Endocrine Flashcards
hyperthyroidism
symptoms
- b receptor stimulation –> hyperreflexia
- staring gaze with lid lag
- muscle weakness - CK elevated (will see muscle weakness in hypothyroid, but no elevated CK)
- hypocholesterolemia due to increased LDL receptor expression
Graves dz: HLA-DR3, HLA-B8
- goiter
- exophalmos - caused by lymphocytic infiltration –> cytokines that stimulate fibroblasts…., enlargement of extraocular muscles (myositis), fibroblast proliferation, and overproduction of mucopolysaccharides
- all in response to thyroid antibodies - fibroblasts have TSH receptors –> increased GAGs (GAGs are also increased in MVP, dermatan sulfate)
- also pretibial myxedema - scalloping of colloid
- treat with b-blockers, thioamide (blocks peroxidase), radioI ablation
- feared complication = thyroid storm (during stress) –> tachy, hyperthermia, vomiting and hypovolemic shock
- treat with PTU, b-blockers, KI, and steroids (4Ps, corticosteroids decrease 5-deiodinase activity) - if you surgically remove a thyroid gland - give postop calcitriol to prevent post hypocalcemia
toxic multinodular goiter = Plummer’s disease
- regions become TSH-indep
- hot nodules are rarely malignant - decreased TSH and rest of gland is suppressed
(v. s cold nodule - most cold nodules in women are benign, any cold nodule in a man/kid is cancer until proven otherwise)
multinodular goiter - due to I DEFICIENCY
- euthryoid - low thyroid results in increased TSH
- Jod-Basedow phenomenon - thyrotoxicosis if pt is made I replete
DKA
high anion gap! (+other findings)
metabolic acidosis = PaCO2 = 1.5*HCO3 + 8 +/- 2
- Kussmaul respirations
but in severe DKA - pts get pulm edema, respiratory fatigue, decreased MSE –> respiratory failure, hypoventilation
lose K - total body K deficit, so low intracellular stores
1) glycosuria-induced osmotic diuresis
2) hypovolemia-mediated increase in aldosterone secretion
- extracellular K+ concentrations are normal/increased
- hyposmolarity (due to volume depletion) –> hyperkalemia
- lack of insulin shift K extracellularly - insulin normally causes K+ to enter cells
* note - insulin and lack of insulin (as well b-agonists) will cause differences in intracellular K vs. extracellular K
- diuretics, mineralocorticoid excess, GI losses will change intracellular and extracellular K in the SAME direction
Klinefelter
progressive destruction and hyalinization of seminiferous tubules
- serum inhibin levels are low due to Sertoli cell damage
- Leydig cell dysfunction - low testosterone
- via feedback - LH and FSH are high
- gynecomastia - due to gonadotropin excess (stimulates aromatase)
- azoospermia
scenario: normal hormones but no sperm = obstruction (CF)
scenario 2: pt is on exogenous steroids - high blood testosterone but testosterone in testes is decreased –> low sperm count
scenario 3: cryptorchidism - Sertoli cells are damaged but Leydig cells are not –> high FSH, normal LH
hypothyroid
muscle weakness, brittle hair, diastolic HTN
T3 inhibits at hypothalamus and pituitary
- T3 is produced in peripheral tissues
hypothyroid - most common cause in US is Hashimoto (HLA-D5, also associated with pernicious anemia)
- autoimmune destruction due to inhibitory TSH receptor antibody- hyperthyroidism –> hypothyroidism
- moderately enlarged, non-tender thyroid
- can see antithryoglobulin and antimicrosomal antibodies - markers of damage, but dont mediate disease
- T3 has a short half-life and conversion in peripheral tissues can be variable = T3 levels fluctuate a lot and can remain normal until relatively-late stage hypothyroidism
- histology: focal formation of germinal centers (enlarging thyroid, be concerned for B cell lymphoma) and Hurthle cell change (follicular epithelium turns pink)
estrogen (preg, OCPs) increase TBG levels - will also increase total T4
cretinism
- 6 Ps: pot-bellied, pale, puffy-faced child, protruding umbilicus (hernia), protuberant tongue, poor brain development
- hoarse cry, prolonged jaundice
- causes - dysgenesis is most common in US
myxedema - hypothyrodism in older kids or adults
- myxedema esp in larynx (deeper voice) and enlarged tongue
subacute thryoiditis (de Quervian) - granulomatous thyroiditis that follows the flu, ESR is elevated, jaw pain - *tender* thyroid, self-limiting
silent thyroiditis - painless, associated with thyroid antibodies, can occur post-partum
Reidel fibrosing thyroiditis - hard as wood, nontender thyroid, fibrosis can extend to airway
- young females
- considered an IgG4-related systemic disease (reidel fibrosing thyroiditis, AI pancreatitis, retroperitoneal fibrosis, noninfectious aortitis
- mimic is anaplastic carinoma
myxedema coma = extreme hypothyroidism –> low CO, etc.
synthetic T3 is not recommended for treatment - it has a short half-life –> wide-fluctuations in T3 levels
progesterone
acts via type 1 nuclear receptor –> binds hormone and translocates to the nucleus
chronology of anterior pit deficiency
GH > FSH > LH > TSH, ACTH > PRL
- latter 3 are centrally located
FSH, LH, TSH, HCG - a and b subunits are paired in the ER and Golgi
POMC –> ACTH, b-endorphin, MSH
GH and prolactin are acidophils
GH
GHRH - binds to Gs–> activates adenylyl cyclase and phospholipase C
- GH contains disulfide bridges
pulsatile secretion - largest burst within 1 hour of falling asleep and during stages 3 and 4
secretion stimulated by: hypoglycemia and decreased FFA concentration, arginine, fasting/starvation
- stress, exercise
- estrogens/testosterones during puberty
- a-agonists and b-antagonists
- clonidine/arginine stim test to assess for deficiency
inhibited by: glucose, somatostatin, obesity/senescence, GH, pregnancy, b-agonists
GH release in low glucose state, a-agonists and b-antagonists
feedback loops:
1) GHRH inhibits its own secretion
2) somatomedin (ex IGFs) - inhibit anterior pit directly
3) somatomedins stimulate hypothalamus to secrete somatostatin –> inhibits anterior pit (Gi)
actions: direct tissue effects, growth mediated by IGF1 (produced in liver)
1) chondrocyte proliferation, increased protein synthesis and organ growth
2) diabetogenic - GH causes insulin resistance = decreased glucose uptake and increased lipolysis –> increased insulin levels
- GHRH analog tesamorelin is used to treat HIV-associated lipodystrophy
deficiency - any number of reasons, failure to generate somatomedins in liver
excess
- acromegaly - …increased risk of colorectal polyps and cancer, typical treatments and can also give cabergoline
Laron syndrome = dwarfism
- defective GH receptors - GH increased, IGF1 decreased
- ….small genitalia
drugs:
ocreotide - somatostatin analog
pegvisomant - GH receptor antagonist
tesamorelin - GHRH analog
prolactin
bromocriptine is a D agonist, cabergoline (more effective at D2, fewer side effects)
somatostatin
TRH and estrogens (OCPs, pregnancy) stimulate prolactin
actions:
1) breast development during puberty (duct proliferation), pregnancy (alveoli)
2) lactogenesis in response to suckling
- during pregnancy, high levels of estrogen and progE down regulate prolactin receptors in breast
3) inhibits ovulation - inhibits GnRH release
long-term complication = osteoporosis
hypopituitarism
pituitary adenoma - apoplexy
craniopharyngioma in kids
Sheehan syndrome - pituitary doubles in size during pregnancy, susceptible to infarct
empty sella syndrome
- idiopathic, more common in obese women
- trauma
- primary defect of sella - where arachnoid and CSF herniate into sella and destroy pituitary
posterior pit
secretory vesicles contain neurophysins - involved in posttranslational hormone processing
ADH = supraoptic nuclei
- blood osm, hypovolemia (decreases in volume by 10% –> baroreceptors –> vagus nerve –> hypothalamus)
- also stimulated by …hypoglycemia, nicotine, opiates, antineoplastic drugs
central DI - water deprivation fails to increase urine osm, greater than 50% increase seen in URINE osm after administration of ADH analog
- due to damage to hypothalamic nuclei! - if post pit is damaged, axonal regeneration and hypertrophy will still allow ADH release into circulation
- will see early SIADH
- treat with ddAVP (can also be used to treat nocturnal enuresis)
nephrogenic DI - treat with thiazides!
1) thiazides inhibit NaCl reabsorption at the early DT
2) ECF and blood volume decreases - GFR decreases
3) and proximal reabsorption of solutes and water is increased = ultimately more water is reabsorbed
- can also use indomethacin, amiloride
SIADH - euvolemic hyponatremia with continued urinary Na excretion
- decreased aldosterone in response to water retention
- hyponatremia - swelling of nerves, seizures. Correct Na slowly to prevent central pontine demyelination.
- SCC lung/pulmonary infection, CNS trauma, drugs (antipsychotics, cyclophosphamide)
- increased urine osmolality during water deprivation indicates psychogenic polydipsia
......... oxytocin = paraventricular nuclei - milk ejection - by stimulating contraction of myoepithelial cells - smooth muscle contraction - inhibited by opioids
adrenal cortex and CORTISOL
mesoderm
CRH is released from PVN (same nucleus where oxytocin is made) –> Gs –> ACTH
1) stimulates transfer of stored cholesterol into mitochondria
2) stimulates binding of cholesterol to CYP450
3) activates cholesterol desmolase
- ACTH stimulated by low cortisol, sleep-wake transition (cortisol secretion is highest after waking), stress, ADH, a and b agonists
steroid hormone synthesis requires CYP450, O2, NADPH, FAD, Fe-containing enzymes
cortisol feedback loop - cortisol inhibits secretion by hypothalamus and ant pit
- also inhibits hippocampus –> hypothalamus
17-a-hydroxylase can be blocked and corticosterone will still be produced without deleterious effect
cortisol: catabolic and diabetogenic
1) mobilizes glucose - gluconeogenesis, protein catabolism, lipolysis (glycerol –> glucose), decreases glucose utilization and insulin sensitivity
2) anti-inflammatory
- induces synthesis of lipocortin - inhibits phospholipase A2
- inhibits histamine and serotonin release from mast cells
- inhibits IL2 production (can cause reactivation of Tb or candida)
- decreases eos, lymphocytes are redistributed to spleen/BM/LNs, monocytes and macrophages cant extravasate
- inhibits neutrophil adhesion
3) a1 receptors
4) inhibits bone formation and decreases fibroblast activity
5) increases GFR by causing vasodilation of afferent arterioles
6) decreases REM sleep
……………….
Cushings = hypercortisolism
- proximal muscle weakness, purple striae
- hyperglycemia –> excess insulin –> truncal obesity and fat deposition
- excess androgens, amenorrhea (due to HPA axis suppression)
- ACTH causes hyperPLASIA
- initially increased ACTH will increase cholesterol metabolism…
- with time - ACTH will induce protein synthesis (steroidogenic enzymes), cell proliferation - no ACTH causes atrophy
- tests: increased 24hr urine cortisol, increased midnight salivary cortisol, no suppression with overnight low-dose dexa
- Cushings disease - pituitary adenoma
- distinguish between pituitary adenoma and ectopic with high dose dexa or CRH stim test (ectopic secretion will not increase with CRH because pit ACTH is suppressed)
- ACTH levels: ectopic > pituitary > adrenal - treat with metyraprone (inhibits 11-hydroxylase - cortisol and aldosterone cant be produced) or ketoconazole
pt is on exogenous glucocorticoids –> widespread atrophy (of hypothalamic neurons, adrenals, etc.)
- cortisol levels that CANT rise in response to stress (surgery, infection) –> relative glucocorticoid deficiency even when pts baseline regimen is maintained
adrenal androgens
major source of androgens in women
adrenal androgens = DHEA and adnrostenedione, testosterone is minimally produced
side chain cleavage enzyme - converts cholesterol to pregnenolone
- first step in steroidogenic pathway
congenital adrenal hyperplasias - low cortisol, high ACTH
21-b-hydroxylase deficiency (AR) - only sex steroids (including 17-hydroxyprogesterone, which is specific to adrenals as opposed to the testes)
11-b-hydroxylase def - weak mineralocorticoids are being produced
17-hydroxylase def - excess of mineralocorticoids so aldosterone will be DECREASED (to due RAAS feedback)
- pseudohermaphroditism XY - ambiguous genitalia, undescended testes
- males and females dont undergo puberty
5a-reductase - inhibited by finasteride
aldosterone
ACTH controls cholesterol desmolase activity (only a tonic ACTH level is required), aldosterone synthase is stimulated by ang2
RAAS is activated by a decrease in ECF volume or increases (ang 2 binds to AT1 receptors on adrenals) in serum K+ (serum K+ acts directly –> triggers Ca2+ influx –> aldosterone secretion)
affinity for mineralocorticoid receptors for aldosterone = cortisol
- 11b-hydroxysteroid dehydrogenase
Conn syndrome - adrenal adenoma or bilateral adrenal hyperplasia
- high aldosterone, low renin = PA/PRA >20, treat with spironolactone and surgery
Secondary hyperaldosteronism - due to RAAS activation
no edema in hyperaldosteronism - because of volume/pressure-induced natriuresis (aldosterone escape mechanism)
adrenal insufficiency
Waterhouse-Friderichsen syndrome - classically young kid who gets an N. meningitidis infection –> DIC, endotoxic shock, petechial rash–> bilateral necrosis of adrenals –> exacerbated HYPOtension
Addison’s disease - autoimmune destruction of entire cortex (west) or Tb-associated destruction
- in general - in primary adrenal insufficiency, you will see cortisol AND aldosterone insufficiency
cosyntropin (ACTH analog) - tests adrenal reserve
metyrapone stim tets - blocks 11-deoxycortisol to cortisol
- normally - if you give metyrapone –> decrease cortisol –> increased ACTH
- in 2/3 adrenal insufficiency - both ACTH and 11-deoxycortisol remain decreased after test (gland has atrophied)
gluco/mineralocorticoids
fludrocortisone - synthetic aldosterone analog
- tox - same as glucocorticoids + edema, HF exacerbation, hyperpigmentation
tox for glucocorticoids - ….peptic ulcers, steroid diabetes, steroid psychosis (confusion, hallucinations)
dexamethasone will NOT cross-react with cortisol detecting assay
catecholamines
b: epi > NE
a: NE > epi
need vitamin C to make NE from DOPA
preG sympathetic fibers of greater splanchnic nerve release Ach –> chromaffin cells of adrenal
neuroblastoma - N-myc, Homer-Wright rosettes (also seen in medullloblastoma), opsoclonus-myoclonus syndrome
- smooth mass that can cross midline
- HVA (breakdown of dopamine) and VMA in urine
- Bombesin and NSE+
pheo - adrenal medulla is brown
- VHL, RET (tyrosine kinase), NF1, MEN2
- remember Hirschsprung’s disease is also associated with RET mutations - ….can get orthostatic hypotension due to low plasma volume
- surgical excision: but first give phenoxybenzamine (irreversible blocker of a receptors –> otherwise will get masssive HTN and death) and next give b-blockade (labetolol)
- rule of 10: 10% bilateral, 10% extra-adrenal (bladder wall), 10% malignant, 10% calcify, 10% kids
dopamine
somatostatin
decreases prolactin and TSH
- dopamine can be decreased - …chest wall injury (via ANS)
somatostatin - decreases GH and TSH
MEN
menin tumor suppressor gene, AD
MEN1: 3 Ps, c11
*primary hyperparathyroidism
pituitary tumors
pancreatic tumors (gastrinoma, insulinoma)
MEN2A: RET, 2Ps
*medullary thyroid cancer
pheochromocytoma
PTH adenoma
MEN 2B: RET, 1P *medullary thyroid cancer pheochromocytoma mucosal (lips, tongue) adenoma associated with marfanoid habitus
apetite
ghrelin - stimulates hunger and GH, produces by stomach
- sleep deprivation and PW increase ghrelin production
leptin
endocannabinoids - act at hypothalamus and NAcc
- increased appetite
signaling pathways
vasodilators work by cGMP - ANP/BNP, NO
insulin and GF - receptor tyrosine kinases –> MAPK
JAK/STAT - EPO/thrombopoietin/G-CSF, cytokines, prolactin and GH
IP3 - GnRH, TRH
- ADH (V1), Ang2, oxytocin
- gastrin, histamine (H1)
cAMP - all else
steroid hormones (including thyroid hormone) - OCPs, pregnancy increase SHBG
thyroid hormone production
1) thyroglobulin - contains large amounts of tyrosine
2) Na+/I- transport - thiocyanate and perchlorate block I- uptake
3) oxidation of I- to I2 by thyroid peroxidase - I2 travels to lumen
4) organification of I2 - thyroid peroxidase catalyzes I2 addition to tyrosine –> MIT, DIT
- Wolf-Chaikoff effect - high levels of I- inhibit thyroid hormone production
5) coupling reaction by thyroid peroxidase - T3 and T4
6) endocytosis of thryoglobulin - upon TSH binding
7) hydrolysis of T3 and T4 by lysosomal enzymes (and thyroid deiodinase)
- Li prevents thyroid hormone release
feedback: T3 inhibits TSH secretion by downregulating TRH receptors on ant pit
TBG decreases in - liver failure, steroids (T4 will be low)
- increases in pregnancy (estrogen inhibits TBG breakdown)
- salicylates decrease binding of T4 to TBG
- thyroid hormone increases SHBG production
- circulating levels of TBG can be assessed by: pts serum + radioactive T3 + T3 resin
5-deiodinase - liver and peripheral tissues
- starvation/illness/stress inhibits 5-deiodinase in muscle –> lower O2 consumption and BMR
- decreased conversion of T4 to T3 - pregnancy, neonatal period, hepatic and renal failure, b-blockers, glucocorticoids, and amiodarone
- obesity increases T4 to T3 conversion
PTU - blocks thyroid peroxidase and 5-deiodinase, safe during first trimester pregnancy
- agranulocytosis, aplastic anemia, hepatotox
methimazole - inhibits thyroid peroxidase
- can cause aplasia cutis
- used in second/third trimesters - risk of PTU-induced hepatotox
changes in thyroid hormones:
1) TSH
2) T4
3) T3
