ENDO - Thyroid Physiology

Question 1

Describe anatomy of the thyroid gland.

Answer 1

• Located in the anterior neck between C5-T1 vertebrae and inferior to the larynx
• Divided into two lobes joined by a central isthmus
• In adults weighs around 20g, but can increase in size during puberty and pregnancy
• Embedded within the posterior surface are the parathyroid glands

Question 2

Describe the thyroid gland histologically.

Answer 2

• Made up of circular structures enclosing a central fluid filled colloid surrounded by a ring of follicular cells.
• C cells found outside of these rings
• Highly vascularised and contains many capillaries that allow hormones to enter circulation

Question 3

What transporters are found on the surface of follicular cells and what do they do?

Answer 3

SODIUM-IODINE SYMPORTERS
- Co-transport 2 sodium and 1 iodide ion into the colloid against the iodide concentration gradient but with the sodium gradient - energy from this process comes from the Na+/K+ ATPase
- Follicular cells also synthesise and secrete thyroglobulins into colloid

Question 4

Describe T3 and T4 production. PART 1

Answer 4

• TPO catalyses coupling of 1 iodide ion to thyroglobulin to form MIT or 2 iodide ions to thyroglobulin to form DIT.
• Two DIT molecules come together to form thyroxine (T4) and one DIT and one MIT molecule comes together to form triiodothyronine (T3)
• Only T3 is physiologically active, but 80% of the products of iodide and TG form T4. T4 is converted to T3 in the blood

Question 5

Describe T3 and T4 production. PART 2

Answer 5

• TSH (produced by anterior pituitary) stimulates every step of the process, including iodide uptake, thyroglobulin synthesis, thyroid peroxidase activity, synthesis of T3 and T4, uptake of T3 and T4 into follicular cells and expulsion into the blood stream
• Several factors can influence the ratio of T3 and T4 production. If Iodine is restricted then the thyroid favours T3 production as it is more biologically active. If the thyroid is overstimulated by TSH (hyperthyroidism) then T4 is favoured

Question 6

Describe the pharmacological basis behind carbimazole and propylthiouracil.

Answer 6

• Treat hyperthyroidism and both inhibit TPO, preventing the oxidisation of iodine and the formation of MIT and DIT, thus reducing T3 and T4 production

Question 7

Describe the link between T3 and T4 production.

Answer 7

• Thyroid gland mainly produces T4 (around 90ug/day, compared with 35ug/day T3)
• All T4 is derived from the thyroid gland
• 75% of T3 is derived from T4 in the blood by the enzyme deiodinase, which is selenium-dependent

Question 8

Describe the hypothalamic-pituitary-thyroid axis. PART 1

Answer 8

• Hypothalamic neurons which synthesise and secrete TRH into the hypophysial portal system are under regulation from various central and peripheral sources.
• Cold stress has been shown to increase levels of TRH and weight loss has been shown to reduce TRH levels
• TRH travels to thyrotropic cells in the anterior pituitary (which comprise around 5% of endocrine cells in the anterior pituitary)
• TRH binds to TRH receptors, triggering the release of TSH into the systemic circulation

Question 9

Describe the hypothalamic-pituitary-thyroid axis. PART 2

Answer 9

• TSH in turn travels to follicular cells in the thyroid to stimulate the synthesis of T3 and T4
• T3 and T4 in turn downregulate the axis by reducing the expression of TRH receptors on thyrotropic cells and reducing the synthesis of TRH.
• T4 is thought to be more potent at reducing the activity of this axis than T3

Question 10

What is special about free T3 and T4?

Answer 10

Only free T3 and T4 are biologically active and are able to negatively regulate the hypothalamo-pituitary-thyroid axis by acting on hypothalamus (TRH) and anterior pituitary (TSH)
- The vast majority of physiological effects of the thyroid gland are mediated through T3

Question 11

Describe the association of T3 and T4 with plasma and proteins.

Answer 11

• Normally only around 0.03% of T4 and 0.3% of T3 are freely floating in plasma - biologically available
• Liver secretes TBG and TTR.
• TBG binds around 70% of available T4 and T3 and TTR binds around 10-15%.
• The rest are bound to albumin or lipoproteins

Question 12

Describe thyroid hormone receptors.

Answer 12

• Nuclear receptors which sit in the cell nucleus
• Thyroid hormones enter the cell through specalised thyroid hormone transporters
• T3 is the most biologically active form of thyroid hormone, with T4 having some, but significantly less affinity for the receptor
• Once bound, the receptor initiates transcription of various genes

Question 13

What are the physiological effects of thyroid hormone?

Answer 13

• Increased expression of UCP - mitochondrial protein which as a result increases oxidation
• Increased Na+/K+ ATPase
• Increased expression of proteins for growth
• Increased mitochondria and respiratory enzymes

↑O2 consumption leading to raised metabolic rate

Question 13

Describe the physiological effects of thyroid hormone on oxygen consumption. PART 1

Answer 13

• To increase O2 consumption, O2 has to increase - requires increased cardiac output and ventilation
• Increased consumption also requires increased fuel, so food intake increases as does mobilisation of endogenous energy stores
• Leads to increased metabolic rate, leading to increased CO2 and thus increased ventilation, increased thermogenesis, decreased muscle mass and decreased adiposity
• All above factors enhanced in hyperthyroidism

Question 14

Describe the physiological effects of thyroid hormone on oxygen consumption. PART 2

Answer 14

• The increased mobilisation of endogenous energy leads to a reduction in the respiratory quotient
• RQ usually 1 for glucose usage - usage of other fuel sources, amount of oxygen required and amount of CO2 produced differs - RQ falls
• Thyroid hormone-induced increase in energy mobilisation results in a decreased RQ, and thus a decrease in muscle mass and adiposity

↓RQ = ↑ fat & protein utilisation for energy

Question 15

Describe the cardiovascular effects of thyroid hormones.

Answer 15

• T3 has been shown to increase the expression of SERCA-2 and Na-Ca exchanger, thereby removing Ca2+ from the cytoplasm much quicker.
• Increased calcium removal increases the velocity of cardiac relaxation.
• Increased clearance of calcium creates a greater calcium concentration gradient, which in turn increases the velocity of cardiac contractility and increased heart rate

Question 16

Describe the respiratory effects of thyroid hormone.

Answer 16

• T3 results in increased resting respiratory rate, minute ventilation and ventilatory responses to hypercapnia, all to increase oxygen delivery to the blood to compensate for the increased oxygen use
• Thyroid hormone also increases the oxygen carrying capacity of blood.
• T3, and the decreased PO2 associated with increased metabolic rate, increase EPO secretion from the kidney, which acts on bone marrow to increase red blood cell production

Question 17

The thyroid gland is the primary iodine using organ in the body. Describe iodine requirements and risk of deficiency across the world.

Answer 17

• Adults require around 140ug iodine per day, mostly derived from dairy and milk products
• Fish are also high in iodine.
• Vegetarians and vegans are particularly at risk of iodine deficiency, as are people from countries with low iodine content in soil (e.g. northern India, mountainous regions of Europe and Andean region of South America)
• Iodine deficiency is quite rare in the UK

Question 18

Describe embryonic disorders of the thyroid gland.

Answer 18

• Maternal iodine deficiency leads to a number of neural developmental issues, due to reduced foetal thyroid function
• Congenital hypothyroidism caused by iodine deficiency is known as cretinism and is marked by learning difficulties and growth disorders
• Rare in the UK, but screening of maternal iodine levels and iodine supplementation if necessary completely prevent this form of cretinism

Question 19

Describe the three types of hypothyroidism and their main cause.

Answer 19

• Primary = Disorder with the thyroid gland
• Secondary = Disorder with pituitary stimulation (e.g. ↓ TSH)
• Tertiary = Disorder with hypothalamus (e.g. ↓ TRH)

Most common cause is iodine deficiency - atrophy of thyroid gland

Question 20

Describe Hashimoto’s thyroiditis.

Answer 20

Primary hypothyroidism
- Autoantibodies develop, sometimes against the TSH receptor, leading to destruction of follicular cells
- In other patients the antibody develops against thyroid peroxidase

Question 21

Describe goitre.

Answer 21

• Swelling in neck caused by thyroid enlargement
• Commonly caused by iodine deficiency (increased TG to compensate) and Hashimoto’s thyroiditis (due to lymphocyte infiltration and fibroid formation)