Exam review Flashcards
Prop1 mutations would cause deficiencies in which hormones?
Prolactin, GH, TSH
LH, FSH
Pit1 mutations would cause deficiencies in which hormones?
Prolactin, GH, TSH
Which hormones are acidophils (eosinophilic staining)?
GH, Prl
remember G-rl
ADH is made in the ______ nuclei
supraoptic nuclei
oxytocin is made in the _____ nuclei
paraventricular nuclei
What is embryologic derivative of anterior pituitary?
oral ectoderm (Rathke pouch)
What is embryologic derivative of posterior pituitary?
neuroectoderm
how does prolactin inhibit ovulation and spermatogenesis?
via inhibiting GnRH
What is role of GH on bones?
- linear growth at epiphyseal growth plates
- increase osteoclast differentiation/activity
- increase osteoblast activity
- increase bone mass by endochondral ossification
what are the anabolic effects of GH?
- stimulates amino acid uptake into tissues and increases muscle
- promotes lipolysis with fat breakdown
- causes insulin resistance
what is the hypothalamic control of GH?
GHRH (+)
somatostatin (-)
release of GH in sleep, exercise, stress, hypoglycemia
what is the hypothalamic control of TSH?
TRH (+) and somatostatin (-)
how is FSH secretion regulated?
stimulated by GnRH
inhibited via negative feeedback from Inhibin from sertoli cells and ovarian granulosa cells
what does ADH do?
binds to V2 receptors in renal collecting ducts which stimulates aquaporin 2 water channels to luminal membrane to allow water reabsorption back into collecting duct cells
what is normal histological appearance of anterior pituitary? posterior pituitary?
ant: reticulin network
post: Herring bodies (axonal expansions) and pituicytes (supportive glial cells)
how do you distinguish PRL producing adenoma from stalk effect?
if PRL elevated but < 150 ng –> stalk effect
If PRL elevated and > 150 ng –> PRL adenoma
histologic findings of GH adenoma?
fibrous bodies
what is Nelson syndrome?
removal of adrenal glands –> enlargement of ACTH adenoma
what markers can you use for nonfunctioning pituitary adenoma?
synaptophysin and chromogranin reactive
what is lymphocytic hypophysitis?
autoimmune disorder, symmetrical pituitary enlargement and ant pituitary destruction and insufficiency. most common in pregnancy/postpartum
what is appearance of craniopharyngiomas on imaging?
calcified mass. derived from rathke’s pouch
histology findings for adamantinomatous craniopharyngioma?
squamous cells, peripheral palisading of nuclei, “wet keratin” –> tx with resection
histology findings for papillarycraniopharyngioma?
well differentiated squamous epithelium, no keratin, less palisading, no calcifications
what do germinomas look like on histology?
tumor cells with clear cytoplasm
which hormones are nuclear receptors?
thyroid hormone, estrogen/testosterone/progesterone, aldosterone, cortisol, calcitriol (active vitD)
insulin uses which type of signaling?
receptor tyrosine kinase
what hormones use cytokine activated receptors?
GH, PRL, leptin
epinephrine binds to what type of receptor?
GPCR for beta adrenergic signaling. Gs signaling. autophosphorylation to shut it down
septo-optic dysplasia involves which mutation most commonly?
HESX1
optic nerve dysplasia, hypopituitarism
what are findings of langerhan’s cell histiocytosis?
infiltrative hypothalamic disease, osteolytic lesions (esp jaw), check diffusion capacity
what is Kallmann’s syndrome?
cause of hypogonadotrophic hypogonadism
forebrain defect, anosmia and absent GnRH with hypogonadism
mutations in anosmin
what is the role of the hypothalamus in energy balance?
- lateral hypothalamus: increases food intake. damage –> decreased appetite and decreased weight
- ventrolateral hypothalamus: decreases food intake. damage –> obesity
Remember lateral LOVES food and ventrolateral is VERY FULL
what is the order of hormone loss?
1) GH
2) LH/FSH
3) ACTH/TSH
what is Laron dwarfism?
GH insensitivity syndrome. autosomal recessive GH receptor mutation
most common cause of adrenal insufficiency?
exogenous steroid d/c
what is the cause of familial isolated pituitary adenoma (FIPA)?
mutation in aryl hydrocarbon receptor interacting gene (AIP) (a tumor suppressor)
what is Carney syndrome?
mutation in type 1a subunit of PKA (PRKAR1A). pituitary adenoma, spotty skin pigmentation, myxomas, schwannomas, Cushing’s syndrome
what are results of dehydration test in pt with diabetes insipidus?
can’t concentrate urine, even though serum osmolality goes up
what antibody is found in hashimoto’s?
anti-thyroperoxidase antibodies
what is used as tumor marker for papillary and follicular thyroid cancer?
thyroglobulin
what is embryologic derivative of thyroid?
endoderm. 1st pharyngeal arch
histo for grave’s disease?
scalloped colloid
what is a common mutation for follicular cell carcinoma of thyroid?
Ras mutations
papillary carcinoma is associated with which mutations?
RET rearrangements, RET-PTC fusion proteins, activating point mutations in BRAF
histo findings for papillary carcinoma?
atypical nuclear morphology, nuclear grooves, psammoma bodies, orphan annie eye nuclei (cells with clear nuclei), inclusion bodies
what is most common mutation for medullary thyroid carcinoma?
RET protooncogene
histo findings for medullary thyroid carcinoma?
stain positive for calcitonin, malignant cells in amyloid stroma
what is major potential complication/side effect of methimazole?
agranulocytosis –> watch for fever, sore throat
what is major potential complication/side effect of PTU/
risk of fulminant liver necrosis
what cardiac risk increases as target lower TSH level?
a fib. also postmenopausal osteoporosis, thyrotoxicosis
embryologic derivative of adrenal cortex and medulla?
cortex –> mesoderm
medulla –> neural crest (ectodermal chromaffin tissue)
what is Conn syndrome?
aldosterone producing adenoma
how can you tell adrenal cortex adenoma from carcinoma on gross path and histo?
gross path: adenoma is yello, carcinoma is hemorrhagic or tan/brown
histo: periadrenal fat cell invasion or other invasion/necrosis in carcinoma
what does pheo look like on gross path and histo?
gross path: areas of hemorrhage or brown in medulla. can see yellow cortex outside.
histo: stain pos for sustentacular cells, zellballen
what is the origin of ganglioneuroma?
neural crest (ganglion cells and schwannian stroma)
what is the origin of neuroblastoma?
neural crest (neuroblastic) origin
what are markers of metastatic renal cell carcinoma?
CA9 stain, clear cytoplasm
What receptor does ACTH bind to?
MRC-2 receptor (a GPCR)
how can you assess the CRH-ACTH-adrenal axis?
stimulate: insulin tolerance, ACTH stimulation, CRH test
inhibit: dexamethasone suppression test
testosterone is highly protein bound to which proteins
albumin and sex hormone binding protein (SHBG)
what is a normal morning cortisol level?
> 10 ug/dL. <4 indicates adrenal insufficiency
what are the different lab findings for primary and secondary hyperaldosteronism
primary: renin suppressed, increased aldosterone. renin can’t be stimulated and aldosterone not suppressible
secondary: increased renin and increased aldosterone. both are suppressible
what are chromogranins?
clinical marker of pheos and paragangliomas
what can you measure to assess for pheo and paraganglioma?
normetanephrine and metanephrine or VMA (circulating catecholamine metabolites)
where are sympathetic paragangliomas found?
chest, abdomen, pelvis
worse prognosis
where are parasympathetic paragangliomas found?
head and neck, upper mediastinum
better prognosis
what mutations are common in familial paragangliomas?
succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD)
SDHB = develop disease earlier (~age 34, increased risk malignancy)
what is tx for pheochromocytoma and paraganglioma?
surgical resection with alpha and beta blockade and high Na diet prior (expand volume, control BP)
alpha FIRST before beta
What glucose transporter is insulin dependent? where is it found?
GLUT-4/ gets recruited to plasma membrane in response to insulin signaling
adipose, muscle
what effect does insulin have on K+?
promotes K+ uptake into cells
ie shift extra –> intracellular
is insulin anabolic or catabolic?
ANABOLIC
increase glucose uptake
increase glycogenolysis
lipid and protein synthesis
decreased glucagon secretion
What glucose transporter is insulin INdependent? where is it found?
GLUT-2
liver, pancreas
What happens when GLUT-2 takes up glucose? what is the signalling pathway?
- glucose is used to make ATP
- increase in ATP blocks ATP sensitive K+ channel
- cell membrane depolarizes
- voltage dependent Ca channel is activated
- Ca enters cell and stimulates insulin exocytosis
- insulin is released into bloodstream
what are GLP-1 and GIP?
peptide hormones secreted in L cells of jejunum in response to feeding. cause glucose stimulated insulin secretion, inhibit glucagon, delay gastric emptying, induce satiety
degraded by DPP4
leptin is the ____ signal
satiety (ie I’m full!!)
secreted by adipocytes
grehlin is the ____ signal
hunger
secreted by epsilon cells and gastric cells
remember: grehlin if your stomach is ~growlin~
what happens in insulin resistance in T2DM?
decreased ability of insulin to decrease circulating glucose concentration, can’t stimulate periphery to utilize glucose, impaired suppression of glucose production by liver
leads to hyperglycemia.
how does beta cell dysfunction happen in T2DM?
pro-amylin accumulates, causing decreased endogenous insulin production
what is the mechanism of hyperglycemia related microvascular complications in T2DM?
- endothelial cells uptake glucose via GLUT-1
- intracellular hyperglycemia leads to oxidative stress and DNA strand breaks
- activation of PARP which then inhibits GAPDH
- this causes increased flux through polyol pathway, increased AGEs, increased flux through hexosamine pathway
hereditary vit D resistant rickets (type 2) is caused by what?
mutation in vit D receptor gene (nuclear receptor)
hereditary vit D resistant rickets (type 1) is caused by what?
mutation in 25 OHvitD 1alpha hydroxylase gene so can’t convert inactive vit D to active vit D
what are two non PTH dependent causes of hypercalcemia?
hypercalcemia of malignancy and granulomatous disorders (ex. sarcoidosis)
what electrolyte abnormality is expected in a pt with primary adrenal insufficiency?
hyperkalemia due to decreased mineralocorticoid secretion
what are the two main features of Kallmann syndrome?
anosmia and hypogonadotrophic hypogonadism (decreased LH/FSH)
what is “thrifty phenotype”
poor fetal growth
risk of developing impaired glucose tolerance and metabolic syndrome
what are risk factors for gestational maternal diabetes
- maternal age > 35
- overweight/obese maternal BMI
- fam hx DM
- parity 2 or more
what is the role of PTH?
regulates calcium levels by increasing Ca2+ in response to low serum Ca2+
in the intestine, what is the role of vit D for calcium?
vit D is NEEDED for Ca2+ absorption in the gut
how do glucocorticoids impact Ca2+ in the gut? in the kidney?
decreased Ca2+ absorption in the gut
increased excretion in kidney
what are the effects of loop diuretics and thiazide diuretics on Ca2+ excretion in the kidney?
loop diuretics increase Ca excretion
thiazides decrease Ca excretion
what does RANK-L do?
made by osteoblasts, binds receptor on osteoclasts to promote fusion, differentiation, activity, survival of osteoclasts
what are markers of osteoblast activity?
alk phos, osteocalcin, collagen peptides
what does sclerostin do?
released from osteocytes to inhibit wnt signaling
this inhibits osteoblast differentiation and activity
what do sclerostin antagonists do?
increase bone formation
because inhibit the inhibitor of osteoblast differentiation and activity
how does PTH regulate Vit D production?
PTH stimulates alpha hydroxylase in the kidney which converts 25OHD (storage) –> 1,25(OH)2D3 (active, calcitriol)
can think of it because PTH responds to low Ca and we need vit D to absorb Ca in the gut.
both Ca and Phosphate are absorbed in vit D dependent manner in gut –> low serum phos also stimulates production of active vitD
what are the effects of active vitamin D?
stimulates intestinal Ca/phos absorption (–> bone mineralization)
inhibits PTH secretion
what are some vit D analogs?
alphacalcidol: doesn’t require 1 hydroxylation so use if 1 hydroxylase is deficient
paracalcitol: use in ESRD, suppresses PTH, minimal effect on gut, good for secondary hyperPTH
what is teriparatide and what is it used for?
PTH analog
anabolic agent for osteoporosis (pulsatile)
risks: hyperCa, risk osteosarcoma
short term use only
what is cinacalcet and what is it used for?
allosteric activator of CaSR. increases sensitivity of CaSR to increased Ca which suppresses PTH.
indications: hyperPTH, parathyroid carcinoma
side fx: hypoCa, adynamic bone disease
what type of signaling is PTH?
acts via GPCR via PKA/PKC pathways
what is the difference between intermittent PTH and constant PTH administration?
intermittent/pulsatile –> anabolic for bone
constant –> catabolic for bone (ie bone resporption)
what does calcitonin do?
acts on mature osteoclasts via GPCRs to inhibit bone resorption
secretion stimulated by Ca2+
can think of when have high Ca, calcitonin stops further Ca release from bone
what does FGF-23 do?
produced by OBs and osteocytes
increased in response to calcitriol and phos
inhibits activation of vit D (renal calcitriol synth) and phos reabsorption
what role does estrogen play in bone health?
antiresorptive and anabolic
inhibits production of RANK-L and IL6, increased osteoprotegerin, induces apoptosis of osteoclasts, decreases sclerostin
how are SERMS used for bone health?
selective estrogen response modulators
raloxifene: prevent/tx postmenopausal osteoporosis, decreased risk breast cancer
side fx: thrombosis, hot flash, contraindicated if may become pregnant
what do bisphosphonates do?
…dronates
accumulate at sites of active resorption, taken up by osteoclasts and then inhibit them –> antiresorptive
tx/prevent osteoporosis, tx bone metastases
side fx: upper GI (esophageal irritation, esophagitis, heartburn), lower GI (abd pain, diarrhea), osteonecrosis of jaw and atypical femoral fractures
what is denosumab?
ab against RANKL
inhibits osteoclast fusion, function, survival = antiresorptive
indications: osteoporosis, bone mets
side fx: hypoCa, rash, osteonecrosis of jaw, infections if weak immune system
what do glucocorticoids do to bone in short term?
can tx hyperCa by decreasing intestinal Ca abs, increase renal Ca excretion
list drugs indicated for hypoCa
vit D, calcitriol, alphacalcidol, thiazide diuretics
all with calcium supplement
list drugs indicated for hyperCa
loop diuretic, bisphosphonates, calcitonin, glucocorticoids
list antiresorptive drugs for osteoporosis
bisphosphonates, denosumab, SERMs, estrogen, calcitonin
all with calcium, vit D, exercise
list anabolic drugs for osteoporosis
teriparatide (PTH analog), abaloparatide (PTHrP analog)
all with calcium, vit D, exercise
which are first line tx for osteoporosis: antiresorptive or anabolic
antiresorptive. prevent bone breakdown, cheaper, less potent
what are lab findings and causes of primary hyperPTH
hyperCa results from abnormally active parathyroid glands
high Ca and normal-high PTH
adenoma
give cinacalcet
what are lab findings and causes of secondary hyperPTH
hypoCa results in reactive overproduction of PTH
low Ca, high PTH
CKD, malnutrition, vit D deficiency
other than primary hyperPTH, what are two other PTH dependent causes of hyperCa?
- familial hypocalciuric hypercalcemia (FHH): aut dom mutation of CaSR so have resistance to Ca and slightly elevated PTH. look for FeCa <1%. neonatal can be more severe (aut rec)
- drug induced (ex. Lithium)
what is a PTH independent cause of hyperCa?
malignancy (will have PTH < 20 pg/mg) (high Ca, low PTH)
paraneoplastic PTHrP, osteolytic metastases, paraneoplastic calcitriol (bc ectopic 1 alpha hydroxylase)
what are sxs of hyperCa?
stones, bones, groans, psychogenic overtones
shortened QT interval
what does hypoCa do to QT interval?
prolongs QT interval
what are common etiologies of hypoparathyroidism?
(low Ca, low PTH)
destruction (surgical, autoimmune, radiation, infiltration)
congenital (DiGeorge, velo-cardio-fascial syndrome)
functional: hypoMg (bc PTH secretion dependent on Mg) (if Mg < 1)
how to dx vit D deficiency?
measure storage form vitD (vitD25 hydroxy)
what virus associated with Paget’s?
paramyxovirus
what is the difference between vit D dependent rickets type 1 or type 2?
type 1: mutation in 25 hydroxyvitD 1alpha hydroxylase gene so can’t convert inactive vitD to active calcitriol
type 2: mutation in vit D receptor gene
what is normal timing of puberty?
girls: 7/8-13
boys: 9-15
when is peak growth rate during puberty?
girls: tanner 2-3
boys: tanner 4
what do you see in central precocious puberty
high LH/FSH, high testosterone or estrogen
what do you see in peripheral precocious puberty
low LH/FSH, high testosterone or estrogen
ex. McCune Albright
what do you see in hypogonadotrophic hypogonadism?
low LH/FSH, low testosterone or esrogen
what do you see in delayed puberty (hypergonadotrophic hypogonadism)
high LH/FSH, low testosterone or estrogen
ex. Klinefelter, Turner
what is Klinefelter’s syndrome?
47XXY
long arms/legs, gynecomastia, psychosocial abnl, inattention, impaired linguistic function, small firm testes with low sperm count/infertility
what is Turner syndrome?
45XO
small ovaries with few follicles, streak gonads –> infertility
short stature, hand/feet swelling, shield chest, low hairline, heart disease, horseshoe kidney, ear infections and hearing lsos, ADHD, non verbal learning disability
what are findings in MEN1
parathyroid (primary hyperPTH), pancreas (gastrinoma, insulinoma), pituitary (prolactinoma)
what are findings in MEN2a
MTC
pheo
primary hyperPTH
extraendo: hirschprung’s disease, cutaneous lichen amyloidosis, familial MTC
what are findings in MEN2b
MTC
pheo
intestinal ganglioneuromatosis
Marfanoid habitus
what are findings in von Hippel Lindau
aut dom
hemangioblastomas, retinal capillary hemangioblastomas, clear cell renal cell carcinomas, pheo, tumors of middle ear, pancreatic tumors, papillary cystadenomas of epididymis and broad ligament
what are findings in NF1
aut dom mutation in tumor suppressor NF1
cafe au lait, neurofibromas, axillary and inguinal freckling, optic pathway gliomas, lisch nodules, endocrine tumors (pheo, paragangliomas, GI tract/pancreatic)
what are findings in Li Fraumeni
aut dom mutation in tumor suppressor p53
sarcomas, premenopausal breast cancer, brain tumors, adrenocortical tumors
what are findings in carney complex?
aut dom mutation of PRKAR1A
myxomas, adrenocortical tumors, thyroid nodules, pituitary adenoma, ovarian cysts, cafe au lait, pigmented lesions of eye
what are findings in mccune albright syndrome
postzygotic activating mutation of alpha subunit of Gs (constitutively active)
triad of fibrous dysplasia of bone, cafe au lait hyperpigmentation, precocious puberty
what gene is mutated in autoimmune polyglandular syndromes?
AIRE gene
what is the difference between allelic heterogeneity and locus heterogeneity?
allelic: multiple diff mutations can occur on same gene (ie diff mutations in androgen receptor gene can cause androgen insensitivity)
locus: similar disease phenotype occurs from mutations in diff genes (ex. nephrogenic DI can come from mutations on diff chromosomes)
what are findings of primary short stature?
linear growth normal but below typical or normal then slows
bone age > chronological
ex. Down’s, Turner, achondroplasia
what are findings of secondary short stature
linear growth is slow (bone age < chronologic age)
ex. GH-IGF axis, endocrine, malnutrition, IGF deficiency (ex. GH resistance in Laron syndrome), IUGR, chronic dz, psychosocial
