Endocrinology Flashcards
T4
80% of thyroid hormone
converted to T3 and rT3 in target tissues
T3
20% of thyroid hormone
4x more potent
rT3
metabolically inactive
T4 –> T 3 + rT3 in equal amounts
increased rT3 conversion in sick eurthyroid syndrome
Free T3
active form
can freely diffuse through plasma membrane
amine hormone
receptor is in the nucleus - hydrophobic
Causes acquired hypothyroidism
Hashimotos
Iodine deficiency (1# cause worldwide)
Iodine excess
Thyroglobulin loss (protein losing enteropathy, ascites, nephrotic syndrome)
Primary congenital hypothyroidism
Main causes
85% sporadic, 15% hereditary
Dysgenesis (structural) 85%
Ectopic (lingual/sublingual)- 45%
Agenesis 33%
Hypoplasia
Dyshormonogenesis (functional- enzyme defect ) 11%
Due to AR genetic defect
Usually have goitre
Congenital hypothyroidism
presentation
95% asymptomatic first 3 months - then too late!
hypotonia
hypothermia
poor feeding
macrogossia
wide posterior fontanelle
distended abdomen
umbi hernia
dry skin
jaundice
constipation
delay passing meconium
Hashimotos
Anti-Thyroid Peroxidase (anti-TPO) 90-95% and Anti-Thyroglobulin 55-90% POSITIVE
USS- diffusely enlarged heterogenous thryroid
TPO iodises iodine to add it to thyroglobulin for the production of T4
Newborn screening is done after 48 hours of life because…
To avoid TSH surge that occurs at birth
Newborn screen detects HIGH TSH (rather than low T3/T4)
Doing it earlier would give many false positives
Newborn screening will detect all causes of congenital hypothyroid except
central hypothyroidism
as this doesnt produce a TSH rise
goal of hypothryroid treatment is to
normalise TSH, T3 or T4?
TSH!
Very sensitive marker of normal thyroid function
Dont really need to check T3 or T4 if TSH is normal
Hashimoto thyroiditis symptoms
weight gain
decreased height velocity
fatigue
lethargy
cold intolorence
bradycardia
goitre- painless, firm, irregular
rare- dysphagia, horseness, pain
increased risk SUFE
Hashimotos investigations
screen with TSH
if abnormal:
Would have low T3/T4
Elevated anti Tg and anti TPO
—> if antibodies not elevated, consider another cause for hypothyroidism
Treatment Hashimotos
L-T4
Goal: normalise TSH
Usually lifelong
Risk Hashimotos is increased in which syndromes
T1DM
Downs
Turners
Kleinfelter
Noonan
Bloods in Graves disease
elevated T3/T4, low TSH
Main antibody: TSH receptor antibody
Also elevated anti- TPO (thyroid peroxidase) and TSI (thyroid stimulating immunoglobulin–> acts like TSH)
Initial treatment of Graves disease
B blockers to block peripheral conversion of T4 to T3
treat 2-6 weeks
Carbimazole
onset of action several weeks thus beta blockers used in interim
avoid PTU - risk hepatotoxicity
Stop B blockers and reduce carbimazole when T4 and T3 are in the upper normal range
Adverse effects:
Embryology of thyroid
24 days
thickening of floor or pharynx
as tongue grows, the thyroid descends into neck
Thyroid hormone synthesis
iodine is taken up into thryroid folliculr cells
combine with thyroglobulin
enzyme- thyroid peroxidase
monoidoine tyrosine + diiodine tyrosine couples
what type of hormone is thyroxine
amine
hydrophobic
crosses plasma membrane to bind to receptor in cytoplasm
steroid hormones
synthesised from cholesterol
released immediately
hydrophobic
need a carrier in blood but can cross plasma membranes
bind to receptors in cytoplasm
affect gene expression
eg oestrogen, cortisol, aldosterone
peptide hormones
synthesised as pro hormones
stored in vesicles
hydrophilic
bind to receptors on cell surface, coupled to internally anchored proteins
complex activates second messangers- signal transduction eg cAMP, Ca, No
Fast onset, transient changes
eg insulin (binds to tyrosine kinase receptor), glucagon, ADH, oxytocin, prolactin, ACTH, PTH
amine hormones
synthesised from tyrosine
stored before release
can be hydrophilic (adrenaline), hydrophobic (T3. T4)
adrenaline acts on membrane receptors
thyroid hormones act on nuclear receptors
thus: adrenaline- like peptide, T3/T4- like steroid
Bound vs free thyroid hormone
free thyroid hormone is active and freely diffuse through plasma membranes
bound thyroid hormone (largely to thyroxine binding globulin - TBG)- cannot pass through plasma memberane, acts as reservoir
TBG made in liver
T4 is converted to…
T3 and rT3 in equal amounts
more rT3 is made when pregnant, fasting, or unwell
it is metabolically inactive
“sick euthyroid syndrome”
obese- more t3 made
central hypothyroidism
low T3/T4 with inappropriately low TSH
ie TSH SHOULD be high with low thyroid hormones
so TSH may be low, normal or slightly high, but not high enough
ie pituitary is putting out an inappropriately low effort to increase thyroid hormones
eg:
isolated TSH deficiency
panhypopituitarism
structural - midline defects eg septo optic dysplasia, cleft palate and palate defects
trauma or birth asphyxia
thyrotopin releasing hormone deficiency
when does the TSH surge peak after delivery
24 hours of life then falls
close to normal by day 5-7 of life
thus do newborn screening after 48 hours
–> only checks high TSH, thus central hypothyroidism will be missed
pendred syndrome
bilateral sensorineural hearing loss
goitre with euthyroid or mild hypothyroidism
causes transient hypothyroidism
Maternal antithyroid drugs eg graves disease
maternal TSH receptor blocking antibodies (TRAbs)–> thus need to do TFTs day 3, 7, and 14 of life
(maternal hypothyroidism doesnt give blocking antibodies so dont need TFTs tested. If Graves by TRAB negative- also no need for TFTs)
maternal iodine deficiency or excess iodine exposure in pregnancy
goitre in neonate - causes
most common with dyshormonogenesis
severe iodine deficiency
**occurs with high TSH stimulating thyroid gland
investigations to consider with hypothyroidism
formal TFT
Maternal TFTs and antibodies
thyroid nuclear medicine scan - is there a thyroid, where is it , and is it taking up iodine??- need to do this preferably before but within 72 hours of starting thyroxine
thyroid uss - delinitate size and structure
Ix results in central hypothyroidism
normal thyroid on uss
decreased uptake on NM scan
reduced or inappropriate normal TSH (may even be slightly high), low T4
ix results in dyshormonogenesis
normal or large thyroid on uss
usually increased uptake on NM scan - trying to take up more iodine to make more hormone
TSH elevated
T4 normal to low normal
what drug is associated with cutis aplasia
carbimazole
wolff chaikoff effect
autoregulatory phenomenon whereby excess iodine transiently inhibits thyroid iodide organification
inihibits organification (ie formation and release of thyroid hormones) to prevent the syntheis of large amounts of hromones after ingesion of large amounts of iodine
eventually “escape” from the mechanism to recommence thyroid hormone production ; but babies “cant escape” and become very hypothyroid when exposed to high iodine, even if topical eg betodine
subclinical hypothyroidism
normal t4 and slightly elevated tsh
normally dont need to treat
hyperthyroidism causes
graves disease
hashimotos toxicosis
toxic adenoma
multinodular goitre
graves disease
tsh receptor antibodies (trabs) binds tsh receptirs and cause activation (may also have anti tpo, or anti Tg antibodies)
low tsh elevated t3/t4
Cryptorchidism
Cryptorchidism is the most common congenital abnormality of the genitourinary tract [1]. Most cryptorchid testes are undescended (by definition, failure to descend by 4 months), but some are absent (due to agenesis or atrophy secondary to prenatal testicular torsion).
Between 2 and 5 percent of full-term and approximately 30 percent of premature male infants are born with an undescended testis [23-27]. Most (approximately 70 percent) undescended testes descend spontaneously so that by one year of age the prevalence is approximately 1 percent
Think of DSD if cryptorchidism is associated with:
-micropenis (DSD or hypopituitarism)
-hypospadias
-hypoplastic/poorly rugated scrotum
Male gonadal development
Genetic males have SRY gene on Y chromosome
SRY genes promote production of testis determining factor ~ week 7 –> acts on undifferentiated gonads –> testes formation
Wolffian duct (aka mesonephric duct) develops into male sex organs and genetalia, stimulated by testosterone (secreted by Leidig cells)
Sertoli cells secrete AMH, which promotes atrophy of Mullarian (paramesonephric) duct
5 alpha reductase coverts testosterone to more potent dihydrotestosterone (acts to masculinize the male genitalia)
Wolffian duct forms into the epididymis, vas deferens, ejaculatory duct, and seminal vesicle
descent of testes and development of external gentitalia both driven by testosterone
Urogenital sinus develops into
urethral folds –> urethra
labioscrotal swellings
primordial phallus
lower 2/3 of vagina
Female gonadal development
Without SRY gene to produce testis determining factor, the undifferentiated gonads develop into ovaries
Paramesonephric ducts form fallopian tubes and uterus, cervix, upper 1/3 of vagina
lower 2/3 vagina and external genitalia develop from the urogenital sinus
***excess testosterone causes elongation of cliterus and formation of scrotum instead of labia majora
Kallman syndrome
hypogonadotropic hypogonadism
isolated GnRH deficiency
Usually presents with delayed puberty and anosmia
HH can present at any age, but the presenting signs and symptoms are a function of the age-related period of reproductive activity.
●During the neonatal period, boys with the more severe cases of IHH can present with microphallus and/or cryptorchidism, presumably due to in utero and/or neonatal GnRH deficiency; approximately one-half of boys with microphallus have IHH as the underlying diagnosis. In comparison, newborn girls with IHH have no obvious abnormal reproductive tract findings that might provide clues to the diagnosis. However, in both sexes, other congenital nonreproductive features may be present (eg, midline facial defects, skeletal abnormalities).
●During childhood, since the hypothalamic GnRH-pituitary-gonadal axis is quiescent, a diagnosis of IHH can generally be heralded only in the presence of nonreproductive phenotypes (eg, the lack of sense of smell in some patients [anosmia] or skeletal abnormalities, such as cleft lip/cleft palate, hearing deficits, or syndactyly).
●At puberty, patients of both sexes can present with a complete form of IHH that is characterized by a failure to initiate sexual maturation (eg, lack of secondary sexual characteristics, primary amenorrhea in girls, lack of virilization in boys) and failure to establish a pubertal growth spurt
Septo optic dysplasia
underdevelopment of the optic nerve, pituitary gland dysfunction, and absence of the septum pellucidum or agenesis of corpus collosum.Two or more of these features need to be present for a clinical diagnosis — only 30% of patients have all three
hypopituitarism –> most commonly GH deficiency, can be all the way to panhypopituitarism
Developmental delay
seizures
must always replace cortisol first as replacing GH or T4 alone can lead to an adrenal crisis
Non classical CAH with 21- hydroxylase deficiency
Up to 50% enzyme activity is retained
Present later in life
Only partial glucocorticoid deficiency; ok in normal circumstances, but not enough in times of stress, so need a stress plan Both genders may present with precocious puberty, advanced bone age, accelerated growth velocity
Hirsutism, irregular menses, anovulation, may be infertile
advanced bone age differntiates CAH from ordinary premature adrenarche; often start puberty years earlier and have a very advanced bone age
↑↑ baseline and ACTH-stimulated 17-beta-hydroxyprogesterone
↑ Androgens
21 hydrohylase deficiency
Classical CAH
Glucocorticoid deficiency
Mineralocorticoid deficiency (salt wasting crisis)
Variation of genital development in females from clitoromegaly to ambiguous genitalia due to fetal adrenal androgen exposure; boys may have hyperpigmented scrotum
May present with salt wasting crisis first 10-14 days of life if not detected at birth – vomiting, hypotension, hyponatremia, hyperkalemia
↓ cortisol ↑ ACTH
↑↑ baseline and ACTH-stimulated 17-beta-hydroxyprogesterone
Hyponatreamia, hyperkalaemia
↑ plasma renin
↑ Androgens
21 hydrohylase deficiency
Simple virulising form
Simple virilizing: Retain 1-2% of 21OH activity, thus produce enough aldosterone to prevent salt wasting crisis
Precocious adrenarche, hirsutism, acne, menstrual irregularity, infertility, rapid skeletal growth, advanced bone age
