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
11 beta hydroxylase deficiency
CAH
Accounts for up to 5% of CAH- 2nd most common type
Blocks conversion of:
i. Deoxycoricosterone (DOC)–> corticosterone (which then –> aldosterone)
ii. 11-deoxycortisol –> cortisol
Consequences
i. ↑ ACTH secretion
ii. Low cortisol
iii. Elevated androgens
iv. RAS suppressed
v. ↑ levels of DOC and 11-DOC
1. Shunted into androgen biosynthesis in similar manner to classical CAH
2. DOC has weak mineralocorticoid function (high levels due to high ACTH, this is able to suppress renin angiotension system–> hypertension, low renin, low aldosterone)
vi. Some cortisone is synthesized from progesterone by the intact aldosterone synthase enzyme – therefore unusual for patients to manifest signs of adrenal insufficiency
Summary
i. Excess androgens – milder than 21-hydroxyalse
ii. Excess mineralocorticoid activity (via DOC)
iii. Hypertension rather than salt wasting
iv. Cortisol insufficiency
3. Clinical manifestations
a. Hypertension + hypokalaemia
b. Female newborns – virulized
c. Boys – may have increased penile size
d. Children not diagnosed at birth
i. Premature adrenarche with advanced bone age
Androgen
insensitivity syndrome.
46XY- range from phenotypic females to males with various forms of ambiguous genitals and
undervirilization to phenotypically normal appearing males with
infertility.
Testes always present (as SRY gene present) but may be undescended
normal to elevated levels of testosterone levels - as receptors are unresponsive
CAH
More than 90% of cases of
CAH are caused by 21-hydroxylase deficiency. The most important problem caused
by accumulation of steroid precursors is that 17-hydroxyprogesterone is shunted
into the pathway for androgen biosynthesis, leading to high levels of androstenedione
that are converted outside the adrenal gland to testosterone. This problem
begins in affected foetuses by 8-10 wk of gestation and leads to abnormal
genital development in females. Masculinised female
genitalia manifest as enlargement of the clitoris and by partial or complete
labial fusion. The vagina usually has a common opening with the urethra
(urogenital sinus). The clitoris may be so enlarged that it resembles a penis,
because the urethra opens below this, some females may be mistakenly presumed
males with hypospadias and cryptorchidism.
Alopecia areata
: Alopecia areata is a rapid and complete loss of hair in round or oval patches on the scalp and on other body sites. Autoimmune lymphocytes react against hair follicles, all patients have autoantibodies to hair follicle antigens. It is associated with atopy; nail changes such as pits, ridges, opacification, serration of the free nail edge, dystrophy, and a red lunula; cataracts or lens opacification; and autoimmune diseases such as Hashimoto thyroiditis, Addison disease, pernicious anaemia, ulcerative colitis, myasthenia gravis, collagen vascular diseases, and vitiligo are also associated.
Most commonly affected hormone after craniopharyngioma surgery
ADH
—> DI post op
What endocrine defect are kids with T1DM most at risk of developing
Hypothyroidism
Investigation for suspected cushings
24 hour urinary cortisol and midnight salivary cortisol
dexamthethosone supression test
Investigation for suspected adrenal insufficiency
Short synacthen test
Administer synthetic ACTH
Measure response- cortisol levels at regular time intervals
Adrenal insufficiency confirmed with minimal cortisol secretion in response to acth
Most common cause of Cushing’s syndrome in kids
Exogenous steroid therapy is the most common cause of Cushing’s Syndrome. In young children who are not on steroids, around 50% of cases are due to a ACTH secreting pituitary adenoma and 50% due to adrenal tumours.After the age of 7 pituitary adenomas account for around 75% of cases.
Only investigation needed for likely constitutional delay
Bone age
If in keeping with pubertal stage likely to be constitutional
Investigations for homocysteinuria
diagnosed by measuring urine homocysteine and methylmalonic acid, or by a plasma amino acid profile (which usually shows elevated plasma homocysteine and methionine). Amino acid profile may be more informative as it can help to predict response on pyridoxine (vitamin B6) treatment.
Craniopharyngeoma
Arise in embryonally misplaced cells of the craniopharyngeal duct in the base of the brain, so that the tumor itself is not neural in origin. Cystic changes and calcified masses are characteristic of childhood craniopharyngiomas.
Clinically often presents with visual disturbances due to the compression of the optic nerves or the optic chiasm.
About 50% of childhood craniopharyngiomas extend upward into the third ventricle and result in hydrocephalus.
Endocrinological function is almost invariably disturbed: growth hormone deficiency (75%); thyroid-stimulating hormone deficiency (25-64%); adrenocorticotropic hormone deficiency (25-56%); luteinising hormone or follicle-stimulating hormone deficiency (40-44%); diabetes insipidus (9-17%, but almost 100% post-op).
Most common cause of central precocious puberty
. CPP in girls is only pathological in 10-20% of cases, but is more likely to be pathological if onset is at <6 years of age and/or is rapidly progressive. Hypothalamic hamartomas are the most common CNS cause of precocious puberty; in some cases puberty is preceded by gelastic seizures. Puberty in these instances is always isosexual. In NF1, optic gliomas interrupting the HPG axis are the most common cause of CPP. Regardless of the causative lesion, treatment with a GnRH-agonist is the treatment of choice for halting pubertal development.
What is most important in controlling parathyroid hormone secretion?
PTH secretion regulated by serum ionised calcium via a sensitive calcium sensing receptor on surface of parathyroid cells. A small increase in serum ionised calcium is detected by the calcium sensing receptor, and causes an inhibition of PTH secretion.
SIADH
where there is excessive secretion of antidiuretic hormone. ADH regulates the
permeability of the luminal membrane of the collecting ducts. ADH results in increased numbers of aquaporin channels in the collecting ducts which increases permeability to water, so more water is reabsorbed which creates more concentrated urine.
Serum creatinine should not be affected. In simple terms excess ADH makes the serum more dilute
and the urine more concentrated.
Stages of puberty
In girls:
The adrenal gland transitions to produce increased levels of DHEA-S at around 6 years (adrenarche)
Breast development (thelarche) is usually the first sign of puberty (10–11 years)
Appearance of pubic hair (pubarche) 6–12 months later
Peak height velocity occurs early (at stage II–III, typically between 11 and 12 years of age) in girls and always precedes menarche
The interval to menarche is usually 2–2.5 years
The mean age of menarche is about 12.75 years
In boys:
Growth of the testes (>4 mL in volume or 2.5 cm in longest diameter) and thinning of the scrotum are the first signs of puberty
Followed by pigmentation of the scrotum and growth of the penis
Pubic hair then appears, axillary hair usually occurs in mid-puberty
Acceleration of growth maximal at genital stage IV–V (typically between 13 and 14 years of age
Transient hypothyroxinaemia
: Transient hypothyroxinaemia. In preterm infants, levels of T4 in the first day vary directly with gestation. However, unlike in term infants, the concentrations of T4 decrease to reach a nadir between day 10 and 14 after birth. This is more severe at lower gestations and birth weights. Thyroid hormone levels then tend to return to normal levels after three weeks, but continue to increase up to six to eight weeks after birth.
GLUT1
brain
GLUT 2
pancreas
liver
small intestine (basolateral)
GLUT3
neurons
GLUT5
small intestine (apical)
spermatocytes
GLUT4
skeletal muscle and adipocytes
Insulin secretion pathway
i. glucose enters pancreas via GLUT2
ii. Glucose is phosphorylated to glucose-6-phosphate by glucokinase
iii. Glucose-6-phosphate can then be metabolised to generate ATP
iv. ↑ ATP leads to closure of ATP-sensitive K channel (K-ATP)
v. Closure of channel = intracellular accumulation of potassium = depolarisation of membrane
vi. Voltage gated calcium channels open
Influx of calcium inside the cell leads to secretion of insulin via exocytosis
MODY types
All AD
i. MODY 1 chromosome 20 = HFN4 alpha
ii. MODY 2 chromosome 7 = glucokinase (CCK)
MODY 3 chromosome 12 = HFN1alpha (most common)–> glucosuria
1 and 3 are reduced insulin secretory response to glucose
2 is defective glucokinase, so higher levels of plasma insulin needed to elicit a normal insulin secretion response
RX: MODY1 and MODY3 = sulphonylurea to increase insulin secretion
MODY 2 = diet
Heritability/genetics of T1DM
a. 85% of newly diagnosed have NO family history
b. No family history – 0.4 %
c. Offspring of an affected mother – 1 to 4 %
d. Offspring of an affected father – 3 to 8 %
e. Offspring with both parents affected – reported as high as 30 %
f. Non-twin sibling of affected patient – 3 to 6 %
g. Dizygotic twin – 8 %
h. Monozygotic twin – 30% within 10 years of diagnosis of the first twin + 65 % concordance by age 60 years
i. HLADR3/DR4 + DQ2/8 1. Results in 1/20 risk of T1DM compared with 1/300 population risk
Diagnostic criteria diabetes
i. Fasting (>8 hours) BSL >7 mmol/L on more than one occasion
ii. Random BSL >11.1 mmol/L on more than one occasion in a patient with symptoms of hyperglycaemia
BSL >11.1 two hours after oral glucose load of 1.75 g/kg (max 75g) in OGTT (rarely done)
Progression of antibodies in D1DM
Anti Insulin –>GAD –> IA-2
Anti insulin antibodies
· Usually detected at T1DM diagnosis
· Present in 50% of children
Tends to appear first – disappears with insulin therapy
Anti-glutamic acid decarboxylase (anti-GAD) antibodies
· One of the most commonly detected antibodies
· 70-80% have antibody detectable at time of diagnosis
· Often present before clinical manifestations
Remain positive for a long time after diagnosis
Anti-insulinoma protein 2 (anti-IA2)
· Appears later than insulin and GAD
· Present in 50-75% of newly diagnosed
Considered the best predictive marker for T1DM development
most common endocrinopathy in kids with t1dm
hypothyroidism in 10%
coeliac disease in 5-10%
presentation of coeliac disease in kids who have T1DM
· Clinical manifestations
o Unpredictable BSL
o Recurrent hypoglycaemia
o Poor glycaemic control
Growth failure (GIT symptoms less likely)
most specific test for coeliac disease
EMA
most sensitive test for coeliac disease
TTG
Antibodies in Graves
anti TSH receptor antibodies (TRAbs) - 95%
Anti TPO- 80%
Antibodies in hypothyroidism
Anti thyroglobulin antibodies
Anti thyroid peroxidase antibodies
DKA severity classification
i. Mild = pH <7.3, bicarb 15
ii. Moderate = pH < 7.2, bicarb 10
Severe = pH < 7.1, bicarb < 5
Potassium in DKA
Often initially (but total body potassium depleted) due to extracellular shift of K in exchange for H+ from acidosis
Insulin –> K into cells –> Hypokalaemia with treatment
MUST replace K
Sodium in DKA
is heritability stronger in T1DM or T2DM
T2DM by far
i. Offspring of one parent with T2DM – 40% ii. Offspring of both parents with T2DM – 60% Monozygotic twins – 90% chance
Biuanide
eg Metformin
- reduces hepatic glucose production, increases insulin sensitivty and increases peripheral glucose uptake
A/E: GI, lactic acidosis
Doesnt cause hypos (only enhances endogenous insulin production)
Sulphonylurea
eg. GLIclade, GLIpizide
increases insulin secretion from pancreatic beta cells
A/E: hypoglycemia (one pill can kill in small kids)
Weight gain
GI upset
Used in MODY type 1 and 3
GLP1 analogues
Eg Exena-TIDE
Improve pancreatic islet glucose sensing, improve gastric emptying, improve satiety
A/E: N/V, headache, weight loss
SLGT2 inhibitors
Eg. Dapa-GLIFLOZEN
Promote glycosuria
A/E: thrush, balanitis
what respiratory condition is more likley in a baby of a diabetic mother
RDS maternal hyperglycaemia delays surfactant production
Leptin
secreted by adipose cells
appetite suppression/satiety
Ghrelin
secreted by parietal cells stomach
stimulates hunger
CCK
· Enteroendocrine cells of duodenum and jejunum
Signals satiety and promotes secretion of bile/pancreatic enzymes
C peptide elevated in
T2DM
C peptide low in
T1DM
Exogenous insulin (factitious)
diabetes insipidus
relative of absolute lack of ADH or inability to responnd to ADH
–> inability to concentrate urine
Concentrated serum, osmol >295
Inappropriately dilute urine
Urine osmol <700 (ie excess free water loss as unable to reabsorb water via ADH mediated aquaporins)
Polyuria
Dehydration with short period of water restriction
A normal person has urine osmol <290 with ability to concentrate urine >800 with water deprivation
Diagnosis of DI vs polyruria
water deprivation test (overnight)
If urine osmol <300 (ie dilute) => DI
If urine osmol >750 (ie appropriately concentrated) => primary polydypsia
Differentiating Central DI vs nephrogenic DI
Desmopressin (ADH anolog)
If urine osmolality increases >800 —> central DI
ie giving ADH fixes the problem
If urine osmol still <300 or still <750
- partial or complete nephrogenic DI
ie kidneys are unresponsive to ADH
Treatment nephrogenic DI
water
low sodium diet
thiazide diuretics
Causes nephrogenic DI
mutation in vasopressin V2 receptor
chronic lithium therapy
Actions ADH
increased plasma osmolality -
reduced plasma volume –> vagal nerve stimulation angiotensin II
-> release ADH from posterior pituitary
ADH ACTS ON:
KIDNEYS: aquaporin insertion into collecting duct (principal cells) - > water reabsorbtion
VASCULAR SMOOTH MUSCLE: increase vasoconstriction –> increased blood volume and BP
if hypovolemic, ADH will be secreted even in hypoosmotic states
Calcitonin
Produced by parafolicular (C) cells of thyroid
OPPOSES actin of PTH
LOWERS calcium level
Can be used as part of treatment of hypercalcemia
Acts to reduce bone resorption , and reduce Ca/PO4 resorption in kidney
Action of PTH
- Bone- increased resorption of calcium by osteoclasts (–> moves calcium and phosphate int extracellular fluid)
- Kidneys- increased calcium resorption, increased phosphate excretion
Increased 1,25 (OH)D formation –> acts on intestines t o increase calcium + phosphate absorption
Overall: increased plasma calcium; reduced phosphate
Hyperparathyroidism
Increased PTH –> increased serum calcium
1: oversecretion of PTH due to parathyroid adenoma/hyperplasia/carcinoma , MEN1/MEN2
2. normal secretion of PTH in response to hypocalcemia or vit D deficinecy
3. ESKD
MoA glitazone/thizaolidinedione
increase insulin sensitivity
hypergonadotrophic hypogonadisjm
kleinfelters syndrome
low testosterone
elevated FSH and LH (and normal GnRH)
hypogonadotrophic hypogonadism
eg Kallaman , prader willis
low testosterone
Low FSH, LH due to low GnRH
what is the only test needed for benign premature adrenarche
ACTH stimulation test (ie short synacthen) to rule out late onset CAH
(check cortisol production in response to ACTH )
early pubic hair, increased sweat and body odor <6 years
no breast development
notmal growth and bone age
modestly elevated DHEA and sex hormones in the pre pubertal range
No treatment needed
what is the most common way to present with complete androgen deficiency
non classical form:
patients will have normal female external genitalia and may not be diagnosed until a failure of normal pubertal development occurs - amenorrhoea.
genotypic males, appear female (externally) BUT have testes inside and no uterus/ovaries as AMH has still been produced to cause regression of anti mullarian ducts
what does aromatase do
catayses conversion of testosterone to oestrogen
aromatase deficency means less eostrogen/more testosterone thus present as a virulised female
what does glucokinase do
phosphorylates glucose to glucose 6 phosphate
which hormone is most commonly deficient after brain surgery when posterior pituitary is impacted
ADH (- diabetes insipidus)
second most common is growth hormone
infant with a STAR mutation will present with
female genitalia +/- palpable gonads
unable to make any steroids
if XY baby- no testosterone made, thus will look like female baby
if XX- no genital anomalies, present with adrenal crisis
HCG test
Looks at testosterone secretion
HCG stimulates LH receptors on leydig cells to stimulate teststerone release
answers the question - is there any testicular tissue?
used if
inhibin B
secreted by sertoli cell s
inhibits FSH secretion
difference in result between PTH and vit D secretion
PTH- increased calcium, reduced phosphate
vit D- increased calcium and phosphate
vit D acts on intestine mainly to increase vit D and phosphate absorption, bone resorption, and increase bone resorption at kidney
PTH acts mainly to increase bone resorption but also increases calcium resorption/phosphate excretion at kidney, and increases formation of 1,25 OH vit D to increase calcium resorption at intestines
