Thyroid

Question 1

where is the thyroid gland found?

Answer 1

1) found in the neck

2) made up of follicular cells and parafollicular cells

Question 2

outline the regulation of Thyroid Hormone Release

Hypothalamic–pituitary–thyroid axis

Answer 2

1) The hypothalamus senses low circulating levels of thyroid hormone (T3) and (T4) and responds by releasing Thyrotropin Releasing Hormone (TRH) (tri-peptide)
2) the TRH stimulates the pituitary to produce thyroid-stimulating hormone (TSH)
3) The TSH, in turn, stimulates the thyroid to produce thyroid hormones T3 and T4
4) T3 and T4 exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from hypothalamus and TSH from anterior pituitary gland
5) TSH can also feedback on the hypothalamus in a negative manner controlling the release of TRH

Question 3

outline the action of thyroid-stimulating hormone (TSH)

Answer 3

1) TSH binds to a G protein-coupled receptor on thyroid follicle epithelial cells which activates both:
- Adenylate cyclase => cAMP/PKA-dependent pathway
- Phospholipase C => PI turnover => DAG and IP3

Question 4

outline the structure of TSH

Answer 4

1) TSH dimeric glycoprotein composed of an alpha and beta subunit
2) Alpha subunit is identical between TSH, LH, FSH, and hCG. Beta subunits differ and confer biological specificity

Question 5

what are thyroid follicles?

Answer 5

Hollow spheres of epithelial cells. Lumen filled with a gelatinous colloid consisting of a large protein called thyroglobulin

Question 6

outline the synthesis of Thyroid Hormones

Answer 6

1) Thyroglobulin synthesized by thyroid follicular cells and exocytosed into the lumen.
2) Thyroglobulin contains high content of tyrosine
3) Iodide is taken up from the blood into follicular cells and transported into the lumen where thyroid peroxidase converts it to free iodine
4) Iodine atoms incorporated into tyrosine residues
5) Coupling of iodinated Tyrosine residues
of thyroglobulin to make T3 and T4

Question 7

explain how the coupling of iodinated Tyrosine residues of thyroglobulin make the thyroid hormones T3 and T4

Answer 7

1) when only one iodine is added to the benzene ring mono-iodotyrosine (MIT)
- when two iodines are added to each tyrosine residue di-iodotyrosine (DIT)
2) Coupling between 2 iodinated tyrosine residues can now occur under oxidising conditions to form a dimer
3) DIT couples with another DIT → T4 or thyroxine
4) MIT + DIT → T3 or Triiodothyronine
5) The fate of the B chain is unclear – either breaks or forms a serine residue.

Question 8

describe how thyroid hormone is released

Answer 8

1) Follicular cells take up a portion of the colloid in the lumen (endocytosis)
2) Lysosomal enzymes in the follicular cells break down the iodinated thyroglobulin liberating ‘free’ T3 and T4.
3) T4 and T3 diffuse through the plasma membrane of the follicular cells into the blood
4) Inactive MIT and DIT are rapidly deiodinated and the released iodine is recycle back to lumen for further use

Question 9

T3 and T4 are hydrophobic and so bind to Thyroxine-binding globulin (TBG). outline the role of TBG

Answer 9

1) T3 and T4 circulate bound to TBG (and albumin) as they have poor solubility in water – very little free T3/T4
2) TBG prevents urinary secretion of T3 & T4
3) TBG buffers against acute changes in thyroid function
4) T3/T4 must dissociate from TBG to exert biological effect

Question 10

summarise the differences between T3 and T4

Answer 10

1) 90% of secreted thyroid hormone from the thyroid gland is T4 and 10% is T3
2) T3 is about 4-fold more potent than T4
3) most T4 is “activated” by peripheral target tissues (especially liver and kidneys) by the removal of one iodine to yield T3

Question 11

explain how the hormones T3 and T4 work

Answer 11

1) transported in bloodstream bound to carrier protein (TBG) to intracellular thyroid hormone receptor
2) The receptor is a hormone-responsive transcription factor (contains both a hormone-binding region and a DNA-binding region)
-T3 is the more active form since it binds to the thyroid hormone receptor with higher affinity than T4.
(local tissues convert T4 to T3!)
3) Activated receptor-hormone complex alters gene expression
4) newly formed mRNA directs synthesis of specific proteins on ribosomes
5) new proteins alter cells activity

Question 12

describe the effects of Thyroid Hormone on the body

Answer 12

1) Increases basal metabolic rate (BMR) - Raised O2 consumption, CO2 production, heat production
2) Cardiovascular system- Increases heart rate and force of contraction
3) Nervous system- Increases activity of sympathetic nervous system . also Enhances the sensitivity to catecholamines
4) In children Growth and maturation (essential):
- Embryo development
- CNS development
- Linear growth (promotes effects of growth hormone)

Question 13

what is a Goitre?

Answer 13

1) swelling of the thyroid gland
2) hypertrophy of thyroid gland caused by excessive stimulation by TSH
3) Often associated with autoimmune disease

Question 14

what percentage of the population is affected by diseases associated with thyroid dysfunction?

Answer 14

1) Common – approx 2% population. more common in women

Question 15

what is Hypothyroidism and what are the symptoms in adults?

Answer 15

lack of thyroid hormone leads to decreased metabolism:

1) weight gain
2) cold intolerance
3) lethargy, depression,
4) puffiness of skin and muscles (myxedema),
5) sluggish reflexes, muscular weakness,
6) reduced pulse rate and cardiac output

Question 16

what are the symptoms of Hypothyroidism in children?

Answer 16

1) In fetus and/or child: Cretinism
2) Fetal brain damage which may be irreversible!
3) shortness, obesity, mental retardation
Therefore, routine neonatal screening for elevated TSH! (High TSH indicates low T3 and T4 due to reduced –ve feedback on hypo. and pit.)

Question 17

outline the treatment for Hypothyroidism

Answer 17

1) Lifelong replacement therapy with T4. Levothyroxine (identical to natural T4)
2) (adult ~150mg/day). Normally given on an empty stomach as absorbed better.
3) Unless due to chronic dietary iodine deficiency in which case give increased/supplementary iodine in diet

Question 18

1) explain why there are not many problems associated with using Levothyroxine
2) in what case would you give T3 (Liothyronine)?

Answer 18

1) Dosing not that critical as T4 has a long half life and a relative shallow dose response curve. Also helped by little normal variation in thyroid hormone output.
2) T3 (Liothyronine) can be given as it is faster acting but has a shorter half life than T4. Used in cases where this is beneficial e.g. myxedema coma (a rare but extreme form of hypothyroidism) or preparation for ablation with radioactive iodine.

Question 19

discuss the possible Causes of Hypothyroidism

• primary : thyroid gland
• secondary : pituitary
• tertiary : hypothalamus

Answer 19

1) Primary failure of thyroid gland (low T3/T4, high TSH, goitre)
2) Secondary due to anterior pituitary failure (low T3/T4, low TSH and/or TRH, no goitre)
3) Tertiary due to hypothalamic failure- rare
4) Primary due to autoimmune damage to gland
5) Primary due to chronic lack of dietary iodine

Question 20

what is Hyperthyroidism and what are the symptoms in adults?

Answer 20

excess thyroid hormone

1) weight loss
2) nervousness
3) heat intolerance
4) high cardiac output
5) hand tremors
6) eyeball protrusion(‘exophthalmos’)

Question 21

Outline the causes of Hyperthyroidism

Answer 21

1) Graves disease (~50% of all cases)- Due to thyroid-stimulating antibodies that mimic TSH! (high T3/T4, low TSH, goitre)
2) Primary due to hypersecreting thyroid tumour
(high T3/T4, low TSH, no goitre)
3) Secondary due to excess hypothalamic or anterior pituitary secretion (high T3/T4, high TRH and/or TSH, goitre)

Question 22

what is the treatment for Hyperthyroidism?

Answer 22

1) “Anti-thyroid drugs” that interfere with thyroid hormone synthesis. These block the thyroid peroxidase enzyme thus preventing the iodination of thyroglobulin
2) surgical ressection of thyroid
3) thyroid ablation using radioactive iodine

Question 23

state the two commonly used drugs to treat Hyperthyroidism?

Answer 23

1) Carbimazole is used in UK. Pro-drug that is converted to active form methimazole (given direct in US)
2) Propylthiouracil is often used in a block replacement strategy with Levothyroxine
- Propylthiouracil used if carbimazole is not well tolerated

Question 24

discuss the Problems associated with the drugs used to treat Hyperthyroidism

Answer 24

1) Long term use normally results in thyroid hypertrophy and a goitre – sometimes called goitrogens. Often drugs only used in preparation for thyroidectomy.
2) Carbimazole commonly causes rashes – can be treated with antihistamines or swap to propylthiouracil.
3) Carbimazole can cause a suppression in bone marrow. Normally presents as sore throat/mouth ulcers and fever.

Question 25

how are thyroid conditions diagnosed?

Answer 25

1) Thyroid function tests are essential for correct diagnosis. Measure TSH and Thyroid hormones by immunoassay.

Question 26

the cause of thyroid conditions could be down to a malfunctioning pituitary. how is pituitary malfunction diagnosed?

Answer 26

1) Diagnosis of pituitary malfunction using TSH stimulation test
2) TRH administered and TSH measured from samples at 0,20 and 60 mins. no response in secondary and slow response in tertiary hypothyrodism

Question 27

explain how chronic iodine deficiency leads to problems

Answer 27

1) no iodine means there is decreased levels of T3 and T4
2) there will be no negative feedback because there is no T3 and T4. so there will be an increase in TRH and TSH
3) this leads to an enlargement of the thyroid gland

Question 28

explain how Graves disease leads to problems

Answer 28

1) thyroid stimulating antibodies stimulate the thyroid gland leading to increased T3 and T4 production
2) there is a strong negative feedback on the hypothalamus and anterior pituitary leading to a decrease in TRH and TSH