Thyroid Hormone and Non-Genomic TH Diseases

Question 1

What are the characteristics of nongenomic functions of TH?

Answer 1

It doesn’t act on nuclear receptors, it is a rapid effect, all forms of TH exert a nongenomic effect, small amplitude, involves signal transduction. Involves membrane receptors and/or modulation of intracellular pathways

Question 2

What are the characteristics of genomic functions of TH?

Answer 2

It acts on nuclear receptors, slower, involves changing gene transcription, T3 causes genomic functions, large amplitude, no signal transduction

Question 3

What are the rapid intracellular effects of TH?

Answer 3

ion flux, mitochondria activity (esp liver), glucose and aa uptake, actin polymerization (critical to remodelling, neural connections, cell movement, intracellular trafficking, muscle contraction, pseudopod formation)

Question 4

What are some of the intracellular proteins that TH acts on?

Answer 4

Calmodulin, integrin, PIPs, cAMP, protein kinase –> these proteins cause rapid intracellular effects of TH

Question 5

What are integrins?

Answer 5

Receptors that mediate attachment between a cell and other cells or the extracellular matrix

Question 6

What is required to promote actin polymerization in rat brain cells for migration during development?

Answer 6

T4 and rT3, but not T3

Question 7

What are the genomic and non-genomic effects of TH on cardiac myocytes?

Answer 7

T3 enters the cell by a specific transporter and acts in the nucleus via TR on the TRE. This causes transcription of genes involved in muscle contraction (myosin and actin). T3 also acts directly on voltage gated ion channels at the membrane (K+). These results act to increase heart rate.

Question 8

How can the nongenomic effects of TH affect the TR in the nucleus?

Answer 8

Through phosphorylation cascades (CDK, MAPK, tyrosine kinase), when TR is phosphorylated it is activated, which causes co-repressor proteins to dissociate

Question 9

What are the ways that there is cross talk between the non-genomic effects of TH at the membrane and the TR in the nucleus?

Answer 9

1. T3 can bind to transporters on the membrane, which activates Na+/Ca+ exchangers to result in Ca signaling through calmodulin, as well as activate EGFR/PDGFR RTKs –> phosphorylate PKA –> enter the nucleus and cause TR phosphorylation, which leads to dissociation of co-repressors (like HDAC, NcoR, SMRT), this leads to binding of T3 which brings in coactivators: HAT, TRAP220, P160/SRCs –> gene transcription
2. T4 can bind to integrin which can activate PKA or PKC –> Raf1 –> MEK –> MAPK –> enters nucleus and phosphorylates TR
3. T3/T4 can also activate PLC, which increase the sensitivity of integrins by activating more PKC

Question 10

What is the most common TH condition?

Answer 10

Hypothyroid

Question 11

What effect does pregnancy have on the thyroid?

Answer 11

It puts high demand on the thyroid, can lead to hyperthyroidsim. There is a complex connection between thyroid hormones and estrogen, estrogen stimulates TSH and increases TBG (thyroid blood globulin) –> equilibrium may not shift

Question 12

What is cretinism?

Answer 12

It is hypothyroidism in a developing child, leading to physical and mental disability

Question 13

When can cretinism begin?

Answer 13

Can begin in utero if the mother has hypothyroidism

Question 14

What are the symptoms of cretinism?

Answer 14

short stature, respiratory difficulty, jaundice, poor feeding, hoarse cry, lethargy, blue/purple skin, bone maturation delayed or permanently damaged, permanent lack of brain development

Question 15

What is the cause of cretinism?

Answer 15

anti-TSH receptor antibodies from the mother (B cells producing antibodies that block binding of TSH to the receptor or T cells binding to TCRs that block binding –> mother has hashimotos), or could be due to severe iodine deficiency or defect in the baby’s thyroid axis

Question 16

When do human fetuses acquire the ability to synthesize TH?

Answer 16

At around 10-12 weeks of gestation. There is also substantial transfer of maternal TH across the placenta, which contains deiodinases that convert T4 to T3

Question 17

What is the effect of hypothyroidism in the fetus or mother?

Answer 17

Results in fetal disease including a high incidence of brain development disability. Also in females with subclinical hypothyroidism, the extra demands of pregnancy can bring on disease

Question 18

What is the biggest effect of TH during fetal maturation?

Answer 18

Biggest effects are in the terminal stages of brain differentiation, including synaptogenesis, growth of dendrites and axons, myelination and neuronal migration –> untreated hypothyroidism in the mother, disabilities in the baby cannot be reversed with treatment after the second trimester

Question 19

What is goiter?

Answer 19

It is enlargement of the thyroid gland caused by overstimulation.

Question 20

What causes goiter?

Answer 20

Low (lack feedback) or high (TRH or TSH overstimulation) levels of TH. This may be due to lack of iodine in diet, drug blocking, autoimmune disease, cancer, genetic mutation

Question 21

What is Hashimoto’s thyroiditis?

Answer 21

It is autoimmune hypothyroidism. It is an autoimmune disease in which the thyroid gland is attacked by a variety of cell and antibody mediated immune processes.

Question 22

What occurs to cells in Hashimoto’s?

Answer 22

Lymphocytes become sensitized to thyroidal antigens (anti-TG, anti-TPO, anti-TSHR antibodies), which causes them to destroy normal thyroidal architecture. T3 levels then fall, which increases TSH due to lack of neg feedback, so goitre compensates, but eventually the gland fails and there is severe hypothyroidism if untreated.

Question 23

What are the common symptoms of Hashimoto’s?

Answer 23

Common first sign is weight gain, lethargy, menstrual irregularity, cold intolerance, depression, swelling

Question 24

What is myxedema?

Answer 24

Swelling, can occur in both hyper or hypothyroidism

Question 25

What is Grave’s disease?

Answer 25

Disorder that is the most common form of thyrotoxicosis (too much T3/T4 activity).

Question 26

Is graves disease more common in men or women?

Answer 26

5x more common in women, peak around 20-40 years old

Question 27

What are the symptoms of Graves disease?

Answer 27

Hyperthyroidism, goitre, bulging eyeballs (opthalmopathy), cardiac arrhythmias, weight loss, profuse sweating, tremor, diarrhea, thyroid eye disease, dental caries

Question 28

What is thyroid storm?

Answer 28

Extreme hypothyroidism that is life threatening