layering, abnormal cerebellum development