Lecture 18; Post Natal Growth 3

Question 1

What is abnormal body proportion defined by;

Answer 1

%ile-height vs %-sitting height or arm span

Question 2

What are the causes of disproportionate growth?

Answer 2

•  Skeletal dysplasia (i.e. Abnormal growth plates, achondroplasia / hypochondroplasia
•  Syndromes (Turner’s (45 XO, and variations)
•  Precocious puberty (breast development <8 years in girls and testicular development <9 years in boys — premature fusion of epiphyses).
• Hypothyroidism

Question 3

What can cause iodine insufficiency?

Answer 3

Overstimulation of the thyroid to produce T3,4

Autoimmune diseases

Question 4

Describe T3,4 structure differences;

Answer 4

T4 = two tyrosine molecules each with 2 iodine molecules (x2 DIT)

T3 = two tyrosine molecules, one with 2 I and other with 1 I (1 DIT and 1x MIT)

Question 5

What converts T4 to T3 in tissues?

Answer 5

Iodinase in target tissues

T3 is 5-8 fold more active that T4

Question 6

What do the parafollicular cells in the thyroid make?

Answer 6

Calcitonin

Question 7

Describe the synthesis of thyroglobulin;

Answer 7

Follicular cells;

• I/Na symporter down Conc. grad
• Diffuses into colloid and is oxidised and attached to rings of tyrosine on thyroglobulin (stabilising protein) (thyroid peroxidase does this)
• Two iodised tyrosine rings are added together forming T3,T4
• Endocytosis of Thyroglobulin containing T3,T4, into follicular cells. T3,T4 then can diffuse into the blood
• Thyroglobulin is recycled

Question 8

How does TSH regulated T3,T4 production?

Answer 8

Promotes Iodine transport

Promotes endocytosis

Question 9

What blocks iodine oxidation?

Answer 9

PTU (drug)

- Doesnt stop I uptake or endocytosis , therefore takes long time to start acting and finish (good control)

Question 10

Describe T3,T4 loop;

Answer 10

Hyp

• TRH = +ive
• Dopamine or somatostatin = -ve

AP
- TSH (+ive)

Thyroid gland
- T3, T4 (-ive at AP and Hyp levels)

Question 11

What is the problem?

 FT4 6 pmol/L (N 11-20)  TSH 65 (0.4-4.0iu/L)

Answer 11

 Feedback dysinhibition!

 Primary hypothyroidism (i.e. reduced activity of thyroid gland), e.g. autoimmune or I deficiency

Question 12

What is the problem?

 FT4 7.5 pmol/L  TSH 3.5 iu/L

Answer 12

 Central (secondary hypothyroidism)  TSH “inappropriately normal”

 Or… Sick euthyroid: major illness, starvation  T4 converted to rT3\  Evolves over time

Question 13

Where is the problem?

 FT4 38 pmol/L (11-20)  TSH < 0.04 (0.04-4.0)

Answer 13

 Primary hyperthyroidism (i.e. excess activity of thyroid gland)
 e.g. autoimmune disease of thyroid
 Thyroid gland usually enlarged, depending on aetiology/timing

Question 14

What enhances iodine uptake?

Answer 14

• TSH
• iodine deficiency (⇑ MIT:DIT ratios)
• TSH receptor antibodies (most stimulate!)
  - autoregulation

Question 15

What is iodine inhibited by?

Answer 15

•  I- excess (Wolff-Chaikoff effect) e.g. surgery administration of excess iodine buffer needed as suddenly excess T4 production
• cardiac glycosides (digoxin)
• Oubain (inhibit Na+-K+ ATPase), and perchlorate (PClO4 -, competes with I- transport proteins).

Question 16

In blood what is T4 bound to?

Answer 16

 Approximately 99.98% of T4 is bound to 3 serum proteins: Thyroid binding globulin (TBG) ~75%; Thyroid binding prealbumin (TBPA or transthyretin) 15-20%; albumin ~5-10%

Question 17

How much T4 is free?

Answer 17

 Only ~0.02% of the total T4 in blood is unbound or free

Question 18

How much T3 is free and whats its half life?

Answer 18

 Only ~0.4% of total T3 in blood is free Half life?

 T1/2 ~ 7 days

Question 19

Are there variants of T3/

Answer 19

yes

T4 can form

T3 (step up)
or
rT3 (step down)

Question 20

What do thyroid hormones do?

Answer 20

Regulate Long-term physiological homeostasis


Principal targets are: skeletal & cardiac muscle, liver, gut, and kidney

Question 21

What specifically do thyroid hormones do?

Answer 21

 T3 and T4 are lipophilic and bind Nuclear Hormone Receptors ⇒ affect gene transcription

⇑ O2 consumption and the Basal Metabolic Rate (BMR) by increasing Na/K ATPase (NOT brain)

Question 22

Whats the role of T4 in skeletal growth?

Answer 22

 T4 facilitates GH release
-  Permissive for chondrocyte proliferation and differentiation
- Low T4 slows growth & epiphyseal ossification
-  High T4 accelerates epiphyseal fusion ( advances bone age)

i.e high and low levels make you short

Question 23

Whats the role of T3,T4 in catecholamine sensitivity?

Answer 23

 T4/T3 increases sensitivity of target tissues to catecholamines

• Lipolysis
• Glycogenolysis
• Gluconeogenesis

Question 24

What does T3 do to b adernergic receptors?

Answer 24

 T3 ⇑ β-adrenergic receptors in the heart & skeletal muscles, adipose tissue, and lymphocytes

Question 25

How does T3 effect the heart?

Answer 25

 E.g. Heart
 Effect on BMR + Catechol effects + direct effects: ⇑ gene transcription of myosin & Ca2+ ATPase

Can cause massive tachycardia

Question 26

What is noted in hyperthyroidism?

Answer 26

Elevated BMR
- Hyperthyroid = 60-65 kcal/m2 body surface area/h
- Hot, sweaty, jittery
 ‘cat’abolism!
especially muscle often notice loss of sporting performance

Question 27

What are the symptoms of hypermetabolism?

Answer 27

 ⇑ cardiac output, ⇑ body temp., warm skin, ⇑ food intake but weight loss, diarrhoea, sweating, hyperactive, exaggerated reflexes, insomnia and irritability, goitre, Exophthalmia (bulging eyes: autoimmune), and short attention span

Question 28

What happens in hypothyroidism?

Answer 28

 Thyroxine slows the metabolic rate and oxygen consumption cold-intolerant, Lethargy, Obesity: 20-25 kcal/m2 body surface area/hr

Question 29

What happens to protein production in low thyroxine states?

Answer 29

 ⇓ Thyroxine ⇒ ⇓ protein synthesis
 brittle nails, thinning hair and dry skin
 slow bone and tissue growth of children, shorter stature

Question 30

What happens to the nervous system in low thyroxine states?

Answer 30

 ⇓ Thyroxine ⇒ ⇓ Nervous System actions
 Slowed reflexes, slowed speech and thought process

(as T4 but not T3 crosses BBB)

Question 31

What happens to the heart in low thyroxine states?

Answer 31

 ⇓ Thyroxine ⇒ ⇓ Cardiac output  slower heart rate = Bradycardia

Question 32

What are the symptoms of hypothyroidism?

Answer 32

Hypothyroid = 20-25 kcal/m2 body surface area/h
 reduced metabolism, weight gain,
Don’t tolerate cold
 In older adults, peripheral edema
due to heart failure is common

Question 33

What is a characteristic of hypothyroidism?

Answer 33

Myexdemic “Puffy” appearance:

fluid under the skin due to altered starling exchange

Question 34

Is thyroxine critical in musculoskeletal development?

Answer 34

 T4/T3 are essential for normal development of the skeletal system and musculature.

Question 35

Is T4 important in brain development?

Answer 35

 T4 critical for normal brain development  regulate synaptogenesis, neuronal
integration, myelination and cell migration

Question 36

What happens if congenital hypothyroidism is left untreated?

Answer 36

An infant with ‘cretinism’. Note the hypotonic
posture, coarse facial features, and umbilical hernia

• constellation of defects
• Screening program is very effective and treatment can allow normal development