Lecture 18; Post Natal Growth 3 Flashcards
What is abnormal body proportion defined by;
%ile-height vs %-sitting height or arm span
What are the causes of disproportionate growth?
- 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
What can cause iodine insufficiency?
Overstimulation of the thyroid to produce T3,4
Autoimmune diseases
Describe T3,4 structure differences;
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)
What converts T4 to T3 in tissues?
Iodinase in target tissues
T3 is 5-8 fold more active that T4
What do the parafollicular cells in the thyroid make?
Calcitonin
Describe the synthesis of thyroglobulin;
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
How does TSH regulated T3,T4 production?
Promotes Iodine transport
Promotes endocytosis
What blocks iodine oxidation?
PTU (drug)
- Doesnt stop I uptake or endocytosis , therefore takes long time to start acting and finish (good control)
Describe T3,T4 loop;
Hyp
- TRH = +ive
- Dopamine or somatostatin = -ve
AP
- TSH (+ive)
Thyroid gland
- T3, T4 (-ive at AP and Hyp levels)
What is the problem?
FT4 6 pmol/L (N 11-20) TSH 65 (0.4-4.0iu/L)
Feedback dysinhibition!
Primary hypothyroidism (i.e. reduced activity of thyroid gland), e.g. autoimmune or I deficiency
What is the problem?
FT4 7.5 pmol/L TSH 3.5 iu/L
Central (secondary hypothyroidism) TSH “inappropriately normal”
Or… Sick euthyroid: major illness, starvation T4 converted to rT3\ Evolves over time
Where is the problem?
FT4 38 pmol/L (11-20) TSH < 0.04 (0.04-4.0)
Primary hyperthyroidism (i.e. excess activity of thyroid gland)
e.g. autoimmune disease of thyroid
Thyroid gland usually enlarged, depending on aetiology/timing
What enhances iodine uptake?
- TSH
- iodine deficiency (⇑ MIT:DIT ratios)
- TSH receptor antibodies (most stimulate!)
- autoregulation
What is iodine inhibited by?
- 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).
In blood what is T4 bound to?
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%
How much T4 is free?
Only ~0.02% of the total T4 in blood is unbound or free
How much T3 is free and whats its half life?
Only ~0.4% of total T3 in blood is free Half life?
T1/2 ~ 7 days
Are there variants of T3/
yes
T4 can form
T3 (step up)
or
rT3 (step down)
What do thyroid hormones do?
Regulate Long-term physiological homeostasis
Principal targets are: skeletal & cardiac muscle, liver, gut, and kidney
What specifically do thyroid hormones do?
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)
Whats the role of T4 in skeletal growth?
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
Whats the role of T3,T4 in catecholamine sensitivity?
T4/T3 increases sensitivity of target tissues to catecholamines
- Lipolysis
- Glycogenolysis
- Gluconeogenesis
What does T3 do to b adernergic receptors?
T3 ⇑ β-adrenergic receptors in the heart & skeletal muscles, adipose tissue, and lymphocytes
How does T3 effect the heart?
E.g. Heart
Effect on BMR + Catechol effects + direct effects: ⇑ gene transcription of myosin & Ca2+ ATPase
Can cause massive tachycardia
What is noted in hyperthyroidism?
Elevated BMR
- Hyperthyroid = 60-65 kcal/m2 body surface area/h
- Hot, sweaty, jittery
‘cat’abolism!
especially muscle often notice loss of sporting performance
What are the symptoms of hypermetabolism?
⇑ 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
What happens in hypothyroidism?
Thyroxine slows the metabolic rate and oxygen consumption cold-intolerant, Lethargy, Obesity: 20-25 kcal/m2 body surface area/hr
What happens to protein production in low thyroxine states?
⇓ Thyroxine ⇒ ⇓ protein synthesis
brittle nails, thinning hair and dry skin
slow bone and tissue growth of children, shorter stature
What happens to the nervous system in low thyroxine states?
⇓ Thyroxine ⇒ ⇓ Nervous System actions
Slowed reflexes, slowed speech and thought process
(as T4 but not T3 crosses BBB)
What happens to the heart in low thyroxine states?
⇓ Thyroxine ⇒ ⇓ Cardiac output slower heart rate = Bradycardia
What are the symptoms of hypothyroidism?
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
What is a characteristic of hypothyroidism?
Myexdemic “Puffy” appearance:
fluid under the skin due to altered starling exchange
Is thyroxine critical in musculoskeletal development?
T4/T3 are essential for normal development of the skeletal system and musculature.
Is T4 important in brain development?
T4 critical for normal brain development regulate synaptogenesis, neuronal
integration, myelination and cell migration
What happens if congenital hypothyroidism is left untreated?
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
