Unit 3 Endocrine Flashcards

Question

Rathke cleft cyst

Answer 1

benign cyst secretes protein bright on T1** only go after these when we think HAs can be attributed to it

Answer 2

infundibulum is large (>5mm)

Answer 3

T1 common bright things: melanoma, fat, certain proteins, subacute blood products, paramagnetic ions (Fe, Gadolinium, Mn, some Ca) white matter is brighter than grey dark: fluid is generally dark T2 bright things: FLUID, gloss (from inc water content), tumors that have high water grey matter is brighter than white dark: tumors w/ low cytoplasmic/nuclear ratios have low T2 signal (dark) blood, hemosiderin, certain Ca complex, air, high conc protein complexes

Answer 4

young (2yo girl) classic: calcification other types of craniopharyngiomas low-grade benign tumors; recurring; stick to adjacent soft tissue

Answer 5

pt presents w/ gelatinous (??) laughing seizures contrast does not enhance the tissue

Answer 6

pt presents w/ gelatinous (??) laughing seizures contrast does NOT enhance the tissue

Answer 7

along top surface of sphenoid sinus enhancing mass pituitary gland is pushed down, and CSF cleft between it like to encase and narrow whatever it is around (vasculature)- adenomas won't narrow vasculature

Answer 8

in contact w/ basal lamina and secrete through it | fenestrated endothelia

Answer 9

sits on median eminence of hypothalamus anterior and posterior are split pituitary in general called hypophysis hypothalamus then infundibular stalk then pituitary anterior part of stalk = pars tuberalis anterior = pars distalis posterior = pars nervosa small slit between = pars intermedia

Answer 10

cell bodies in hypothalamus- supraoptic and paraventricular axons go into pituitary and make the stalk release ADH and vasopressin directly from bulbous ends (in pars nervosa) pituicytes- think of them as astrocytes or gliocytes w/ cell bodies throughout the stalk and pars nervosa

Answer 11

blood enters via 2 vessels superior hypophyseal artery and inferior hypophyseal artery one of the superior hypophyseal branches goes into a capillary bed - this capillary bed then goes into infundibular collar and goes to anterior pituitary - this is called hypophyseal portal system - set of neurons sitting in median eminence supply releasing factors/hormones into these capillaries to stimulate cells which basically sit as clumps of cells in the ant pit and endocrine cells trabecular artery- another superior hypophyseal branch goes into a capillary network into the posterior pituitary drainage of blood via small vessels that go into hypophyseal vein

Answer 12

clumps of cells and capillaries w/ endothelial cells can secrete FLAT PiG FSH, LH, ACTH, TH, PRL, GH

Answer 13

lots of ends of axons w/ granules of hormones that get secreted into local vessels -Herring bodies secretes ADH, oxytocin

Answer 14

TSH-RH, DRH, GHRH

Answer 15

capsule layers of cells that easily identifiable via staining Zona glomerulosa- outside; dark; up against capsule Zone fasciculata- bigger cells Zona reticularis- reticulated cells that run as cords Medulla- clumps of cells around medullary veins that lead to major medullary vein

Answer 16

blood comes in through series of arteries originally from superior middle and inferior suprarenal arteries majority of these branch into tiny capillaries - sub scapular capillary plexus -occasionally one that runs down and doesn't branch until gets to reticularis or medulla- long cortical arteries

Answer 17

Zona Glomerulosa- mineralocorticoids (aldosterone) Zona Fasciculata- Glucocorticoids (cortisol) Zona Reticularis- sex hormones all of these prod steroids (cholesterol derivatives) Medulla- EPI, some NE -stimulated by sympathetic and parasympathetic NS, enkephalins (Catecholamines derived from AAs, stimulated by NS)

Answer 18

layers of follicular epithelial cells all w/ nucleus in them center is called colloid- filled w/ protein for thyroid gland calls thyroglobulin TG -thyroid hormones are derived (tyrosine residues and iodinated tyrosine residues) extensive vascularization that forms a basket around each follicle another set of cells that stain clear- sit in regions between the follicles -calcitonin secreting cells parafollicular C cels thyroid itself has superior thyroid artery coming into it and inferior thyroid artery inferior/superior thyroid veins that all branch into capillaries surrounding follicles Iodide gets converted to I2 en route to colloid and thyroglobulin tyrosine gets iodinated that causes bi-linking w/ another structure on the way out, TG gets degrade to T4 and T3 stimulated by TSH from anterior pit -both production of thyroglobulin and iodination

Answer 19

embedded in the thyroid gland don't have separate vascularization- sit on thyroid arteries produce parathyroid hormone PTH acting on osteoclasts and kidneys to get more Ca into serum circulation adipose cells also in parathyroid gland oxyphil cell- filled w/ mito; stained a little lighter than parathyroid cells don't really know function also arranged in clumps

Answer 20

islet of Langerhans cells | clumps of cells

Answer 21

4 weeks: umbilicus w/ yolk sac and cloaca at the end -endoderm that has not broken through the ectoderm -neural tube forming what looks like beginning of brain and spinal cord -floor of diencephalon at the base of "brain" -outside layer = ectoderm floor of diencephalon begins to bulge out, and at same time the region of oral ectoderm bulges out (Rathke's pouch) -come into contact w/ e/o -top of oral ectoderm pinches off and starts to form anterior pituitary w/ little post pouch pouch/collar --- pars distalis (anterior) and tuberalis (collar) the floor of the diencephalon goes to form posteior pituitary (nervosa) -the little indentation is called sella turcica that it all sits in

Answer 22

3 weeks cross section: neural tube, then notochord, then dorsal aorta, then large coelom surrounding early endoderm sitting on top of coelom you have urogenital ridge w/ nephrotomes and Wolffian body; also have mesothelial cells of coelom -also from neural crest- you have cells that migrate down called sympathogonia ----causes other clusters of cells to migrate down and populate the medulla later stage -sympathogonia initially said as acidiphillic cup of cells to form reticular chromatin cells migrate down from sympathogonia and populate the medulla/medullary region 2nd wave of cells also layering along outside of reticular that eventually forms fasciculata and glomerulosa capillaries and vessels from mesoderm are also starting to populate the area even later stage formally layers of glomerulosa and fasciculate (2nd wave of mesothelial cells) some regression of reticularis (1st wave of mesothelial cells) and medullary region w/ chromatin cells

Answer 23

4 weeks part of endoderm that will form pharynx- forms pharyngeal pouches and clefts that develop into other things pharynx will join the stomodeum pharynx develops 4 pouches (pharyngeal pouches- 8 total) on either side from oral cavity -looked at ventrally, the center will have thyroid diverticulum endoderm- pharyngeal pouches 3rd pouch- INFERIOR pharyngeal pouch 4th pouch- SUPERIOR pharyngeal pouch also just after 4th pouch is ultimobronchial body- gives rise to calcitonin cells of thyroid comes from neural crest/ectoderm going back to thyroid diverticulum w/ 4 pouches: begins to grown down and under the larynx will be connected via thyroglossal duct to pouches and eventually pinches off most individuals have the duct form little degraded remnants, but sometimes don't fully degrade and become cystic in some peds sometimes thyroid diverticulum doesn't grow fully below larynx- ectopic thyroid

Answer 24

parathyroids and thyroid come from endoderm vasculature comes from mesoderm

Answer 25

paracrine- effector cell releases a signal into the blood to act on a target cell downstream - somatostatin - delta cells of pancreas autocrine- effector cell releases a chemical that regulates itself -CRH definition is purely based on mechanism, NOT hormone**

Answer 26

tyrosine derivatives -EPI, NE, TH peptides -hypothalamic hormones proteins -insulin, GH these are are water soluble- stuck in cell, membrane impermeant, stored in vesicles to be exocytosed -requires inc in intracellular Ca levels (Ca dependent exocytosis) short half life steroids -cortisol, sex steroids lipid soluble, hydrophobic, controlled at level of hormone synthesis and released across plasma membrane when needed (not stored in effector cell) most are bound to carrier proteins (~99%) -body only cares about free hormone- it's the one that's regulated

Answer 27

water and mineral ADH, aldo Energy Insulin, GH growth IGF, testosterone reproduction Estrogens, testosterone

Answer 28

bioassays -tests function of hormone -ex. measure serum insulin of pt -insulin drives glucose transporters into muscle cells myocytles in culture w/ a tracer glucose molec that allows you to trace the transporter glucose in the medium insulin will drive the labeled glucose into the cell and calc the est of how much glucose entered the cell and the func of insulin -downside- complex infrastructure and process immunoassays -tests for the hormone peptide or hormone protein -more commonly used, specifically radioimmunoassay RIA -ex. radio labeled I-insulin + Ab I-Insulin-Ab serum that has insulin + radio labeled Insulin + Ab labeled I-Insulin-Ab + Insulin-Ab know competing numbers, and calc how much insulin there was in the serum -quick, doend't require lot of infrastructure -measuring the protein, not necessarily the function ----ELISA use a tag enzyme instead of radio labeling Ex. insulin binds to Ab, wash off excess, add 2nd Ab that is linked to an enzyme, you can measure activity of enzyme to measure how much insulin there was in the sample

Answer 29

each hormone has its own receptor on target cells protein/peptide/tyrosine hormones: want the detectors in the plasma membrane because hormone can't enter (water soluble) ``` 3 classes of receptors: -GPCR hypothalamic hormones -Cytokine family GH, PRL -EGFR family insulin, IGF ``` steroid hormones -all intracellular receptors either cytoplasmic or nuclear binding to its receptor can alter gene expression

Answer 30

classic- through feedback mech when there's an inc in hormone levels, the target cells endocytose the receptors back into the cell and reduce the number available for the hormone -called receptor downregulation or could have reverse case -spare receptors and excess receptors on the cell surface to provide maximal chance of binding

Answer 31

serum glucose conc when glucose is low you activate glucagon from alpha cells when it is high, you activate insulin from beta cells

Answer 32

pulsatile ex over time, GHRH is released in spurts every 90 min by regulating pulsations, you can regulate the end levels of hormones circadian -can have GHRH conc vary across a day and superimpose circadian and pulsatile release graphs together

Answer 33

happens in major axis of endocrine sys from hypothalamus to pituitary to target gland - hypothalamus prod TRH to act on pituitary to prod TSH to go to target glands as TH - when TH exceeds its nl set-point you exert a negative feedback mech (most common for regulating hormone prod) to inhibit TSH and TRH prod

Answer 34

neurons of hypothalamus send neurons directly to posterior pituitary can't do that w/ anterior- solved w/ small portal system called hypothalamo-hypophyseal portal system -important that they reach the ant pituitary because released in small amounts and need best chance possible to reach ant pituitary

Answer 35

TRH--> thyrotrophs --> TSH CRH- corticotrophs- ACTH GnRH - gonadotrophs - LH, FSH GHRH- somatotrophs- GH somatostatin - somatotrophs- dec GH PTH - Dopamine - dartotrophs- dec prolactin

Answer 36

Gs inc adenylate cyclase--> inc cAMP ex TRH, GHRH Gi decrease adenylate cyclase - dec cAMP ex somatostatin, dopamine Gq PIP2--> (Ca2+ activates IP3) IP3 + DAG ---> protein Kinase C (PKC)

Answer 37

protein hormone released by lactotrophs of anterior pituitary via Ca dependent exocytosis -mostly unbound/free cytokine receptor family- need to activate receptor by binding PRL, activates a tyrosine kinase called Janus Kinase, a special phosphorylating kinase known as Signal Transducers and Activators of Transcription STATs PRL binding to a PRL receptor activates a Janus kinase pathway causes STATs, phosphorylation of STATs gets them transported to nucleus for transcription AKA JAK-STAT receptor family simple cascade of phosphorylation that results in regulation of gene transcription

Answer 38

mammogenesis (growth of gland) lactogenesis (prep of gland for prod) galactopoiesis (synthesis of milk components)

Answer 39

``` primarily regulated by Dopamine from hypothalamus inhibitory control (Gi) ``` also some TRH control that inc PRL (hypothyroidism) during pregnancy- estrogens and progesterone regulate prolactin actions stimulate mammogenesis but inhibit lactogeneis and galactopoiesis Hypothalamus goes to pituitary to inc PRL, which then dec GnRH back on hypothalamus (therefore dec LH, FSH)

Answer 40

rare consequence of low pituitary function Sheehan's syndrome- failure to lactate, ischemic infarct of pituitary from postpartum bleeding/hemorrhage

Answer 41

``` AKA somatotrophin (from GHRH) most abundant pituitary hormone structurally similar to PRL half life 20-25min 6-8 discrete pulses/day youth- most pronounced w/ onset of sleep ``` transported as mainly free hormone w/ little bound (like PRL) when reaches target, binds to cytokine receptor family (like PRL)- mediates signaling through JAKSTAT

Answer 42

metabolic need E sources that allow you to invest in growth growth need growth itself

Answer 43

stimulates gluconeogensis CRH to insulin if there's excess GH, it makes it diabetogenic increases serum FAs by stimulating hormone sensitive lipase stimulates AA uptake into muscle

Answer 44

growth effects mediated via IGF -GH induces production of IGF, provides growth effects of GH -need GH + insulin to make IGF IGF acts on receptor, which is EGF-family of receptors, phosphorylation of insulin receptor substrate IRS promotes long bone growth increases muscle growth

Answer 45

primary regulation comes from 2 hypothalamic hormones GHRH and Somatostatin (GHIH) hypothalamus- pituitary- GH GH has negative feedback to GHRH GH secretion inhibited by glucose and somatostatin release via negative feedback hypoglycemia powerfully stimulates GHRH and GH production also serum AAs stimulates GHRH, acting as a stress hormone to give glucose to the brain fed state: high glucose, high AAs, which will increase insulin and GH, which makes IGF starved state: don't want to invest any E resources into growth have low glucose and low AAs low insulin and low GH so no IGF production

Answer 46

hyperGH tumor, chronic high level of GH for some reason -high level of serum glucose that overrides insulin- diabetogenic, could get diabetes also get excess IGF production high GH before puberty= gigantism, cardiac hypertrophy, life expectancy 20s high GH post puberty = acromegaly- tips of body; hands, feet, face; less severe cardiac hypertrophy, longer life expectancy hypoGH leads to dwarfism Laron's dwarfism- problem with GH receptors African Pygmies- GH receptors are nl, but very poor IGF response

Answer 47

``` stimulation: sleep low glucose exercise stress puberty high AA/protein GHRH glucagon alpha-adrenergic ``` ``` suppression somatostatin high glucose aging FFAs ```

Answer 48

``` assess liver IGF-1 Dx elevated IGF-1 (GH fluctuates) OGTT-GH for ambiguous or post-opp Pituitary MRI macro adenomas in >80% ``` ``` acromegaly GH excess after puberty (done w/ linear growth) acral/facial changes HA hyperhidrosis oligo/amenorrhea OSA HTN dyslipidemia parasthesias/carpal tunnel syndrome impaired glucose tolerance/DM tx multi-modal/disciplinary surgery med tx (Somatostatin analog, GH receptor antagonist) radiation ``` gigantism GH excess before puberty (growth plates)

Answer 49

assess liver IGF-1 14% decline per decade w/ age of adults ``` manifestations body composition: inc fat deposition, dec muscle mass/strength/exercise capacity bone loss and fracture risk inc cholesterol levels inc inflamm and prothrombotic markers (CRP) impaired E and mood hindered QOL ``` Adult-onset growth hormone deficiency AoHD GH therapy still controversial- cost/benefit ratio; only modest benefits Dx- low IGF-1 (setting of multiple other pit hormone deficiencies) Provocative testing for GH reserve: LIMITED REAGENTS --insulin induced hypoglycemia (gold standard) contraindications: elderly, seizures, CAD/cerebrovascular disease --Arginine and glucagon stimulation tests

Answer 50

hypogonadism physiological: pregnancy, suckling, sleep, stress pharmacological: estrogens/OCPs antipsychotics, TCAs antidepressants, anti-emetics (Reglan), opiates Patho: pituitary stalk interruption hypothyroidism, chronic renal/liver failure, seizure PROLACTINOMA

Answer 51

failed lactation etiology: severe pituitary (lactotrope) destruction from any cause present: failed lactation postpartum females no known effect in males Dx low basal PRL level

Answer 52

rarely clinically evident assess gonads for testosterone and estradiol ``` hypergonadotropic -congenital anorchia Klinefelter's syndrome testicular injury autoimmune testicular disease glycoprotein tumor (rarely) ``` gonadotrope adenoma: majority of tumors are clinically silent rare presentation incl ovarian hyper-stimulation syndrome or macro-orchidism -middle aged pts w/ macro adenomas and related mass effects (HAs, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies) gonadotropinoma dx: blood tests usually low FSH/LH, T/E2 pituitary MRI immunohistochemical analysis of resected tumor

Answer 53

adrenal insufficiency assess gonads for testosterone and estradiol hypogonadotropic hypogonadism hypothalamic/pituitary diseases: -macro adenomas, prolactinomas, XRT -isolated GnRH deficiency (Kallman's = anosmia) -Hemochromatosis functional deficiency: -critical illness, OSA, starvation, meds-opiates, glucocorticoids ``` hypogonadism in F: anovulatory cycles (amenorrhea, infertility) vaginal dryness, dyspareunia hot flashes dec libido breast atrophy reduced bone mineral density BMD ``` hypogonadism in M: low libido erectile dysfunction oligospermia or azoospermia infertility low muscle mass, testicular atrophy and decreased BMD hot flashes w/ acute and severe onset of hypogonadism

Answer 54

hyperthyroidism assess TSH and T3,T4 secondary: thyrotropin secreting pituitary tumor- very rare <1% thyroid hormone resistance (rare) thyrotropinoma: central hyperthyroidism AKA TSHoma similar clinical presentation to primary hyperthyroidism (goiter, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also w/ assoc mass effects (HAs, vision loss, loss of pituitary gland func) from macro adenoma dx: elevated free T4 and non-suppressed TSH pituitary MRI >80% macro adenomas

Answer 55

hypothyroidism assess TSH and T3,T4 central TSH deficiency etiology pituitary/hypothalamic diseases and/or tx's critical illness/starvation-euthryoid sick syndrome congenital defects (TSH-beta mutations, PROP1, POUF1 mutations), pediatric onset drug induced supra physiologic steroids, dopamine, retinoids clinical presentation: similar to primary hypothyroidism (fatigue, weight gain, cold intolerance, consitpation, hair loss, irregular menses). possible mass effects dx low free T4 levels in setting of low or nl TSH

Answer 56

SIADH- syndrome of inappropriate AVP release/action in absence of physiologic osmotic or hypovolemic stimulus hallmark is excretion of inappropriately concentrated urine in setting of hypo-osmolality and hyponatremia --SIADH is one of most frequent causes of hyponatremia, occurs 15-22% hospitalized pts, 5-7% ambulatory pts ``` etiologies malignant disease pulm disorder CNS disorder drugs (narcotics, nicotine, anti-psychotics, carbamazepine, vincristine) misc- nausea, stress, pain ``` presentation depends on severity and rapidity neuro symptoms from osmotic fluid shifts and brain edema (SEVERE HYPONATREMIA) (asymptomatic- anorexia, N/V, HA, irritable- altered sensorium, gait probs- seizure, coma, death) dx criteria Hyponatremai (Na <135) and hypotonic plasma (osmolality <275mOsm/kg) inappropriate urine conc (urine osm >100!!) w/ nl renal function!! euvolemic status!!! (no orthostatic hypotension) exclusion of other potential causes of euvolemic hypo-osmolality (hypothyroidism, hypocortisolism) tx identify and reverse underlying cause tx depends on severity mild-moderate hyponatremia: water restriction, V2 receptor antagonists, salt tablets, urea, Lasix Severe: (usually Na <120) HYPERTONIC 3% saline if pt is symptomatic rapid correction of hypotonic state (following rapid adaptation after water gain) will cause osmotic demyelination

Answer 57

Diabetes Insipidus

Answer 58

assess adrenal gland- cortisol and DHEA-S

Answer 59

peripheral: primary disorder target organ central: secondary disorder (pituitary gland) tertiary disorder (hypothalamus)

Answer 60

most common functional pituitary adenoma 30-40% F:M 10:1 median 34yo F: galactorrhea, menstrual irregularity, infertility, impairs GnRH pulse generator MICRO adenoma M: galactorrhea, visual field abnormalities, HA, impotence, EOM paralysis, anterior pituitary malfunction MACRO adenoma

Answer 61

Dx random PRL level -usually correlates w/ tumor size Pituitary MRI ``` Tx Dopamine Agonists Bromocriptine start low and go slow common side effects: GI upset, nasal congestion, orthostatic dizziness preferred only if planned pregnancy ```

Answer 62

catabolic stress hormone primary functions: gluconeogenesis metabolism of fat and protein control inflammatory rxns ACTH acts on adrenal cortex to prod cortisol episodic ACTH/cortisol secretions daily major burst in early morning before awakening most cortisol bound to transcortin (cortisol binding globulin CBG) 10% bound to Albumin 5% unbound/free

Answer 63

``` changes in carb, protein, and fat metabolism -peripheral fat/muscle wasting central obesity, moon facies, fat pads osteoporosis diabetes hypertriglyceridemia ``` change in sex hormones amenorrhea/infertility F- hirsutism impotence salt and water retention HTN and edema impaired immunity neurocognitivie changes

Answer 64

ACTH dependent 70-75% corticotrope adenoma (Cushing's disease) ectopic cushing's (ACTH/CRH tumors) ``` ACTH-independent 25-30% adrenal adenomas adrenal carcinoma nodular hyperplasia (micro/macro) ```

Answer 65

non-specific obesity, fatigue, menstrual irregularities, hirsutism, HTN, glucose intolerance/DM, dyslipidemia, acne, anxiety/depression, peripheral edema, metabolic syndrome specific plethoric/moon facies wide >1cm violaceious striae (abdominal/ axillary) spontaneous ecchymoses proximal muscle weakness early/atypical osteoporosis (automatic rib fracture)

Answer 66

Disrupted Circadian Rhythm -midnight salivary or serum cortisol increased filtered cortisol load -24hr urine free cortisol attenuated negative feedback -low dose 1mg dexamethasone suppression test (late night)

Answer 67

over activation of the HPA axis, without tumorous cortisol hyper secretion ``` severe depression/anxiety/OCD severe obesity OSA? alcoholism poorly-controlled DM/hypoglycemia physical stress (Acute illness, surgery, pain) ```

Answer 68

etiologies of Central (secondary/tertiary) AI: - ----Suppression of the HPA axis - s/p tumor resection of Cushing (pituitary, ectopic, or adrenal) - supraphysiologic exogenous glucocorticoid use (most common)- prednisone use - drugs: opioids and menace - ----hypothalamus/pituitary diseases and their tx's - ----other- isolated ACTH deficiency (very rare) ``` clinical presentation fatigue, anorexia, N/V, weight loss generalized malaise/aches scant axillary/pubic hair (DHEA-S dependent in females) hyponatremia and hypoglycemia ``` basal testing random AM cortisol <3 dx; >18 nl stimulation test insulin-induced hypoglycemia (gold standard)- assesses entire hypothalamic-pituitary-adrenal Axis cosyntropin (synthetic ACTH) stimulation test- valid for assessing HPA only if prolonged- need time for adrenal atrophy

Answer 69

deficiency of 1 or more pituitary hormones panhypopituitarism: loss of all pituitary hormones etiologies: congenital- genetic diseases (transcription factor mutations) -acquired- pituitary lesions and/or tx's 75% macroadenomas/pituitary surgery/radiation therapy infiltrative/infectious/granulomatous TBI/subarachnoid hemorrhage apoplexy autoimmune hypophysitis-immune-tolerance disorders (anti-cytotoxic T lymphocyte antigen-4 CTLA-4, Ipilmumab) clinical presentation depends on severity of pituitary hormone deficiency and their rate of development -generally similar presentation to target gland hormone deficiency, w/ some exceptions: -primary adrenal insufficiency also presents w/ hyperkalemia from mineralocorticoid deficiency and hyper pigmentation from ACTH excess dx basal and dynamic testing management tx of anterior pit hormone deficiencies (end organ hormone replacement)

Answer 70

clinical syndrome of HA, vision changes, ophthalmoplegia, and AMS caused by sudden hemorrhage or infarction of pituitary gland happens in ~10-15% pituitary adenomas sub-clinical disease is more common dx pituitary MRI or CT tx emergency surgery indicated for evidence of severe vision loss, rapid clinical deterioration, or MS changes !!stress dose steroids for adrenal insufficiency

Answer 71

common w/ metastatic tumors (breast, lung, GI) or craniopharyngiomas, but not pituitary adenomas

Answer 72

-thyroid: multiple L-thyroxine's available adrenal: hydrocortisone or prednisone - -medic alert bracelet, sick day rules for glucocorticoid replacement - -no mineralocorticoid replacement needed gonadal various oral/transdermal E2 formulations, transdermal/IM testosterone gonadotropin or pulsatile GnRH therapy ``` GH subcutaneous shots (NOT orally active) ``` prolactin SQ formulation, research purposes only

Answer 73

releases ADH and oxytocin clinical syndromes primarily assoc w/ disorders of AVP (arginine vasopressin) = ADH release controlled primarily by high-osmolar states (via hypothalamic osmoreceptors)

Answer 74

release also controlled by hypovolemia via baroreceptors MOA of ADH V1- vascular vasoconstriction, plt aggregation V2- antidiuretic effects in kidney -adenylate cyclase activation --> movement of aquaporin water channels to the cell membrane --> water reabs regulation of ADH release: high plasma osmolality (dehydration)- more ADH release (less water excretion), more thirst, and more water intake = more water retention = decreases plasma osmolality (hydration)

Answer 75

hyponatremia complication dysarthria/dysphagia lethargy/obtundation paralysis/locked-in syndrome reducing risk: limit correction of chronic (>48hrs) hyponatremia: <=12mmol in the 1st 24hrs slower correction w/ other risk factors (hypokalemia, alcoholism, poor nutritional status) ------NO LIMITATIONS w/ acute onset hyponatremia (<48hr onset, marathon runners) -------quickly give hypertonic saline to normalize them

Answer 76

syndrome of hypotonic polyuria as a result of either: inadequate ADH secretion inadequate renal response to ADH hallmark- voluminous dilute urine ESP nocturia main causes central DI nephrogenic DI pregnancy- increased ADH metabolism from placental vasopressinase, but generally not clinically relevant primary polydipsia: relates to osmoreceptors, not really an ADH problem!!! clinical significance can lead to severe dehydration if thirst mech's are impaired, or if pt has limited access to water

Answer 77

nephrogenic DI congenital X linked AVP V2 receptor mutation drugs: demeclocycline, lithium, amphotericin B electrolyte abnormalities: hypokalemia and hypercalcemia infiltrative kidney diseases: sarcoidosis and amyloidosis vascular disease: sickle cell anemia neurogenic DI neoplasms: craniopharyngioma, metastatic pituitary disease idiopathic congenital defect: auto dom AVP gene mutation inflamm/infectious/granuloma pituitary diseases trauma/vascular event

Answer 78

classic triphasic response primary phase: DI-polyuric phase due to axonal shock/decreased AVP release (1-5 days) ----impaired ADH release!!!! secondary phase: SIADH from degenerating neurons/excessive AVP release (days 6-11) tertiary phase: permanent DI after depleted ADH stores and if >80% AVP neuronal cell death - permanent DI is uncommon complication w/ experienced surgeon - ---isolated second SIADH phase- more common (~25%)

Answer 79

confirm polyuria w/ 24hr urine vol collection (normalized to creatinine) exclude hyperglycemia (osmotic diuresis), renal insufficiency, and electrolyte disturbances (K/Ca) assess urine and plasma osmolalities consider water deprivation test pituitary imaging for suspected neurogenic DI- BRIGHT SPOT on post pituitary makes it very UNLIKELY you have neurogenic DI

Answer 80

fluid restriction to stimulate ADH release measure urine Osm, Posm, serum Na, and urine output urine conc response to dDAVP +/- ADH level after mild dehydration neurogenic DI will have very low plasma VP psych will have middle plasma VP nephrogenic DI will have super high plasma VP

Answer 81

ADH replacements: first line- dDAVP -longer half life than ADH no vasopressor effect (don't have to worry about HTN spikes) second line: ADH goals: resolution of polyuria/polydipsia -minimal disruption of sleep/daily routine normal serum Na

Answer 82

all are surgical candidates WHO grade 1 grow locally, but ability to recapitulate in a dysregulated neoplastic manner and be hyper functioning w/ excess hormone optic chasm and dura (HAs) are nearby, so visual/HA symptoms are common bell-shaped curve for age of dx- most are middle aged 85% of sellar region masses are pituitary adenomas (WHO grade 1) most common or rare masses closely mimic pituitary adenomas on imaging and mimic the mass effects/visual disturbances ALL except craniopharyngiomas (2 peaks- 5-15yo and middle aged) predominately affect middle aged adults

Answer 83

TTF-1 staining shows posterior pituitary and anterior are very different (posterior pink; anterior dark purple w/ pink blobs) anterior: nesting pattern, dark purple w/ pink blobs highly vascularized (helpful for endocrine func) posterior: hormones transported via neurons not highly vascularized

Answer 84

micro adenoma <1cm macro adenoma >1cm well-demarcated gives promise to being surgically resectable do NOT invade and occlude blood vessels they can infiltrate nerves (eye movement, esp CN6- diplopia)

Answer 85

>95% pituitary tumors are sporadic (<5% familial) ID of inherited pituitary syndromes is important because associated pathologies -pituitary tumors might be presenting feature -4 genes w/ familial pituitary tumor syndrome: MEN1, CDKN1B, PRKAR1A, AIP up to 20% of pts w/ clinical features of multiple endocrine neoplasia type 1 do not have a mutation in MEN1; these pts might have mutations in CDKN1B or other genes not yet identified AIP has been ID'ed as a mutated gene in pts w/ familial isolated pituitary adenomas, particularly those who have adenomas that secrete GH features that suggest an inherited pituitary tumor syndrome incl: parathyroid tumors, pancreatic endocrine tumors, atrial myxomas, lentigines, Schwann-cell tumors (Carney complex), FHx and young age at onset ---FHx and multiplicity of tumors and/or early onset are suggestive of a genomic syndrome but most of the time they're sporadic

Answer 86

related to DICER1 mutation almost always ACTH ICH(+) pediatric/young adults occasionally get pituitary adenomas and this population is enriched for syndromic examples --very rare infantile pituitary masses are a different entity: pituitary blastoma almost all other pituitary adenomas are SPORADIC -incidental pituitary adenomas are very common at autopsy and neuroimaging

Answer 87

will shed a bunch of monomorphic cells onto the slide- unregulated, unchecked, ruined the pituitary histo pattern-- reticulin disruption (destroyed acinar patterns) a nl gland will keep its reticulin look workup of pituitary adenoma incl H&E, RETICULIN, SYNAPTOPHYSIN, and a bunch of others

Answer 88

all start w/ same lineage Rathke pouch stem cell--> then delineate based on transcription factors

Answer 89

85% of ACTH adenomas are micro adenomas and often missed on imaging most prolactinomas in premenopausal women are microadenomas

Answer 90

generally present w/ symptoms of mass effects most often gonadotroph adenoma(need to do hormone stains to know- single cell population- presence of FSH/LSH) present w/ HAs visual field defects (medial/inferior chasm compression-- causing bitemporal hemianopsia) CN palsies (ptosis/eyelid droop) diplopia (double vision) pituitary hormone deficits (panhypopituitarism) rarely: stroke, seizure, CSF leak ((prolactinomas are most common pituitary adenoma))

Answer 91

clinically nonfunctioning AND show now IHC(+) for the hormones GH, PRL, FSH, LH, TSH, ACTH most of these are SF-1 (+), indicating gonadotroph lineage

Answer 92

densely granulated growth hormone cells- monotony of population ---responds well to drugs sparsely granulated GH adenoma -keritnated balling up into fibrous body doesn't respond well to drugs docs go right to 2nd line treating morbidity and mortality from excess GH

Answer 93

something that makes a mix of 2 hormones ex. mixed GH-PRL adenoma has both prolactin and GH overproductions

Answer 94

symptomatic in pre-menopausal women men often present w/ megasymptoms amenorrhea galactorrhea symptoms may be subtle, and presentation is often to OBGYN doc cause is unknown but not related to use of OCPs impotence in men (often longstanding, tumors almost always macro adenomas, sometimes giant >4cm) depends on specific high fidelity immunostains to make the dx MIB1 is a pseudo marker for cells in cycle except resting phase (0)

Answer 95

usually presents w/ prolactinemia but discordance between large size of adenoma and relatively modest serum PRL elevation aggressive, need to follow closely

Answer 96

excess cortisol secretion causes Cushing's densely granulated type- difficult workup sparsely granulated type- often huge, invasive, macro adenoma morphological proof of elevated cortisol levels- CROOKE CELLS in adjacent non tumorous anterior gland

Answer 97

PITUITARY ADENOMAS craniopharyngiomas hypophysitis spindle cell oncocytomas

Answer 98

PITUITARY ADENOMAS craniopharyngiomas hypophysitis spindle cell oncocytomas

Answer 99

adamantinomatous: complex, multi cystic tumor causes mass-effect symptoms own set of genetics- WNT pathway, downstream gives rise to beta-catenin low-grade tumor, but still huge area for targeted therapies because they're in a bad place and don't respond well to radiation or chemo papillary: much less common, more likely in adults you have a stain that diagnoses this well developed target therapy- anti-BRAF

Answer 100

from posterior pituitary | looks similar to a pituitary adenoma, but TTF1 staining/marker makes the diagnosis

Answer 101

metastasis is not common, but most commonly happens via breast cancer estrogen receptor is positive in the metastatic breast cancer

Answer 102

``` control tumor growth mass effects preserve nl residual pituitary function prevent recurrences relieve symptoms control GH and IGF-1 hypersecretion- GOAL GH is <1ng/mL!! ```

Answer 103

medical therapy prolactinomas- FIRST LINE IS MEDS GH secreting tumors (usually after surgical debulk) surgery- FIRST LINE for all except prolactin-secreters radiation careful observation

Answer 104

depends on surgeon preference transnsasal microscopic approach 2-D transnasal endoscopic approach 3-D

Answer 105

post-op spinal fluid leakage -requires placement of spinal drain w/ increased hospital stay to 4-5 days diabetes insipidus - injury to the posterior pit gland w/ inability to concentrate urine - requires use of DDAVP - usually transient; 2-3 days after surgery injury to optic nerves injury to carotid artery (stroke) injury to normal pituitary gland (usually firmer than cottage cheese tumor) chronic sinusitis meningitis (very low risk, even w/ spinal fluid leak)

Answer 106

AKA somatropin decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly increased by GHRH, exercise, hypoglycemia, Dopamine, L-dopa, Arginine, Ghrelin works indirectly stimulates IGF-1 synthesis in growth plate cartilage and liver- linear and skeletal muscle growth IGF-1 feeds bad to hypothalamus to increase somatostatin to inhibit anterior pituitary prod of GH produces anabolic and metabolic effects- positive N balance, lipolysis --> high FFA and glucose MOA- JAK/STAT pathway to alter gene expression can't be given orally t1/2 25 min peak levels in 2-4 hrs active levels persist 36 hrs

Answer 107

inhibited by DA

Answer 108

``` ADH~=~ vasopressin ADH acts on V2 (Gs) vasopressin acts on V1 (Gq) CNS= DDAVP kidney: increase fluids, HCTZ, NSAIDs inc ADH= SIADH, dec fluids, V2 antagonists, 3% NaCl soln decreased in DI ```

Answer 109

``` hypofunction management- hormone replacement (PHYSIOLOGIC) therapy ``` hyper function management- suppression of hormone synthesis or effect (non hormonal agents) control of non-endocrine disorders: drug therapy for variety of diseases using PHARMACOLOGIC doses

Answer 110

GH deficiency replacement therapy in children daily at bedtime SC injection or sustained release for weekly SC injection $10-50k per yr GH insensitive deficiency GH receptor mutation- Laron dwarf tx w/ recombinant IGF-1 called Mecasermin --concern w/ hypoglycemia, so carb intake prior to SC injection children w/ idiopathic short stature- controversial response to GH is highly variable, psych evidence, and cost other uses Poor growth- Turner Syndrome, Prader-Willi Syndrome, Chronic Renal Insufficiency tx of wasting or cachexia in AIDS pts pts w/ short bowel syndrome dependent on TPN off-label (NOT FDA approved) - athletes for muscle mass/performance - stacked AAs to stimulate GH release - anti-aging - increased rates of adverse events (edema, MSK pain, carpal tunnel, skin numbness/tingling), may inc growth of pre-malignant cells and inc possibility of DM hGH is exception among drugs in that off-label use has been deemed illegal- should not be recommended - generally safe in children - adults- insulin resistance and glucose intolerance; idiopathic intracranial HTN (pseudo motor cerebra), pancreatitis, gynecomastia, nevus growth, misuse in athletes (acromegaly, arthropathy, extremity enlargement, visceromegaly)

Answer 111

comes from hypothalamus to stimulate anterior pituitary to prod GH (binds to GPCR coupled to Gs--> increases cAMP and Ca levels in somtotrophs) ((Ghrelin also stimulates GH release via different GPCR)) GHRH analog: Tesamorelin! - --use in HIV pts w/ lipodystrophy 2ndary to use of highly active retroviral therapy (HAART) - -reduces excess abdominal fat no PO potential use for children w/ idiopathic GH deficiency adverse effects: rare, facial flushing, antibody formation w/ continued use -potentially fewer side effects

Answer 112

released by hypothalamus to inhibit anterior pituitary from producing GH receives positive feedback from IGF-1 inhibits GH release via GPCR coupled to Gi/o, decreasing cAMP levels and activating K channels decreases secretion of gastric enzymes and acid - dec GI motility - suppresses 5HT and peptide release reduces insulin and glucagon release -complex effects on blood glucose interferes w/ TSH release via action on TRH t1/2 3-4 min- limited therapeutic usefulness octreotide t1/2 90min (12hrs) give SC every 6-12 hrs octreotide give IM every 4 weeks lanreotide give SC every 4 weeks

Answer 113

pituitary uses excess of of GH- acromegaly and gigantism surgical resection when possible long-acting analog Lanreotide preferred drug therapy Dopamine agonists inhibit GH secretion in some pts -not as effective as SST analogs- Cabergoline!! is preferred get for adjuvant management as DA agonist (oral) GH receptor antagonist- Pegvisomant mutated GH molec- polymers attached to extend t1/2 single daily dose admin SC

Answer 114

octreotide: control bleeding from esophageal varies and GI hemorrhage -direct action on vascular smooth muscle to constrict splanchnic arterioles -fewer side effects than vasopressin GI indications: carcinoid tumors, VIP-secreting tumors, glucagonoma, gastronome symptoms of WHDA syndrome (watery diarrhea, hypokalemia, achlorhydria)

Answer 115

transient deterioration in glucose tolerance HYPERGLYCEMI then subsequent improvement abdominal cramps, loose stools cardiac effects incl sinus brady and conduction disturbances

Answer 116

prolactin release is under inhibitory control by hypothalamic Dopamine at D2 receptors main stimulus for release is suckling- 10-100 fold inc within 30min stimulates milk prod w/ appropriate levels of insulin, estrogens, progestins, and corticosteroids stimulates proliferation and differentiation of mammary tissue during pregnancy inhibits gonadotropin FSH/LH release and/or ovarian response to these hormones (via dec GnRH release) -relates to lack of ovulation during breastfeeding uses: hypoprolactinemia- NO preparation commercially available hyperprolactinemia- ex prolactinomas (pituitary adenomas that are MOST amenable to pharmacotherapy) -symptoms of galactorrhea and amenorrhea Dopamine agonists are avaialbe that decrease both secretion and tumor size -all available as ORAL preparations

Answer 117

Cabergoline preferred agent more selective for D2 receptor and more effective in reducing prolactin secretion better tolerated (less nausea, some hypotension, and dizziness) -concern w/ higher doses and valvular heart disease (agonist action at 5HT2b receptors) Bromocriptine prototype of long-standing use -Ergot derivative that also activates D1 receptors -frequent side effects! incl N/V, HA, postural hypotension, and less frequently psychosis or insomnia

Answer 118

released from hypothalamus critical control of body water via cells in distal nephron and collecting tubules main stimulus for release is rising blood osmolality -also released in response to decrease in circulating blood vol -release can be inhabited by ethanol renal actions mediated by V2 receptors (GPCRs coupled to Gs) - increase rate of insertion of aquaporins - increases water perm- leading to antidiuretic effect - also activates urea transporters and increases Na transport in distal nephron - nocturnal enuresis (oral dDAVP) non-renal V2 actions coagulation factor VII and von Willebrand's factor- elevates levels of Von Willebrand factor (via IV desmopressin) -tx for moderate hemophilia A- elevates factor 8 levels (via IV desmopressin) Vasopressin- acts at V1 receptors- GPCRs coupled to Gq (increase Ca) -mediates vasoconstriction of vascular smooth muscle -attenuates pressure and bleeding in esophageal varies via vasoconstriction of splanchnic arterioles ((((Octreotide is better tolerated and now preferred agent if drug used w/ or w/o endoscopy)))) -used as a vasopressor for tx of pts w/ SEVERE SEPTIC SHOCK -Pressor (constriction) responses occur only at much higher Cp than needed for physiological antiduiresis ``` admin parenterally (not PO) t1/2 20min ``` Desmopressin DDAVP- ADH analog that is more stable to degradation t1/2 1.5-2.5hrs also an option for nocturnal enuresis (children)

Answer 119

hypofunction: central (neurogenic) DI inadequate ADH secretion from post pit Desmopressin is tx of choice ----1-2% bioavailability orally (+side effects); most pts tolerate nasal (minimal side effects); SC-IV and oral have side effects Chlorpropamide (1st gen sulfonylurea) potentiates action of small/residual amounts of ADH (MOA not clear) -option for pts intolerant to desmopressin (side effects or allergy) other options: Carbamazepine, Clofibrate (not US), thiazides, NSAIDs

Answer 120

hypofunciton: peripheral (nephrogenic) DI inadequate ADH actions- congenital (aquaporin mutations) or drug-induced Drug-induced causes -----Lithium- reduces V2 receptor stimulation of adenylyl cyclase (ADR in 20-40% bipolar pts on Li) -----Demeclocyline (tetracycline antibiotic) MOA not understood- block of ADH binding to receptor treatment fluids, low salt, low protein diet Thiazide diuretics: paradoxically reduces polyuria - MOA not understood but antidiuretic effect parallels ability to cause natriuresis - low vol --> high Na-H2O at PCT --> low H2O at CT NSAIDs (indomethacin): Prostaglandins attenuate ADH-induced antidiuresis- inhibition of prostaglandin synthesis may relate to enhance antidiuretic response thiazide and indomethacin can be used in combination

Answer 121

SIADH incomplete suppression of ADH secretion under hypoosmolar conditions--> hyponatremia (not enough Na excretion) ``` drug classes most commonly implicated in SIADH: psychotropic agents: SSRIs, haloperidol, TCADs sulfonylureas (chlorpropamide) vinca alkaloids (chemotherapy) methylenedioxymethamphetamine MDMA (ecstasy) ``` tx of hyponatremia: restriction of free water intake (conservative measure) V2 receptor antagonists -therapeutic advance for hyponatremia- also tried in HF Demeclocycline: inhibits ADH effect on distal tubule preferred drug in pts w/ inadequate response to conservative measures Tolvaptan- oral, limited use by cost, hepatotoxicity, inc thirst) Conivaptan- IV, useful in hospitalized SIADH pts -given w/ hypertonic 3% saline if severe symptomatic hyponatremia--> more rapid correction warning against TOO RAPID of hyponatrmeia correction--> cerebellar pontine myelinolysis--> fatalities!!! (DeMasters published this paper)

Answer 122

cholesterol--> pregnenalone pregnenalone--> aldosterone pregnanlone--> (17-alphahydroxylase)--> 17-OH-pregnenalone --> (17,20-lysae)--> dehydroepiadnosterone DHEA 17-OH-pregnenolone--> cortisol DHEA--> sex steroids

Answer 123

``` major stress hormone in body- released into blood steroid hormone (lipid soluble) prod in Zona fasciculata ``` >90% cortisol exists in bound form to CBG (cortisol binding globin) (free matters) HS90 (heat shock 90) binds w/ cortisol inside cell then HS90 dissociates, then you have cortisol + receptor get transported into the nucleus, change DNA, and regulate gene expression ---effects of cortisol are delayed but longer lasting metabolic effects -glucose for E source to combat stress; increase in glycolysis in an indirect way- permissive effects on EPI (presence of cortisol enhances EPI effects on glycogenolysis and lipid metabolism); or gluconeogenesis, CRR for insulin - fatty acids- hormone sensitive lipase- permissive forEPI; causes centripetal distribution of fat (removes extremity and deposits fat on trunk)- moon facies and buffalo hump - protein- break down protein to prod AAs from skeletal muscle ``` other effects -circulatory sys- RBC production- inc cortisol causes polycythemia dec cortisol causes anemia permissive for EPI, and up regulates beta adrenergic receptors ``` fibroblasts- inc cortisol will inhibit fibroblast proliferation and cortisol synthesis bone- cortisol is a Vit D antagonists; inhibits Ca abs, prolonged elevation of cortisol can lead to osteoporosis anti-inflammatory P lipase A2--> arachidonic acid --> PGs and THX wound response: PGs and leukotrienes and fibroblasts contribute to wound healing cortisol is inhibitor of phospholipase C so you don't reach arachidonic acid cortisol also inhibits fibroblast proliferation (which is supposed to seal off wound form rest of body)--- run serious risk of getting infections in wound immunosuppression- cortisol inhibits T cell proliferation and activation

Answer 124

primary regulation from hypothalamus--> CRH--> pituitary--> ACTH --> adrenal gland --> cortisol cortisol has strong negative feedback on hypothalamus -key hormone in this pathway for regulation is ACTH ACTH is produced as a pre hormone called proopiomelanocortin POMC based on the kind of cleavage of POMC, you release different hormones, incl ACTH ACTH acts on adrenal cortex to control its functions- generalized control over cortex, but its regulation is primarily to cortisol -cell numbers, adrenocortical enzymes

Answer 125

adrenal cortex hypofunction -autoimmune adrenal atrophy (primary chronic adrenal insufficiency) ``` low cortisol high ACTH (trying to compensate for low cortisol) low aldosterone (low production from adrenal) not much sexual dysfunction (controlled by gonads)- JFK had Addison's disease lol ```

Answer 126

problem with pituitary low cortisol low ACTH (there's the problem) same/nl aldo (adrenal gland isn't damaged)

Answer 127

``` primary- Cushing syndrome high cortisol (adrenal problem) low ACTH (trying to slow down cortisol) ``` secondary- pituitary tumor (Cushing Disease) high cortisol high ACTH (from pituitary) normal aldo (still being controlled by RAAS) tertiary- exogenous Cushing's

Answer 128

chromaffin cells- prod EPI, stored in vesicles, released by calcitosis tyrosine --> (tyrosine hydroxylase) --> L-DOPA--> (AA decarboxylase) --> Dopamine --> into vesicle via VMAT1 in the vesicle, DA gets converted to NE via dopamine beta hydroxylase the NE is transported from vesicle back to cytosol and converted back to EPI via PNMT then EPI is pumped back into vesicle --in the vesicle, 90% is EPI, small amount is NE, so the main hormone released from chromaffin cells is EPI release of EPI from chromaffin cells is via Splanchnic nerve -splanchnic nerve releases ACh onto chromaffin cells that triggers the EPI release ACH acts on nicotinic and/or muscarinic acetylcholine receptors -Nicotinic- ligand gated; cationic channel channel opens and lies in mainly Na, some Ca influx too depo cell Ca then drives Ca-dependent exocytosis to release EPI very fast Muscarinic- GPCR Gq -Gq pathway- prod IP3, acts on IP3 receptors on ER, releases Ca from ER longer lasting, but slower acting tougher, both of them raise cyto-Ca sufficiently to cause Ca-dependent exocytosis

Answer 129

from chromaffin cell vesicles when EPI reaches target- acts on 2 receptors: alpha adrenergic receptors - alpha1- coupled to Gq- inc PLC- inc Ca, PKC (protein kinase C) - alpha2- couple to Gi- decrease cAMP beta adrenergic receptors GPCRs, stimulate Gs to prod adenylylate cyclase, which increases cAMP to inc protein kinase -beta1, beta2, beta3 EPI through beta adrenergic receptors gives you: inc glucose, primarily activated by glycogenolysis inc FFAs- stimulate hormone-sensitive lipase -net decrease insulin release via alpha2 receptors -allows you to provide a lot more serum glucose available to pump into skeletal muscle/other tissue during times of stress stress goes to 2 places: hypothalamus- prod CRH- ACTH- cortisol (long term stress) -through activation of splanchnic nerve- EPI (immediate response to stress- CV function, E sourceS) Locus ceruleus - prod NE (inc attn, arousal, aggressiveness)

Answer 130

tyrosine derived hormone that behaves differently- it's between a peptide and steroid hormone -ether makes it a lot more hydrophobic so it acts like a steroid hormone skeletal molec known as thyronine- 2 tyrosine residues linked by ether the skeletal molec is iodinated to form thyroid hormone - 4 possible positions 3,5,3',5'= tetraiodo thyronine (T4)- pro hormone - 3,5,3' = triodo thyronine (T3)- active - 3,3',5'= reverse T3- inactive need tyrosine and iodine source to make TH external source of iodine- trace element present in water -taken up by thyroid gland to make TH -Thyroid needs to be efficient in sampling iodine and taking it up because of its relatively small amount (hence all the vasculature) (developing countries with bad water have thyroid problems)

Answer 131

making the hormone: all the action relies on follicle cell in thyroid gland (vs the C cells that prod calcitonin) iodine process: follicle cell: iodine from blood is taken up via Na/I symporter Na then gets pumped out in Na/K ATPase iodine taken to luminal side of cell/gland where it binds to enzyme thyroperoxidase TPO converted to active iodide, ready to be transferred to tyrosine residues 30x more iodine in these cells compared to blood- follicle cells act as a iodide trap tyrosine proces: tyrosine residues come from thyroglobulin hormone TG (a protein make in the follicle) TG secreted into lumen of gland at very high conc's so that TG forms a suspension (colloid of lumen) TPO already has active iodide on it, so then it transfers iodide to tyrosine to make iodinated tyrosines onto the TG proteins TPO then forms ether link between the iodinated tyrosine residues (T4,T3) hormone is still bound to TG molec, so in the lumen there's no free hormone now the new TG molec is endocytosed into the follicle cell where it's taken up by lysosomes gets degraded into its individual components: get T3,T4, reverse T3, AAs, iodotyrosines, etc T3,T4 then get transported out into the bloodstream to be used

Answer 132

ether bond makes TH act like a steroid hormone -when carried in the blood, TH + THBG TH-THBG over 99% is in bound form if you increase THBG conc in the blood, the total TH levels will also increase free TH levels will be maintained --free TH levels always controlled within a set point --important concept to remember for all steroid hormones (incl TH) --free level is what is important TH that's carried in blood reaches target cell, taken into cell via transport mech T4--> T3 via monoiodinase T3 transported to nucleus, binds to TH receptors to act as transcription modifiers

Answer 133

BMR regulation via TH reflects balance of all anabolic/catabolic processes in body low T3--> shift balance to anabolism --predict low E production, excess weight, cold intolerance (not enough heat prod) high T3--> shift balance to catabolism --prod excess E, heat intolerance, lose weight role in development TH is critical, esp in early development early TH test when baby is born -luckily, early supplementation seems to reset development to nl -if it's ignored for a while, you get severe developmental delays- growth and mental ---need nl TH levels to get nl levels of other hormones, etc permissive for beta adrenergic effects -cardiac tissue, hyperthyroidism = tachy, low= brady brain development psychological functions and susceptibility to other mental illnesses --depression test- check TSH levels

Answer 134

hypothalamus --> pituitary --> thyroid TRH--> TSH --> T3--> feedback regulation to TRH key regulation hormone is TSH - clinical point of view- the hormone is always used to test thyroid hormone levels - not enough free TH to get a good reading - TSH acts on thyroid gland to essentially control all functions of thyroid gland - --growth of #follicle cells is regulated by TSH - -regulates all components of thyroid hormone synthesis- transporters, TPO, TG - -organification of iodide- putting free iodide onto a protein

Answer 135

hypothyroidism ``` primary: Hashimoto thyroiditis = autoimmune destruction of thyroid gland -low T3 (where the destruction is) high TSH (trying to compensate and make more T3) ``` secondary: Hypopituitarism low T3 (not being stimulated enough) low TSH (where the problem is) ``` hyperthyroidism primary: Graves disease high T3 (unchecked production) low TSH + TSI!!! (thyroid stimulating immunoglobulins- autoantibodies against the TSH receptor) ``` secondary: pituitary disorder high T3 high TSH (not responding to the negative feedback signal)

Answer 136

Type 1/2 deiodinase takes T4--> 3,5,3' T3 ``` this doesn't work during: starvation severe illness severe stress neonatal period glucocorticoids Propanolol Amiodaraone Amiodarone* Radiocontrast dyes ``` so T4--> shunted to reverse T3 via Type 3 deiodinase

Answer 137

serum total T4 = bound + free total T4 = 4-12microg/dL free T4 = 0.02% = 0.8-1.8nanog/dL 99.98% T4 is bound/inactive to: TBG, TPBA, Albumin half life = 7 days T3 serum total T3 = bound + free total T3 - 80-180 nanog/dL free T3 = 0.2% = 1-4 picog/mL 99.8% T3 is bound/inactive/cannot enter cells: TBG, Albumin half life = 1 day

Answer 138

``` increased TOTAL: hyperthryoidism/thyrotoxicosis increased binding proteins!!! --estrogen thyroid hormone resistance ``` increased FREE: hyperthryoidism/thyrotoxicosis thyroid hormone resistance --binding protein issues are NOT important here hypothyroidism decreased serum protein binding euthyroid sick syndrome (nonthryoidal illness) drugs liver or kidney disease (total T4, total T3)

Answer 139

TSH is the SINGLE BEST test to screen for thyroid dysfunction --TSH stimulates iodine uptake into thyroid follicular cells and TH production elevated in primary hypothyroidism (lack of negative feedback by TH) suppressed in primary hyperthyroidism (excess negative feedback by TH) when you cannot rely on TSH: abnormal pituitary -ex. panhypopituitarism, TSHoma, idiopathic central hypothyroidism

Answer 140

``` Hyperthyroidism: nervousness weight loss inc appetite (4% have dec appetite) fatigue tremor heat intolerance others: palpitations, hyperdefacation, insomnia, diaphoresis ``` ``` hypothyroidism: mental slowness weight gain dec appetite (2% inc appetite) fatigue muscle cramps cold intolerance others: brady, constipation, hypersomnia, dry skin ```

Answer 141

overt: low TSH high Free T4 (high free T3) subclinical: low TSH nl free T4 (nl free T3) DO NOT order free T3 levels if serum TSH is nl, pt is "euthyroid" --RARE exceptions incl TSH-producing tumor, thyroid hormone resistance

Answer 142

thyrotoxicosis: high levels of circulating TH, which is SUGGESTIVE of hyperthyroidism could be caused by: overproduction of T4 and T3 = hyperthyroidism no overproduction, but HIGH RELEASE of preformed/stored T4 and T3 (not true hyperthyroidism) do a radio labeled iodine-123 test for thyroid uptake TSH stimulates thyroid to take up iodine and synthesize T4 and T3 in thyrotoxicosis, TSH should be low (hypothalamus and pituitary sense elevated T4 and T3 levels, and secretion of TRH and TSH is suppressed) --if TSH is suppressed, there should be no uptake of iodine!!!! but still having a thyroid excess in this case is due to high release of PREFORMED thyroid hormone (not true hyperthyroidism)--- THYROIDITIS - -a normal or high level of iodine uptake in the setting of low TSH is abnl and indicates autonomous production of TH---- this is a true hyperthyroid state!! - pattern gives info on etiology (Graves vs hot nodule vs multi nodular goiter)

Answer 143

high iodine uptake (true) hyperthyroidism: *****Thyrotropin receptor antibody **** ---Graves disease!! (or hashitoxicosis) ***Thyroid autonomy ** ---Toxic adenoma ** ---Toxic multi nodular goiter (MNG) HCG ---hydatidiform mole, choricocarcinoma TSH ---TSHoma (pituitary tumor) ---Thyroid hormone resistance low uptake (not true) thyroiditis "hyperthyroidism": ``` Subacute thyroiditis: ***---Granulomatous thyroiditiis (viral); deQuervain's (PAIN) Chronic lymphocytic thyroiditis ***---Hashimoto's thyroiditis !!! (NONTENDER) ***---Postpartum thyroiditis Radiation induced thyroiditis (PAIN) Infectious thyroiditis (PAIN) Drug-induced thyroiditis Ectopic thyrotoxicosis ---FACTICITOUS!!! ---struma ovarii (ovary teratoma) ``` thyroid scan will be dark- no need for scan

Answer 144

Graves exophthalmos- bulging eyes pretrial myxedema- doughy feeling

Answer 145

``` medications: antithyroid drugs (methimazole, propylthiouracil)- to inhibits synthesis of TH ``` beta blockers- reduce systemic hyperadrenergic symptoms and effects (primarily tremor, palpitations, etc.) radioactive iodine I-131 surgery

Answer 146

ex subacute/granulomatous thyroiditis or postpartum thyroiditis at first- low TSH very high free T4 may need beta blockers by about 4 months- TSH will surge very high free T4 will drop very low may need LT4 bridge

Answer 147

small decrease in free T4 = LARGE increase in TSH

Answer 148

primary hypothyroidism: ``` *****chronic autoimmune (Hashimoto's) thyroiditis!!!! transient hypothyroidism ***---silent or postpartum thyroiditis ***---subactue or granulomatous thyroiditis iatrogenic ***---thyroid surgery/thyroidectomy ***---radioactive iodine ---external neck irradiation iodine deficiency or excess drugs --antithyroid drugs*, Lithium**, Amiodarone***, tyrosine kinase inhibitors, Iron,, Cholestramine, phenytoin, carbamazepine infiltrative diseases ---hemochromatosis, sarcoidosis, amyloidosis, fibrous (Reidel's) thryoiditis, scleroderma infectious ---M tuberculosis, P carinii congenital ``` ``` central hypothyroidism (2ndary/tertiary) ***pituitary tumor trauma postpartum pituitary necrosis (Sheehan's syndrome) hypophysitis craniopharyngiomas radiation therapy infiltrative disease TSH or TRH resistance ```

Answer 149

Thyroid autoantibodies to: TPO and TG anti-TG and anti-TPO people who can also have these antibodies: general pop, pregnant women, T1DM, relatives of autoimmune thyroiditis, Graves disease! autoimmune thyroiditis! in general, pts w/ high TSH and +autoantibodies develop hypothyroidism at a rate of ~5%/yr --TPO Abs alone ~2%/yr

Answer 150

TSH >10 (nl TSH 0.4-4) whether to treat TSH between 5-10 is very controversial -cardiovascular risk treat w/ LEVOTHYROXINE-- synthetic T4 treatment goal is 0.51- 3.0

Answer 151

an extreme form of hypothyroidism, so severe as to readily progress to death unless dx promptly and treated vigorously true endocrine emergency!! - low CO, brady, resp depression, edema, AMS, hypothermia, metabolic derangements - ---high mortality rate!

Answer 152

``` Aldosterone released in response to: high AngII high serum K high ACTH (lesser stimulus) ``` Cortisol: high ACTH high Arginine Vasopressin (lesser stimulus) androgens: high ACTH NE and EPI: sympathetic nervous system synthesis is dependent on high local concentrations of cortisol

Answer 153

aldosterone: binds mineralocorticoid receptors to regulate: blood vol Salt/water homeostasis cortisol: binds glucocorticoid receptor to regulate: E balance CVS, metabolic, and immune homeostasis Androgens: bind androgen receptors to regulate: pubarche NE/EPI bind adrenergic receptors to regulate: CVS effects and bronchial dilation

Answer 154

primary: insufficient adrenal gland- can't make cortisol, androgens, or aldo -----deficiency of BOTH glucocorticoids and mineralocorticoids (cortisol AND aldosterone) low cortisol low aldosterone high ACTH ---causes: 70% are autoimmune (Addison's- 21-hydroxylase enzyme) 10-20% TB, Fungi, HIV infection other reasons less likely: infiltrative, hemorrhage, metastatic cancer, metabolic, drugs, surgery secondary: pituitary, hypothalamus, anything above the adrenal gland in the H-P-A axis *****---can still make Aldo (main stimulus is RAAS system w/ Ang2 and K levels) -key distinction between primary and secondary ------deficiency of glucocorticoids ONLY low cortisol inappropriately low/nl ACTH nl Aldosterone ---causes: most common = drugs (withdrawal of chronic glucocorticoids, high dose opioids) tumor (pituitary adenoma, meningioma, others) surgery radiation, infectious hemorrhage infiltrative metastatic cancers

Answer 155

symptoms/ signs fatigue, weakness, anorexia, nausea, abdominal pain, weight loss, myalgia, vomiting, postural dizziness, arthralgieas, HA, Hypotension, tachy hypoglycemia, hyponatremia, eosinophilia Primary only: salt craving vitiligo, hyper pigmentation hyperkalemia Primary specific symptoms: because you get both glucocorticoid (cortisol) and mineralocorticoid (Aldo) deficiency no aldosterone to act on MCR to signal to the Na, K transporters on the principal cells--> you get low Na, high K, and low BP hyper pigmentation due to increased POMC processing - -no cortisol/aldo production from adrenal gland means you'll stimulate MORE ACTH and CRH production in the HPA axis - ACTH is made w/ MSH as breakdown products from POMC

Answer 156

emergency! N/V, fever, syncope, hypotension, tachy give stress dose steroids --hydrocortisone 100mg IV every 8 hrs

Answer 157

half of pts w/ autoimmune adrenalitis have at least 1 other autoimmune disorder Polyglandular autoimmune syndromes APS: Type 1: adrenal insufficiency, hypoparathyroidism, mucocutaneous candidiasis, risk of primary hypogonadism, celiac sprue, vitiligo, hypophysitis, pernicious anemia Type 2: adrenal insufficiency, autoimmune thryoididits (AKA Schmidt's disease), and risk of T1DM, vitiligo, primary hypogonadism, pernicious, anemia, celiac sprue

Answer 158

nl 7-8AM cortisol level >18 (no AI) adrenal insufficiency cortisol <5 when less than 16-18, may represent nl function or partial or complete adrenal insufficiency if below 5, treat w/ steroids until you can figure out what's going on if baseline cortisol is lowl, then do cosyntropin (synthetic ACTH) stimulation test: measure baseline ACTH and cortisol levels give 250mcg IV cosyntropin over 2 min measure either 30 or 60min cortisol ---any cortisol value over 20mg/dL means no AI ---any low cortisol values means you have adrenal insufficiency (partial or complete, based on how close to 20 it gets- you can still live normally w/ partial deficiency, but you'll have trouble responding to a stressor)

Answer 159

will have: low cortisol inappropriately low/nl ACTH nl Aldosterone MRI pituitary may show pathology if you don't make ACTH chronically, your adrenal gland will atrophy eventually but if it's a new adrenal insufficiency disease, then you still might be able to stim your cortisol to above 20 since adrenal gland is still capable of making it

Answer 160

primary replace BOTH glucocorticoids and mineralocorticoids Hydrocortisone or prednisone daily Fludrocortisone daily Secondary replace glucocorticoids: Hydrocortisone or prednisone no mineralocorticoid replacement --fix underlying cause if possible

Answer 161

JGA and renin regulation renin is released in response to: low afferent arteriole vol (low renal perfusion) low distal tubule Na conc (tuboglomerular feedback) renin is suppressed in response to: high afferent arteriole vol (high renal perfusion P) high distal tubule Na conc (tuboglomerular feedback) RAAS: high K and Ang2 stimulate Aldosterone synthetase in the zona glomerulosa ACTH can also stimulate aldosterone synthetase (to lesser extent) Aldosterone regulates EC volume and K balance - -Aldo binds mineralocorticoid receptor MCR in the distal cortical collecting duct principal cells - -moves to nucleus to stimulate transcription of genes to increase # of Na and K channels - -results in increased Na reabsorption and promotes K and proton secretion - -increased Na reabs means increased plasma vol and increased BP (which then switches off Renin production and angiotensin2)

Answer 162

primary aldosteronism (Conn's) secondary aldosteronism -cirrhosis, heart failure lidless syndrome -mutation in epi Na channel Deoxycorticosterone mediated -genetic recombination of genes Licorice ingestion -pseudohyperaldosteronism

Answer 163

AKA Conn's ``` resistant hypertension hypokalemia mild hypernatremia metabolic alkalosis muscle weakness is possible ``` * *K may fall to severely low levels - K wasting is common in mineralocorticoid (aldosterone) excess syndromes but is not absolute - pts MAY have hyeraldosteronism and nl serum K ``` screen: <30yo w/ HTN (esp if nl weight and no FHx) unexplained hypokalemia and HTN resistant HTN (more than 2 meds) adrenal indidentaloma and HTN ```

Answer 164

early morning aldosterone: renin ratio Ratio >20 with aldo >15 and nl K at time of testing stop interfering meds before testing esp mineralocorticoid receptor antagonists (spironolactone, epleronone) if ratio is elevated, further testing is required: need to demonstrate inappropriate aldosterone secretion after salt loading (Renin goes up when macula densa senses low salt) -give 2L normal saline over 4 hrs and measure aldo -nl: aldosterone suppresses below 5 hyperaldo: aldosterone is above 10 once biochem dx is certain, CT or MRI should be performed to look for adenoma or hyperplasia then adrenal vein sampling AVS should be done for lateralization (which adrenal gland is it?) AVS lateralization: catheters into R and L adrenal veins -relies on finding several-fold difference in Aldo secretion between 2 sides -if not, could be idiopathic hyperaldosteronism (or bilateral adrenal hyperplasia) -if there is an adenoma on 1 side, and pt is <35yo, can consider skipping AVS because that probably means the nodule is your problem (the older you get, the more "nl" nodules you can have, so a nodule doesn't absolutely mean that's your problem)

Answer 165

if unilateral aldosterone secreting adenoma, surgical resection often leads to cure (lots of HTN pts can come off meds after surgery) if bilateral adrenal hyperplasia is the cause, tx w/ mineralocorticoid antagonist (sprinolactone or eplerenone) if not a surgical candidate, despite unilateral aldosterone secreting adenoma, can use med tx

Answer 166

cortisol-cortisone shunt mineralocorticoid receptor has higher affinity for cortisol than Aldo Also sensitive tissues (like kidney) have 11-beta-HSD2 to shunt cortisol to cortisone (inactive) licorice inhibits the 11-beta-HSD2 enzyme , so you have high cortisol produced in the kidney, so cortisol starts regulating the aldo receptor - MCR is activated by cortisol - leads to HTN and hypokalemia

Answer 167

glucocorticoid (cortisol) excess (Cushing syndrome) ACTH dependent: pituitary adenoma ectopic ACTH production ACTH independent: adrenocortical adenoma adrenocortical carcinoma nodular adrenal hyperplasia iatrogenic or surreptitious: exogenous glucocorticoid use (MOST COMMON!!!- steroid use) Endogenous Cushing's is rare

Answer 168

high ACTH high cortisol feedback mech does not work to turn off ACTH Cushing's disease: pituitary mediated hypercortisolemia Tumor in anterior pituitary: corticotroph adenoma ``` Ectopic Cushing Syndrome or Tumor in neuroendocrine cell (ex small cell lung cancer, bronchial carcinoid, medullary thyroid cancer, carcinoid, pancreatic neuroendocrine tumor, pheochromocytoma) will cause: very high ACTH very high cortisol feedback mech does not work to turn off ACTH (coming from lungs, ex) ```

Answer 169

high cortisol low ACTH feedback mech still works causes: Cushing syndrome (adrenal mediated) Tumor adrenal cortex (adrenal cortical adenoma or carcinoma) bilateral adrenal hyperplasia (both adrenals are overproducing)

Answer 170

24 hr urinary free cortisol midnight salivary cortisol (diurnal rhythm: normally cortisol should be low at midnight) 1mg dexamethasone suppression test - pt takes 1mg dex at midnight before an 8am blood draw for cortisol - nl: cortisol suppresses to <1.8 - autonomous prod of cortisol: feedback doesn't work, cortisol won't suppress despite presence of dexamethasone ACTH dependent vs ACTH independent cause: baseline AM cortisol and ACTH --if ACTH is low, implies adrenal source (independent)- do adrenal imaging --if ACTH is high, implies pituitary/ecotopic source (dependent) Pituitary vs Ectopic ACTH source: MRI pituitary -about 55% corticotrophin adenomas are seen on MRI 8mg dex suppression test -Pituitary source: cortisol suppresses to <5 or more than 50% of baseline ----not always reliable ****Inferior petrosal sinus sampling IPSS*** -catheters up to pituitary (petrosal sinuses), draw baseline ACTH at intervals after stim w/ CRH (or desmoressin) -pituitary source = ACTH is higher in petrosal than central IVC -ectopic source = ACTH similar in petrosal and central IVC

Answer 171

correct underlying cause surgical adrenalectomy or transsphenoidal pituitary surgery or removal of ectopic source- 1st line med tx is second line: ACTH secretion inhibitors- Cabergoline Pasireotide ``` Cortisol synthesis inhibitors- Adsrenolytic agents (mitotane, ketoconazole) ``` cortisol receptor blocker- Mifepristone

Answer 172

synthetic glucocorticoids developed to exploit anti-inflammatory and immunosuppressant effects of glucocorticoids -RA, lupus, Hepatitis, MS, Vasculitis, transplant, allergy, IBD, sarcoidosis, lymphoma, thrombocytopenia, hemolytic anemia, cerebral edema/spinal cord injury, preterm labor side effects of chronic glucocorticoids: Iatrogenic Cushing's syndrome!! Assoc w/ use of any supra physiologic dose don't forget to ask pts about steroids- asthma, cream, nasal, etc that they don't think of

Answer 173

neuroendocrine tumors are a zebra diagnosis pheochromocytoma and paraganglioma- derived from chromaffin cells of embryonic neural crest origin tumors often benign, but can cause problems: mass effect over-secretion of catecholamines/metanephrines (HTN, heart disease, stroke, death)-- increased alpha-adrenergic stimulation head and neck paraganglionmas HNPGL= often non-secretory adrenal medulla tumors= pheochromocytoma PCC tumors at other sites= paragangliomas PGL clinical presentation: CLASSIC TRIAD: HA, palpitations, sweating "Pain, perspiration, palpitations" also HTN of different varieties also anxiety, tremors, weight loss, flushing, hyperglycemia or could be asymptomatic

Answer 174

adrenal medulla: receives input from sympathetic NS via preganglionic fibers from spinal cord medulla is like a nerve ganglion, but lacks synapses from postganglionic fibers and releases secretions directly into blood!!! -Tyrosine enters chromaffin cells, and is converted to DOPA, dopamine, NE, and EPI ---Tyrosine --> DOPA via Tyrosine Hydroxylase (rate limiting step in catecholamine synthesis!!) ---Cortisol promotes EPI synthesis in medulla by up regulating PNMT (which takes NE--> EPI) medulla makes 80% EPI and 20% NE metanephrines, normetanephrines, and vanillymandelic acid (VMA)--> alpha adrenergic receptors for flight or fight response

Answer 175

``` Plasma metanephrines!! (also urine Mets) draw after 20min rest, in fasting state -no Acetaminophen for 5 days -diff ranges for sitting/standing (prefer supine) -if borderline- order 24 urine test ``` other screening tests: plasma catecholamines -less reliable, often abnl -often only useful in established pheo or known mutation carriers Clonidine suppression test -normally plasma Met decreases more than 40% 3hrs after 0.3mg Clonidine given- rarely done (blood/urine tests are getting better)

Answer 176

``` Acetaminophen SSRIs Serotonine NE inhibtors Marijuana and other illicit drugs among others ``` will give you false positives

Answer 177

pt needs radiographic imaging to localize tumor start w/ CT/MRI of abdomen/pelvis -majority will be in intra- or extra-adrenal in this area I-123 MIBG: localization of extra-adrenal, recurrent, and metastatic tumors (MIBG will be high conc's where there is high NE conc from a tumor) treatment: surgery must do peri-operative blockade prior to surgery ---alpha-blocker as 1st line therapy (phenoxybenzamine!!!, or Doxazosin, Prazosin, Terazosin as a selective alpha1 blocker) ---CCB as 2nd line ---add BB LATER to control expected reflex tachy from alpha-blockade tyrosine hydroxylase inhibitor: Metrysoine -prevents Tyrosine from going to DOPA, then to NE,EPI, VMA, etc surgical options: laparoscopic adrenalectomy adrenocortical sparing surgery -for bilateral adrenal tumors, or for pts w/ genetic syndromes at risk for future recurrence during surgery: typical response is to see BP surge when tumor is being manipulated, then severe hypotension when tumor is removed ---intra-op may need IV phentolamine (alpha antagonist) to prevent BP surges ---post-op can require alpha agonist to support BP (Phenylephrine/NE) for 1st 48rhs

Answer 178

``` old dogma- not true anymore now 20% extra-adrenal 10% still bilateral now 25% malignant now 13-55% asymptomatic now 30-40% hereditary ---children numbers are different ``` susceptibility genes: VHL, NH1, MLN2 are common SDHB- this gene has inc risk for MALIGNANT pheo ---dopamine secreting associated w/ malignancy

Answer 179

Multiple endocrine neoplasia type 2 activating RET mutations on Chr10q11.2 autosomal dominant ``` MEN2A: Medullary thyroid carcinoma MTC hyperparathyroidism pheochromocytoma (50% of pts)- can be bilateral cutaneous lichen amyloidosis ``` ``` MEN2B: MTC pheo multiple neuromas, marfinoid habitus --NOT hyperparathyroidism ```

Answer 180

30-40% of pts w/ pheo/para will have a susceptibility gene mutation - --ALL pots w/ pheo/para need referral for consideration of genetic testing - -helps guide screening, surveillance for pt and family members need lifelong F/U - for recurrence, metastatic disease, additional primary tumors - if genetic mutation, screen for other assoc tumor types

Answer 181

presence of distant metastases defined by WHO can have long latency period- up to 20yrs occur more often from extra-adrenal PGL and tumors over 4-5cm 5 yr survival is ~50%

Answer 182

overall 2-10% depending on study increases w/ age most are nonfunctioning tumors 2 questions after finding an incidental nodule: secreting or non-secreting? benign or malignant? (malignant- primary or metastasis?; does pt have Hx of malignancy?)

Answer 183

all adrenal nodules should be ruled out for hormonal hyper secretion - -plasma metanephrines of 24hr urine Met/Cat - ------screen for pheo, too - -1mg overnight Dex suppression test - ------screen for hypercortisolism if pt is HTN, screen for primary aldosteronism w/ aldo/plasma Renin activity

Answer 184

Hounsfield scale HU************** -measures x-ray attenuation water = 0 HU adipose tissue = -20- -150 HU if adrenal mass has HU <10 on CT (density close to water and fat)--> likely is a benign adrenal nodule w/ high intracellular lipid --good thing MRI is as effective as CT scanning here- non contrast ``` benign adrenal masses: <4cm homogeneous w/ smooth/regular borders HU<10 rapid enhancement of contrast; rapid loss of contrast (high washout!) ```

Answer 185

guidelines in flux surgical removal: >4cm progressive growth, esp if HU>20 hormone hyper secretion ``` monitor: HU<10 <4cm non-secreting image regularly hormone profile annually for 4 yrs ```

Answer 186

give for anti-inflammatory!!!!! (GC-AI) potential for iatrogenic cushing's if used for >3 weeks via suppression of pituitary ACTH release) ex dexamethasone, prednisone carbs: hyperglycemia (diabetes-like state) protein: muscle wasting, skin-CT atrophy fat: more lipogenesis (centrally via insulin action) --> centripetal obesity

Answer 187

has salt retaining potential ex fludrocortisone can cause: ***fluid retention, HTN, and HYPOkalemia**** (increased Na reabs at kidney, inc blood vol and BP, loosely coupled to K and H excretion) Glucocorticoid effects can be separated from Mineralocorticoid effects BUT can't separate GC metabolic side effects form anti-inflammatory and I-S therapeutic effects

Answer 188

MC- salt retaining! **Fludrocortisone- super high MC (very, very small: cortisol and prednisone) ``` GC- anti inflammatory! Dexamethasone- super high AI then Fludrocortisone then Prednisone then Cortisol (AKA hydrocortisone) ``` both MC and GC activity needed in primary adrenal insufficiency!!!! (Addison's) prednisone is inactive until hepatic conversion to prednisolone- NO topical activity or parental activity

Answer 189

11-beta-hydroxysteroid dehydrogenase 11-beta-HSD liver: 11-beta-HSD1 converts prednisone --> prednisolone activating kidney: 11-beta-HSD2 converts cortisol back to cortisone inactivating fetus: 11-beta-HSD2 protects fetus from effects of maternal steroids (cortisol back to cortisone)

Answer 190

chronic- Addison's oral hydrocortisone 2-3x/day (mimic diurnal) dexamethasone, prednisone (long acting) ---temporary dose inc necessary w/ illness or surgery fludrocortisone can be added if more salt-retaining activity s needed (if pt is hypotensive) DHEA supplementation needed in some women (mood and well-being) Acute- Adrenal crisis electrolyte abnormalities (low Na and high K) and plasma volume depletion -volume replenish w/ nl saline or D5 nl saline -if previous dx, large amounts of IV hydrocortisone -w/o previous dx, Dexamethasone -additional MC action- hydrocortisone not needed acutely unless hyperkalemia present (heart block arrhythmias!)

Answer 191

Surgery is tx of choice!!: pituitary, chest, abdomen Med tx generally for adjunctive tx in refractory or inoperable cases ACTH secretion inhibitors: Cabergoline- D2 agonist Pasireotide- SST analog Cortisol synthesis inhbitiors- Ketoconazole**** (for fungal infections, very effective)- (early syn block/broad effect) Metyrapone, Etomidate (late syn/specific effect) Adsrenolytic agents mitotane cortisol receptor blockers- mifepristone****

Answer 192

Ketoconazole: most commonly used- higher dose than anti fungal use also inhibits C17-20 desmolase (dec testosterone synthesis) ADRs: HA, N/V, gynecomastia- impotence, reversible hepatotoxicity Metyrapone lesser used (mild dz)- add on to ketoconazole inhibits 11-beta-hydroxylase- can increase adrenal androgen production! ADRs: inc hirsutism in women, Na retention and HTN (increase in DOCA synthesis)

Answer 193

loop- super effective, K wasting Thiazide- less effective, less K wasting loop + thiazide- very effective, very K wasting aldo antagonist- mildly effective, but very K sparing Spironolactone, Eplerenone aldosterone antagonist plus BP meds (CCB, ACEI, ARB) goal: normalize hypokalemia and BP CCBs on K channels are neutral ACEI and ARB will inhibit aldo, but will be K sparing- too much K= heart block arrhythmias

Answer 194

Dihydropyridines (ex nifeDIPINE) greater ratio of vascular dilation to cardiac (rate/conduction/contractility) effects (but then you'll get reflex tachy) Verapamil and Diltiazem each at distinct site, have prominent effects at cardiac nodal tissue and on cardiac muscle lowers HR, increases SA/AV connection and contraction

Answer 195

ACEI's- give you a cough because of the increased bradykinin -pril ARB -sartan both decrease BP!

Answer 196

``` pre-op: Alpha blocker-1st phenoxybenzamine*** (irreversible nonsel block) prazosin terazosin (reversible a1 block) doxazosin (reversible a1 block) -----vasodilation via block of alpha1 ``` + BB- 2nd (after alpha blockade, otherwise you'll turn EPI into pure, unopposed alpha1 vasoconstrictor!!!) metoprolol/atenolol (beta1 blocker) labetalol (alpha1 beta1 beta2 blocker) ------rate control via block of Beta1 or CCBs (alone) Nicardipine (if bp control is inadequate) then adrenalectomy (laparoscopic or open) Metrosine (catecholamine syntesis inhibitor- if inoperable or metastatic)

Answer 197

majority is in bone signaling- 2nd messenger for many signaling pathways synaptic signaling regulates excitability of cells - -decreasing extracellular Ca means you have hyper excitable cells -- leading to tetany and seizures - -hypercalcemia- decreased excitability - you require VG Na channels to open at a given voltage based on voltage sensor - if you lower Ca, you make the outer surface a little more neg, so the cell is a little more depo'ed at baseline, and it's easier to fire

Answer 198

``` bone high E compds- ATP membrane phospholipids regulation DNA, RNA ```

Answer 199

diet- 1g/day gut- which can go 2 places: - lose ~825mg in feces per day - equilibrium w/ serum 8-10mg/dL (narrow window b/w hypo and hyperCa) ``` serum can go 4 ways: equilibrium w/ gut intracellular kidney--> excreted in urine BONE-- 250 mg exchanged freely/day; ---and a faster 10g conversion ``` Ca in blood: 50% free 40% bound to Albumin 10% bound w/ PO4 and HCO3 under nl circumstances- there's a conc gradient between blood and canicular fluid - -Ca is higher in blood - -canaliculi /blood ratio = 0.6 - -Ca goes down the gradient into the canalicular fluid, gets taken up by osteocytes, and transported back across and pumped into the blood through surface osteocytes

Answer 200

surface osteoblasts osteocytes- differentiated osteoblasts within canaliculi osteoclasts- in matrix (phagocytic)

Answer 201

osteocytic osteolysis: exchanges about 10g Ca per day only Ca; doesn't affect PO4 large and fast process Osteoclastic remodeling phagocytize the bone matrix for remodeling chews up matrix -CaPO4 Ca and PO4 released ---Ca and PO4 both affected 250mg exchange per day between bone and blood kidney: kidney sees about 10g/day >98% taken back into blood net excretion 175mg/day in urine

Answer 202

more efficiently moved around in the body than Ca 1.4g in through diet gut 500mg lost through feces 3-4mg/dL serum range (from 1100mg abs from gut) kidney--> urine kidney samples 7g/day and takes back 6.1 net loss 900mg PO4 per day in urine bone 210mg exchange -only process is osteoclastic remodeling w. destruction of bone matrix intracellular

Answer 203

key hormone that regulates Ca in the blood prod by chief cells in parathyroid gland LOW serum Ca triggers release of PTH: chief cells release PTH from vesicles when there's an INC in intracellular Ca how this happens: Ca sensor (transmembrane receptor) under nl cases, you have Ca sensor that are bound to Ca, and as long as Ca remains bound the sensor are inactive when Ca drops outside the cell, you remove the Ca bound to the sensor, then the sensor acts through a Gq GPCR mech to prod IP3 to act on ER ER releases Ca into the cell to cause exocytosis of the PTH vesicles

Answer 204

PTH's purpose is to raise serum Ca back up to its set point PTH acts on all mech's for Ca exchange across all compartments modulates compartments toward raising serum Ca Osteocytic process: (the fast process) direct effect bone breakdown is expedited by PTH the slow process: PTH drives bone break down indirectly increases osteocytic osteolysis (direct) increase osteoclastic exchange through indirect process (via osteoblasts) net consequence: shifting the bone/blood balance toward blood kidney sampling: PTH causes reuptake by kidney to be bigger (smaller excretion) PTH increases bone resorption back into blood, BUT it also increases kidney excretion of PO4 (to not mess w/ CaPO4 solubility) -otherwise get calcifications in the body (kidney stones, etc) PTH in gut: increases Ca abs in gut indirectly via Vit D3 Vit D3: pod in skin from sun; inactive goes to liver- D3--> 25-OH- Vit D3 (still inactive) goes to kidney--> 1,25-(OH)2-Vit D3 (active) the two hydroxylase enzymes to make these conversions are regulated by PTH if you get PTH deficiency, you're also not activating Vit D3 main role of Vit D3 is Ca abs from gut via binding protein Calbindin ---Vit D3 is antagonized by Cortisol (stress can cause Ca deficiency) --Vit D3 deficiency will give you rickets/bone malformation

Answer 205

tumor of parathyroids glands release PTH-like peptides is most common cause of hyperPTism skew the equilibrium towards more Ca in blood- drive osteoclastic and osteocytic processes and reabs from kidney to get hypercalcemia --hurting bone but at the same time you're going to get kidney and uritic stones --also excreting a lot more PO4 in the urine

Answer 206

hypo function of PT gland most commonly from surgical errors when people remove PT glands along w/ thyroid gland -also autoimmune (Candidiasis) low levels of PTH- drop in Ca levels in blood, seizures pseudohypoparathyroidism- inherited condition PTH levels are nl/elevated, but the receptors are deficient you don't get the effects of PTH

Answer 207

major mineral intake require >100mg/day 1200-1500g in body total; mot abundant Ca hydroxyapatite- 99% of Ca (bone, teeth) metabolic: signal transmitter

Answer 208

``` low serum Ca: increase PTH to: inc bone resorption of Ca inc Ca reabs in ascending loop of Henle inc P excretion via kidney --inc Vit D to: inc Ca intestinal abs dec Ca excretion in urine ``` high serum Ca: Calcitonin causes deposition of Ca into bone decrease in PTH Passive abs: throughout all of intestine -via conc gradients ---major source when Ca intake is high Active abs: occurs in3 steps Ca from lumen into enterocytes via active transporter Ca from apical to basolateral membrane via transporter Ca pump from basolateral membrane into blood ---occurs mostly in duodenum ---esp active when Ca intake is lower classic transcription regulated pathway: 1,25-(OH)2-Vit3 binds to VDRE upregulates genes for expression to increase Ca reabs in intestine and kidney

Answer 209

if you decrease Ca in your diet, you'll increase your relative abs but even though Ca abs is increased by ~10%, the total/net absorbed is still lower so increased Ca abs is only able to compensate for low Ca diets to a certain extent- chronic low Ca diets is assoc w/ low bone mass and vice versa Ca abs is enhanced by: physiological: Vit D, inc physiologic demand (pregnancy, adolescence) dietary: gastric acidity, lactose, dietary protein - --Bone mineral depletion does NOT feedback to give you more Ca abs- Ca abs is more regulated by serum Ca, not bones ``` Ca abs is impaired by: Vit D deficiency Steatorrhea Dietary: -gastric alkalinity -oxalic acid (spinach) -Phytic acid (legumes, corn, wheat,) -caffeine- (easy to offset) -dietary protein (inc Ca excretion in urine, probably net neutral) ```

Answer 210

avg adult 25% fetus: 80% transfer in 3rd trimester (330mg/day at 35 weeks- 30g total- prematures at risk for osteomalacia of prematurity) infants 40-60% (lactose) early puberty 34% (can cause Ca dependent rickets) pregnant women 50% may decrease in elderly dietary/ DAIRY Ca intake is important in young children!!! steep accrual of bone mass in adolescence- esp women!!! - -bone accretion is HIGHEST ~2000mg/day at early puberty - -poor Ca intake at this time can predispose you to fractures later in life - peak bone mass at 30yo - but curves look different for everyone- * *70% genetic

Answer 211

Physiological NOT DIETARY requirements increase pregnancy: Ca abs increases (Active) to accommodate fetal demand lactation PTH increases and bone mass is lost, but is recovered w/ post-weaning -Ca is being dumped into breastmilk

Answer 212

high in 9-18yo -want opportunity to maximize Ca deposition into bone high in >51yo your abs is likely to decrease pregnancy/lactation- DRIs DO NOT change ``` high risk groups for Ca deficiency: premature infants adolescents esp F peri-menopausal women Bariatric surgery (removed duodenum abs) ```

Answer 213

Ca carbonate - TUMS best abs w/ meals! Ca citrate best abs between meals! 43% Americans/70% older women consume Ca supplements in relation to BMD: there's a small benefit to those at-risk (low diet Ca, older, institutionalized, compromised BMD) but there's such a thing as too much (could inc CV risk), esp if dietary consumption was already high --Ca + Vit D supplementation is supported for pts at high risk of Ca and Vit D deficiency and in those who are receiving tx for osteoporosis Supplement rules of thumb from lecturer: try diet/food first supplement when necessary, appropriately -use common sense- don't be stupid and over-supplement

Answer 214

initial bone mineral density - peak bone mass - hereditary hypogonadism (esp low estrogen)- anorexia or amenorrhea pt age- strongest empiric factor for BMD meds est corticosteroids!!! chronic illness behavior/lifestyle tobacco and alcohol- depresses osteoblast activity, lower dietary intake weight bearing exercise- helpful for telling Ca to increase bone abs

Answer 215

Diets- DASH diet (lower Na consumption = lower Ca excretion in urine) lifetime Ca intake Vit D status oxalic acid and phytic acid Caffeine (increase urine Ca, but easy to offset) protein intake (both ways) sodium intake (inc urine Ca) vegetarian diet- (lowers urine Ca) ``` Phosphorus for hydroxyapatite Mg deficiency (hypoparathyroid)- actually a problem for Americans Vit C- collagen cofactor Vit K- cofactor for osteocalcin Vit D ```

Answer 216

wholistic and lifecycle approach achieve peak bone mass when possible- best risk reduction of osteoporosis is when you're young, esp adolescents!! dietary focus: Ca, Vit D, Vit K, protéine, low Na (DASH diet) maintain ovulation/regular menses weight bearing exercise avoid: alcohol, smoking, steroids supplement: judiciously when necessary

Answer 217

hormones: PTH 1,25 (OH)2 Vit D Calcitonin Organs: intestine bone kidney

Answer 218

inc bone resorption kidney: decreases Ca excretion (and increases excretion of PO4) --makes active Vit D, which indirectly helps gut Gut: inc Ca abs

Answer 219

skin and animal diets give you D3 cholecalciferol plants give you D2 ergocalciferol liver: uses 25-hydroxylase to change to 25(OH) Vit D-- major storage form of Vit D (ng/mL) kidney: 1-alpha-hydroxylase (stimulated by PTH) to make active Vit D measured in picog/mL active Vit D overall raises serum Ca and PO4 levels - Vit D toxicity causes hyper in both - Vit D deficiency causes hypo in both

Answer 220

made in parafollicular C cells in thyroid gland causes decreased bone resorption and lower serum Ca

Answer 221

Parathyroid cell- PTH secretion parafollicular C cell- calcitonin secretion renal tubular cell- Calcium excretion transmembrane domains where Ca binds, then an intracellular domain as well the amount of Ca that binds to the EC domain sends a signal whether it's too high or too low

Answer 222

most common cause: primary hyperparathyroidism next most common: hypercalcemia of malignancy these 2 account for 90% of hypercalcemic disorders first thing to do you when you have hypercalcemia- measure PTH level **2 hypercalcemia disorders assoc w/ PTH: primary hyperparathyroidism familial hypocalciuric hypercalcemia ---when change in Ca and PO4 are in OPPOSITE directions, you think PTH disorder!!!!!! (so you'll have high PTH)

Answer 223

85% adenoma- 1/4 of glands affected - the other 3 are suppressed because of the 1's overactivity 15% hyperplasia- general enlargement of all 4; look relatively nl but all are too active- most familial disorders <1% carcinoma- severe hypercalcemia and invades local tissues can be just 1 gland serious but rare ``` clinical features: >50% asymptomatic BONES (skeletal disease) STONES (kidney stone) GROANS (GI disease/pain) PSYCHIATRIC OVERTONES arthritis, muscle weakness, band keratopathy (eyes), HTN, anemia ``` brown tumor: osteoclastoma chonedrocalcinosis (calcifiation in articular cartilage- breaking can cause pseudo gout)

Answer 224

high serum Ca low serum PO4 high (or inappropriately nl) serum PTH (only disorder w/ low serum PO4) ``` 90% sporadic 10% familial -familial HPT -MEN1 -MEN2a ``` ``` tx: surgery is only cure - take out 1 for adenoma -take out 3.5 for hyperplasia meds can bind Ca receptors and lower PTH levels or anti-resorptive bone drugs ```

Answer 225

``` MEN1- multiple endocrine neoplasia 3 P's Pituitary tumors Pancreatic islet tumors Parathyroid hyperplasia germine mutation-- germ cells, so you tend to have multiple tumors Menin gene! ``` ``` MEN2a Parathyroid hyperplasia Pheochromocytoma Medulla thyroid carcinoma germinal mutation- Ret Gene! ```

Answer 226

more common than primary occurs when PTH glands prod too much PTH from an external stimulus -if you correct problem, PTH levels should go back to nl main causes: HYPOcalcemia HYPERphosphatemia low active Vit D

Answer 227

``` most common: lung cancer (esp squamous cell) breast cancer head and neck cancer lots others listed ``` mediated by: PTH-RP in 90% of these cancers --1st 13 AAs are identical to the 13AAs PTH uses to bind to its receptor- both can bind to PTH receptor and/or PTH-RP receptor TGF-beta is a big chunk of the rest

Answer 228

high serum Ca low serum PTH high serum PTH-RP (or other mediator)

Answer 229

``` high Ca nl Phos PTH is high (or slightly high) urine Ca is low!!! Ca/CC ratio is very low!!! ``` Ca sensitive receptor is insensitive to binding Ca and send negative feedback -Ca is allowed to raise aggressively w/o suppressing PTH

Answer 230

low serum Ca Vit D deficiency- mot common hypoparathyroidism (CONSISTENTLY low PTH) others hypoproteinemia- most common cause of low serum Ca in hospitalized pts -actually due to low serum Albumin -correcte serum total Ca: add 0.8mg Ca to every 1g Albumin is below 4

Answer 231

paresthesias- numbness/tingling muscle cramps muscle weakness Ckvostek's sign (Facial nerve) Trousseau's sign (BP cuff)

Answer 232

low serum Ca low PO4 low 25-OH Vit D high serum PTH (2ndary hypoparathyroidism) high serum alk phos (inability to mineralize bone; suggests osteomalacia) ``` osteomalacia: pseudo fracture (Milkman's fracture or loser's line)- where pulsating artery crosses ```

Answer 233

acquired Vit D deficiency - poor intake/malabs - inadequate sunlight acquired active Vit D deficiency - renal disease - hypoparathyroidism congenital 1 alpha hydroxylase deficiency -Vit D dependent rickets type 1 congenital Vitamin D receptor deficiency -Vit D dependent rickets type 2 -congenital reasons are usually partial and can be reversed w/ enough Vit D

Answer 234

low Ca high PO4 low PTH

Answer 235

low Ca high Phos suggest PTH disorder high PTH but body isn't responding to PTH- PTH receptor mech is abnl- pseudohypoparathryoidism signs: Albright's Hereditary osteodystrophy- short 4th and 5th metacarpals

Answer 236

osteoclasts secrete osteolytic enzymes and acid to carve out resorption pit osteoblasts are stimulated to move in and replace the remodeling cavity w/ new bone- called osteoid Ca x PO4 >24 gives allows you to calcify/minearlize the osteoid osteoblasts will be embedded in the new bone and become osteocytes -mechanoreceptors sense stress on bone and tell whether you need to form new bone or not RANK-L binds to receptor RANK stimulates osteoclastic bone resorption (main regulator) OPG- decoy receptor that can sequester RANK-L and prevent it from binding WNT major stimulator for osteoblastic bone formation inhibited by Sclerostin

Answer 237

compromised bone strength predisposing to increased risk of fragility fractures! (low trauma fracture) spine/vertebral > Hip > wrist 2/3 are asymptomatic and don't hurt (shorter - kyphosis; wedge fractures)

Answer 238

age previous fall low bone mass ****previous fracture BMD is related to fracture risk Osteopenia when T score is low- up to 6fold increase in having a fracture

Answer 239

when OC resorption > OB formation bone mass is lost critically occurs during menopause also when you age, or if you take steroids ``` risk factors for low bone mass: non-modifiable: age, race, gender, FHx, early menopause modifiable: low Ca, low VitD, estrogen, sedentary, smoking, alcohol, caffeine, meds ```

Answer 240

not always osteoporosis!! need an H and P exam ex meds- glucocorticoids SSRIs, anticonvulsants

Answer 241

impaired bone MINERALIZATION resulting in soft, weak bones (bones have osteoid, but it's soft and weak because it doesn't mineralize) inadequate Calcium x PO4 product for bone mineralization osteomalacia- adults pain deformaties (bowing of long bones, flaring ends, delayed epiphyseal calcification) fractures, pseudofractures (Milkman's fractures and loser's lines) ``` rickets- children pain deformities muscle weakness short stature ```

Answer 242

acquired hypophosphatemia - poor intake - renal phosphate wasting- esp hospital acquired congenital hypophsphatemic rickets -Vit D resistant rickets!!! doesn't respond to Vit D alone primary abnormality is disorder in renal tubule that results in renal PO4 wasting ----renal po4 wasting ----impaired active Vit D formation- need PO4 and active Vit D both to correct problem ----this accounts for 95% of all congenital rickets!!!

Answer 243

idiopathic bone condition characterized by excessive/unregulated bone resorption and formation trabecular structure is disordered and weak ``` either from: genetic predisposition (familial, gene mutations, esp SQSTMI mutation) ``` chronic paramyxovirus infection (geographic variation, dog ownership, time trends, viral studies) unifying hypothesis: requires: genetic component (enhances osteoclast formation/reactivity) paramyxovirus infection (induces changes in osteoclast precursors) Beethoven

Answer 244

``` clinical features: skeletal: pain* deformity* fractures* osteoarthritis hypervascularity (excessive bleeding) acetabular protrusion osteogenic sarcoma commonly monostotic or polystotic when it sets in, and it usually stays that forever pelvis skull vertebrae femur tibia ``` neuro: deafness- CN8 compressed in osteum spinal cord compression (hypervascularity- compressing spinal cord) CVS: atherosclerosis aortic stenosis CHF (high output- high flow to bones) clinical course 1- osteoclastic (high NTC/CTX) hyperactive bone resorption 2- mixed (high NTC/CTX AND high alk phos) bone formation catches up w/ resorption rate (alk phos secreted by osteoblasts) 3- osteoblastic (w/ high then low alk phos) resorption stops and excessive formation remains; alk phos high until osteoblasts stop

Answer 245

remodeling markers- elevated (alk phos) ``` X ray features- very specific osteolytic lesions "blade of grass" sign in long bones osteoclastic lesions near lytic areas thickened, disorganized trabecular thickened, expanded cortex expansion of bone size ``` bone scan- very sensitive focal areas of intense uptake bone biopsy- occasionally needed, but very classic inc osteoclast numbers w/ increased nuclei increased osteoblasts in periphery disorganized, mosaic, woven bone

Answer 246

metabolic syndrome 35% obesity 20-30% diabetes 6-22% etc ``` thyroid nodules 30-60%!!! 40% noticed by pt 30% noted by other person 30% detected by other tests ----risk for cancer is 10-15%; small but NOT insignificant ```

Answer 247

benign: adenoma ``` malignant: papillary 85-90% (multifocal, LN) follicular/Hurthle 5% (vascular spread) anaplastic <2% (very aggressive) medullary 5% (familial) Lymphoma (rare) Sarcoma (rare) Metastatic (rare) ```

Answer 248

benign neoplasm solitary nodule follicular/Hurthle cell DDx: hyperplastic nodule follicular ca careful evaluation of the capsule!!

Answer 249

``` thyroid follicular/Hurthle cell carcinoma: 2 types: minimally invasive --vascular or capsular invasion!!!!!! widely invasive --more extensive invasion!!!!! ```

Answer 250

``` papillary carcinoma: most common 85% well-differentiated multifocal lymphatic spread excellent prognosis -lots of purple numbs w/ pink centers on a white background -highly cellular aspirate -+/- colloid -papillae w/ vascular core ``` ``` NUCLEAR FEATURES make the dx -optically clear nuclei!!! -nuclear pseudo inclusions -nuclear grooves!!!!! (like coffee beans) -rare or absent mitoses -Psammoma bodies -----little orphan Annie eyes!!!!! papillary cellular aggregates ```

Answer 251

older age group (poor survival) rapidly growing mass necrosis and hemorrhage --can see the transition to anaplastic!!! from mostly light pink to dark purple/dark pink/ light pink swirls 3 patterns: spindle cell giant cells squamoid cells gross: lots of little cubbies; looks like star crunch

Answer 252

solid proliferation of cells w/ granular cytoplasm (C cells) highly vascularized stroma hyalinized collagen and/or amyloid may have Psammoma bodies immunostains: Thyroglobulin - Calcitonin + Chromogranin +

Answer 253

background autoimmune thyroiditis large fleshy masses (skeletal muscle looking) DDx: anaplastic ca of thyroid Positive LCA, usually B-cell gene rearrangement

Answer 254

sarcomas: blank? ``` metastatic: melanoma renal lung breast head/neck colon ```

Answer 255

first do H/P and TSH level: LOW TSH: nuclear imaging ``` nl/HIGH TSH: DIAGNOSTIC US ---no nodule: FNA not indicated ---nodule(s) that meet FNA criteria--> FNA ---malignant= preop US and surgery ---benign = monitor ---non diagnostic = repeat US-guided FNA ---indeterminate= consider nuclear imaging or surgery ``` ``` FNA biopsy: 98% that look benign are benign 98% that look malignant are malignant of the suspicious ones, 80% are benign -drop on slide, scrape, wash 3x in dye alcohol solns ```

Answer 256

proto-oncogene nl gene which codes for a protein that promotes nl cell division oncogene mutated gene which codes for a protein that causes unregulated cell division tumor suppressor gene nl gene which codes for a protein the restrains cell division or that promotes cell differentiation, DNA repair, or apoptosis tumors result form oncogene activation or tumor suppressor gene loss - cells transformed by genetic mutations are likely to develop more mutations - cancers result from multiple sequential genetic mutations ``` mutations: papillary ca: RET/PTC rearrangement 20% Ras point mutation: 20% BRAF point mutation: 40% p53 inactivating mutations on the "brakes"- poorly differentiated thyroid cancers ``` thyroid tumor signaling: venn diagram FTC: follicular thyroid carcinoma Ras, Pax8-PPARgamma (50%), radiation, oxidative stress, genetics PTC: RET/PTC, Ras, BRAF, MEK-ERK, (p53?) middle/shared: PI3K, beta-catenin

Answer 257

thyroid gland is made of 2 lobes located along either side of trachea connected across midline via isthmus 10-40% of nl pts have small pyramidal lobe superior to the isthmus in front of thyroid cartilage variable size

Answer 258

anatomic imaging US, CT, MRI -indicated to detect/characterize palpable or incidentally found thyroid nodule --US is best!!! functional imaging Iodine-123 or 131 scan to evaluate for canton of thyroid gland/nodule in pt w/ abnl thyroid function evaluate for distant metastatic disease PET/CT scan staging and restating of thyroid cancer radiograph - NOT useful to detect thyroid disease - may incidentally suggest thyroid enlargement/mass by noting mass effect on soft tissues or on tracheal air column

Answer 259

no radiation, real time, doppler capability the BEST modality to detect/characterize nodule best modality to detect lymph node metastasis in post-op pt of thyroid cancer -real-time guidance for FNA biopsy thyroid nodule on US discrete lesion w/in the thyroid gland that is radiologically distinct from the surrounding thyroid parenchyma --nonpalpable, incidentally discovered nodules are termed "incidentalomas"

Answer 260

essential in setting of thyroid cancer detection of lymph nodes characterization- nl vs abnl mapping: lymph node mapping will alter the surgery in 40% of pts, as it may find abnl nodes in different compartments of the neck

Answer 261

hyper dense on non-contrast hyper vascular w/ IV contrast radiation need IV contrast to detect local invasion CT: useful to define local extension of cancer in adjacent structures -detect abnl lymph nodes, esp in areas not visualized by US -distant metastasis

Answer 262

useful in ID'ing infiltrative disease, esp in post-therapy neck where anatomy is distorted -detection of invasion of adjacent structures and deep nodal tissue T2- thyroid is slightly hyper intense cannot differentiate solid vs cystic nodule can't visualize micro-calcification expensive

Answer 263

radio iodine demonstrates distribution of functioning thyroid tissue, incl ectopic tissue must discontinue iodine containing preparation and meds that could potentially affect the ability of thyroid to accumulate iodine to do this test I-123 scan: to eval the func of the thyroid nodule in pt w/ abnl thyroid function half life 13 hrs I-131 scan: diagnostic and therapeutic role half life 8 days detect local and distant thyroid cancer metastasis tx of hyperthyroidism as well as for well-differentiated thyroid cancer image thyroid gland after 6hrs w/ gamma camera calculate uptake w/ thyroid probe nl gland takes up iodine uniformly hot/large gland: likely Graves disease

Answer 264

cold: next- do an US to determine solid vs cyst if solid- 15-25% cancer risk do a US guided FNA if cystic- benign hot: malignancy unlikely in functioning nodule <1% 5-10% nonfunctioning nodules are cancerous

Answer 265

hot lymph nodes hot lungs nl low-level salivary gland activity

Answer 266

no imaging modality is reliable!!! tissue dx by FNA should be obtained on suspicious lesions nonpalpalble (incidentalomas) have same malignancy risk as palpable nodules of same size generally only nodules >1cm should be evaluated occasionally <1cm nodule needs to be evaluated based on suspicious US findings, assoc lymphadenopathy, Hx of head and neck irritation, or Hx of thyroid cancer in first degree relatives

Answer 267

ultrasound iodine scan

Answer 268

``` search for guidelines based on: quality of evidence benefits vs harms applicability (cost, resource) pt values and preferences ```

Answer 269

how you should judge whether a clinical guideline is trustworthy est transparency (process and funding explicit and public) manage conflicts of interest (disclosure, divestment, exclusion) group composition (multidisciplinary- methodology experts, clinicians, pts/consumers) collaboration/coordination with systematic evidence review establish and provide explanation for, and strength of recommendation - describe benefits and harms - summarize evidence and gaps (quality, quantity, consistency) - describe any influence of other factors (values, opinions, theory, clinical experience) - provide level of confidence/certainty, rating of strength, and explanation of difference in opinion provide clear, standardized articulation of recommendation external review by full spectrum of relevant stakeholders (experts, organizations, agencies, pts, public representatives provide updating w/ monitoring of the literature and updates based on new info

Answer 270

Canadian AGREE instrument assess methodological rigor and transparency w/ which a guideline is developed to: - assess the quality of guidelines - provide a methodological strategy for the development of guidelines - inform what info and how info ought to be reported in guidelines

Answer 271

independent panel of nationally recognized, non-federal experts experienced in primary care, prevention, evidence-based medicine, and research methods charged by US Congress to: - review scientific evidence for clinical preventive services and - develop evidence-based recommendations for the health care community recognized in the Affordable Care Act Steps in Explicit Process - define the question about the providisoin of a preventive service with an analytic framework - define and retrieve relevant evidence - judge the quality of individual studies and adequacy of evidence for key questions - synthesize and judge the adequacy of the body of evidence across key questions - judge the certainty of net benefit (balance of benefits and harms) - link magnitude and certainty of net benefit to a recommendation statement/letter grade ----No "Divestment" requirement- meaning I'm going to remove those stocks 16 members - no sub-specialists - no pts/advocates, but there is inclusion of consumer input an ideal study is a randomized control trial that shows reduced morbidity/mortality for screening efforts- actually pretty rare!! - --screening for the diseases is rare, so you have to study 100000s of people over time to generate cases, and what drives these studies is number of cases - --a lot of task forces don't have this level 1 evidence good quality = HIGH INTERNAL VALIDITY

Answer 272

Do the studies have the appropriate research design to answer the key question? To what extent are the studies of high quality (internal validity)? To what extent are the studies generalizable to the US population (external validity)? How many studies and how large have been done to answer the key question (precision of the evidence)? How consistent are the studies? Are there additional factors supporting conclusions? convincing evidence is: derived from several high-quality studies w/ consistent, logical results generalizable to the US primary care population and setting then judge the certainty of net benefit (estimate it) certainty = the risk of being wrong better health outcomes = making morbidity/mortality go down

Answer 273

whiskers- CI if they cross RR of 1, it's not significant -could make a bunch of individual non-significant studies, when combined, significant. RR = that % decrease/increase in mortality

Answer 274

pros: creates recommendations based on evidence without bias standardized set of recommendations high bar of evidence to make recommendations cons: most commonly is "Insufficient" evidence no consideration of pt values or cost/effectiveness expensive and time consuming process doesn't answer the vital questions (periodicity, age to start/stop screening, effectiveness in diverse pop's) uncertain of how well it works in rare diseases

Answer 275

integration of best research evidence! w/ clinical expertise! and pt values! best research evidence- strong to weak systematic review of RCTs!!!! randomized control trials!! controlled observational studies (cohort, case control, cross-sectional) uncontrolled observational study (case series) physiologic and animal studies unsystematic clinical observations, expert opinion why EBM matters: ID of best available evidence and integration of evidence into practice has the potential to: improve health and well-being avoid harms and conserve resources

Answer 276

systematic- summary of the best available evidence to address a focused question --use standard methods designed to reduce bias!!!! question- focused sources, search- explicit, comprehensive selection- criterion-based appraisal- critical synthesis- systematic (narrative or quantitative) inferences- evidence based ``` lit reviews- like all research, are subject to selection and info bias question- broad sources, search- unspecified selection- unspecified appraisal- variable synthesis- variable (narrative) inferences- sometimes evidence-based ```

Answer 277

start w/ summaries and guidelines (guidelines decision analyses) then reappraised research (systematic reviews) then nonpreappraised research (primary studies)

Answer 278

are the results valid??? - clearly focused question (pop studies, intervention given, outcomes considered!!), - inclusion criteria, comprehensive search, assessed for validity - PICOS pop, interventions, comparisons/controls, outcomes, study design types (ideally RCT) - --publication bias*** are the valid results meaningful??? - consistent results? (measuring the same thing? heterogeneity) - size of tx effect? - precision of tx effect? are the valid, meaningful results relevant to my practice? - can they be applied to my pt? - were all important outcomes considered? - are benefits worth harms and costs?

Answer 279

``` pros- summary statistic (common measure of effect from different studies) ``` reliability- more accurate est of effect size power- overcomes the small studies w/ small sample sizes cons- may inappropriately combine heterogenous studies (apples and oranges) doesn't control for bias problems in interpretation of the summary statistic

Answer 280

PTH gland: hypocalcemia is MAJOR stimulus for release Vit D and high Ca INHIBIT PTH release via distinct receptors intestine: high Ca abs via increased 1-25 Vit D synthesis bone: activates OCs--> increase bone remodeling acute effect: increase bone resorption --> increase serum Ca kidney: increased reabs of Ca at DCT increased excretion of PO4

Answer 281

loop diuretics: decrease plasma Ca thiazide diuretics: increase plasma Ca

Answer 282

PT gland: decreased release of PTH (via feedback inhibition of PTH synthesis) intestine: increased synthesis of Ca binding protein and channel -enhanced dietary abs of Ca and PO4 bone: induce RANK-L in OBs- role in bone mineralization kidney: decreased excretion of Ca and PO4 UV light: makes pre D3 heat: makes D3 cholecalciferol (preferred over D2) kidney: takes 25-D3 (calcidiol) from liver---option in liver disease!! takes D2 (ergocalciferol) makes 1,25-D3 (calcitriol) --choice in renal disease

Answer 283

Vit D3- cholecalciferol preferred over other Vit D metabolites for repletion- modest cost Vit D2- ergocalciferol (from plants) less efficient in elevating 25-OHD levels than D3 in repletion states ``` 1,25-Vit D3 calcitriol active form of Vit D most useful in CKD and Vit D dependent rickets!!!! rapid onset of action, t1/2 6 hrs ``` 25-OH Vit D calcidiol not readily available in US useful in pts w/ liver disease*** Dihydrotachysterol activated by hepatic 25-OH - equivalent to 1-OHD3 in function can be used in disorders where calcitriol is used

Answer 284

calcimimetic drug- Cinacalcet!!!!!! ----decrease PTH release bind to Ca-sensing receptor CaSR in PT gland -increases sensitivity of CaSR to Ca--> reduced release of PTH (no hypercalcemia!!!)--- no effect on D3 in gut, and no effect on OC/OB activation complementary mech to Vit D and analogs that target the VDR used in secondary hyperparathyroidism!! and non-surgical pts in primary hyperparathyroidism!!! anti-resorptive bone drug -Bisphosphonate!! Denosumab!!!

Answer 285

Calcitriol analogs: paracalcitol!!! inhibits PTH release from gland via action at D3 receptor (VDR) used in secondary hyperparathyroidism! does NOT increase Ca abs or mobilization from bone--- NO hypercalcemia clinical advantage over calcitriol is uncertain

Answer 286

it's a secondary regulator the calcitonin cells are in thyroid gland, and if you get them removed (during hyperthyroidism surgery fix) there's no major effect on Ca homeostasis released from parafollicular cells of thyroid--> primary stimulus for release is hypercalcemia! bone: inhibits OC bone resorption kidney: increases Ca and PO4 excretion

Answer 287

positive effect on bone mass- agonist at ERalpha receptors on OBs and OCs -estrogens directly regulate OBs- cause differentiation and decreased apoptosis MAJOR EFFECT of estrogens--> decrease number and activity of OCs - --estrogens INCREASE OB production of osteoprotegerin OPG!!! - OPG is a decoy receptor- binds RANK-L and prevents OC activation!!!! low estrogen in post-menopauses causes: longer lifespan of OCs and shorter of OBs/osteocytes --> more bone resorption- more fragile bones- bone fractures!!

Answer 288

glucocorticoids decrease bone density lowering of serum Ca (antagonist Vit D effect on gut) --> increase in PTH then stimulates OC activity increase production of RANK-L by OBs and decrease OPG--> increase OC activity --> increase bone resorption!!! risk of osteoporosis!!! when GCs used for inflammation - dose/duration dependent - adequate Ca/VitD intake is essential plus suppressive effects on osteoblasts!!

Answer 289

PTH and Vit D are on both sides of the OB and OC cell activators RANK-L increases OCs OPG decreases OCs OB precursors are required for maturation of OCs!!!, which then enhance maturation of OBs RANK-L is on the OB precursor

Answer 290

Warfarin is a Vitamin K antagonist can cause GI problems, but also OSTEOPOROSIS contraindicated in pregnancy (crosses placenta)

Answer 291

alter bone remodeling decrease bone resorption OR increase bone formation - meds do one or the other ``` anti-resorptive agents: Bisphosphonates!!! (end in -dronate!!!) Denosumab Raloxifine Calcitonin Estrogens ``` Anabolic agents: Teriparatide

Answer 292

anti-osteoclast increase OPG synthesis -estrogen Raloxifine decrease RANK-L Denosumab decrease OC activity BISPHOSPHONATES -ex. Alendronate

Answer 293

ex Alendronate, Risedronate, Ibandronate, Zoledronate MOA: pyrophosphate analogs w/ high affinity for bone at Ca-P interphase BPs bind to active site of bone remodeling-- direct inhibitory effects on OC! - induce OC ptosis - inhibits prenylation or proteins necessary for OX func - buried in bone, recycled when resorptive site undergoes remodeling- may persist 10+ yrs Q week or more- the med has phosphoric acid in it and you don't want that coming up the esophagus --take on empty stomach and remain upright- abs problems ADRs: GI irritation, esp esophagus osteonecrosis of the jaw currenlyt the MOST effective drug for tx/prevention of osteoporosis

Answer 294

SERM- Raloxifine SERM (Bazedoxifene) + Estrogen SERMS- selective estrogen receptor agonists agonists on bone-liver, inactive-antagonist on uterus antagonist on breast SERMS reduce risk of osteoporotic fractures, but less efficacy than estrogen or BPs SERM + estrogen showed greater increases in BMD than SERM alone advantages vs estrogen: reduced risk of breast cancer and coronary events disadvantages: worsening of menopause vasomotor symptoms (leg cramps) ((NOT SERM + estrogen though)) --0% risk of breast-endometrial-ovarian cancer ---RISK of VTE disorders choice in pts intolerant of BPs and at increased risk of invasive breast cancer risk

Answer 295

reduce bone resorption via inhibitory effects on OCs -most effective <5yrs after menopause benefit possibly outweighs by: increased risk of heart disease, breast cancer, stroke, VTE Estrogen should be limited to women w/ significant vasomotor symptoms who are not at risk for heart disease!

Answer 296

prevent/tx osteoporosis MOA: humanized monoclonal Ab against RANKL reduces OC activation improving bone mineral density subQ injection every 6mo ADRS: Generally well tolerated- hypocalcemia possible Role: tx of pts at high risk for fractures- intolerant or non-responsive to other threrapies

Answer 297

tx osteoporosis MOA: inhibition of OC bone resorption modest inc in bone mass- less effective than the others given via nasal spray or SC ADRS: Nausea, hand-swelling, urticaria, concern w/ inc cancer rates role: FDA approved for tx, but not prevention of osteoporosis- use is declining

Answer 298

prevent/tx osteoporosis MOA: only agent for tx of osteoporosis that STIMULATES BONE FORMATION- all other tx are anti-resorptive continuous high levels--> bone demineralization and osteopenia (the OBs will activate OCs) intermittent admin- increases OB activity and bond formation!!! daily subQ injection ADRs: Nausea, HA, dizziness, muscle cramps Role: tx of severe osteoporosis in postmenopausal women and men at high risk of fractures

Answer 299

secreted by osteocytes inhibits bone formation by blocking OB differentiation!!!! stimulates RANKL expression w/ subsequent stimulation of OC formation Sclerotin antibodies- Romosozumab increases bone formation and inhibits resorption

Answer 300

1st endocrine gland to develo arises from 2 distinct embryogenic lineages: follicular cells- endodermal pharynx prod thyroxine parafollicular C cells- neural crest prod Calcitonin gland originates as proliferation of endodermal epi cells on median surface of pharyngeal floor between 1st and 2nd arches initially hollow solidifies and becomes bilobed connected to tongue via thyroglossal duct (foramen cecum) as it begins initial descent - completes descent in 7th gestational week - begins to trap maternal iodide and secrete THs at 10-12 weeks - H-P-thyroid axis fictional at midgestation and feedback control evident by 25 weeks both TSH and T4 gradually increase to term within 30min after birth, TSH rises to 60-80microU TSH results in inc T4 and T3 levels by 24hrs

Answer 301

lingual, sublingual, or ectopic thyroid gland anywhere around the neck -not enough cells, can't grow to nl size

Answer 302

if fetus doesn't make TH placenta allows small passage of maternal T4 fetal brain rich in Type 2 deiodinase converts T4-->T3 both of these play critical roles in minimizing adverse effects of fetal hypothyroidism

Answer 303

low TH from birth - assoc w/ irreversible neuro/growth problems if not detected/tx early - newborn screening allows for early detection causes: -defect in thyroid gland- thyroid dysgenesis -defect in TH synthesis- thyroid dyshormonogenesis TSH resistance transient forms central (hypothalamic/pituitary deficiency)

Answer 304

85% of all congenital hypothyroidism cases aplasia, hypoplasia, or ectopy probably some underlying genetic component PAX8 defect*** -auto dom, varied phenotype, can have compensated or overt hypothyroidism, few assoc w/ renal agenesis TITF1 defect*** also expressed in lung, forebrain, and pituitary gland -humans w/ heater mutations assoc w/ combos of CH, resp distress, neuro disorders TITF2 defect*** homozygous mutations= Bamforth-Lazarus Syndrome CH, cleft palate, spiky hair, variably bifid epiglottis and choanal atresia

Answer 305

accounts for 10-15% of congenital hypothyroidism auto recessive Goiter may be present mutations in genes coding for proteins involved in TH synthesis

Answer 306

mutation of gene SLC26A4 encodes pendrin, a protein that mediates iodide efflux from follicular cell to colloid auto recessive assoc w/ goiter and sensorineural congenital deafness!! thyroid phenotype mild appears to depend on nutritional iodine intake seldom presents in newborn period

Answer 307

mutation in TSH receptor TSHR encodes transmembrane receptor- which mediates effects of TSH critical for development and function of thyroid gland hetero mutation- partial resistance nl size gland TSH elevation homo mutation- CH w/ hypoplastic gland decreased T4 synthesis defective TSH signaling!! transient forms: maternal TSH receptor-blocking antibodies maternal iodine deficiency/excess maternal radiodine admin maternal meds --Amiodarone, propylthiouracil, methimazole

Answer 308

hypothalamic or pituitary deficiency usually occurs in setting of multiple pituitary hormone deficiencies need to eval other pituitary hormones and obtain cranial MRI

Answer 309

baby usually appears entirely nl for a few weeks ``` large posterior fontanel prolonged jaundice macroglossia umbilical hernia hypotonia feeding difficulties hoarse cry ```

Answer 310

screen- best 2-3 days of age 2 different screening methods: primary T4- if T4 is in lowest 10% of results that day, TSH will also be measured -if TSH>20, considered abnl and call PCP -if TSH<20, not call PCP but could still be abnl primary TSH screen Dx if abnl screen, draw confirmatory labs -in infants w/ proven CH, 90% have TSH >50 75% have T4 <6.5

Answer 311

complicated by high degree of protein binding of T4 and T3 T4 bound by TBG, TBPA, and Albumin --deficient and excess thyroid binding proteins cause changes in values of total thyroid hormones free hormone is active its measurement is theoretically most useful assessment of thyroid func some assays may give inaccurate results in presence of extreme variations in the conc's of these proteins

Answer 312

if T3 uptake and T4 are in same direction- Thyroid disease (ex hypothyroid) if T3 uptake and T4 are opposite- TBG abnormality (ex high uptake and low T4= TBG deficient)

Answer 313

start tx w/ levothyroxine ASAP!!! have parents crush tablet- don't have pharmacy make suspension monitor 4 weeks later, then every 3 months for first 3yrs early and high dose tx give you excellent outcomes! :)

Answer 314

synthetic T4 2nd most frequently prescribed in US narrow therapeutic index drug bioavailability best in ileum-colon abs may be impaired in severe myxedema empty stomach w/ water before breakfast drugs that can impair abs: metal ions (antacids, Ca and Fe supplements) Ciprofloxaxin, bile acid sequestrates --avoid interaction by spacing levo dose between other drugs resolution of symptoms begins within 2-3 weeks (T4 half life is 7 days) requires 6-8 weeks maintenance to reach steady state plasma levels -use causing initiating therapy if underlying cardiac disease exists! (overstimulation of the heart) ``` increase dose in pregnancy due to: inc TBG levels (via increased estrogen) decreased free T4,T3- no intact gland to increase production -increased placental metabolism of T4,T3 avg doses increase 25% ``` no evidence to support superiority w/ any brand names pharmacists can switch products unless prescriber indicates "dispense as written"- advisable to use same T4 product throughout treatment for any pt

Answer 315

increase binding: Estrogens/ SERMS Decrease binding: anticonvulsants phenytoin-carbamazepine

Answer 316

the activating enzyme (type 1 or 2 deiodinase) is inhibited by: glucocorticoids beta blockers (amiodarone) propylthiouracil (in higher doses)

Answer 317

acute medical emergency w/ low Na, low glucose, hypothermia, shock, death large doses of T4 required IV loading dose!! followed by daily IV dosing hydrocortisone to prevent adrenal crisis as T4 may increase endogenous hydrocortisone metabolism

Answer 318

Liothyronine- synthetic T3 -wel abs, rapid action shorter duration that permits quicker dose adjustments -----NOT recommended for routine replacement due to short half life HIGH COST -----AVOID in pts w/ cardiac disease (cardiotoxicity) -----may inc risk of osteoporosis ``` Liotrix 4:1 mix of T4:T3 not advantage more expensive rarely required, not recommended may lower TSH and increase markers of bone turnover ``` Thyroid USP dessicated porcine thyroid extract containing T3 and T4 -abs is same as non-combo products ------disadvantages: variable T4/T3 ratio and content (toxicities!!!) protein antigenicity product instability -less desirable than levo- should be AVOIDED for use in hypothyroidism

Answer 319

``` meds: interfering with hormone production: antithyroid drugs- methimazole!!! thionamides iodides inhibits synthesis of TH ``` modifying tissue response: symptomatic improvement beta blockers- reduce systemic hyperadrenergic symptoms and effects (tremor, palpitations, etc) corticosteroids glandular destruction: radioactive iodine surgery

Answer 320

Thionamide inhibits thyroid peroxidase prevents T4/T3 synthesis beta blockers alleviates symptoms until thionamide takes effect only for thyrotoxicosis from excess production (Gravies- high RAI) NOT excess release (low RAI) Methimazole 100% abs; PTU is incomplete both cross placenta and concentrated by fetal thyroid -requires pregnancy caution (PTU crosses less readily- more protein bound) short half lives but accumulate in thryoid- clinical actions are longer effective alone IF: small goiter, low level of anti-TSH receptor Ab, and mild-moderate hyperthyroidism -remission/recurrence is common ADRs: 3-12% pruritic rash, GI intolerance, arthralgias agranulocytosis (dangerous, but rare) ----PTU: hepatotoxicity (rare but serious) overall: Methimazole generally preferred: efficacy at lower doses, once-daily dose, and lower side effect incidence PTU is safer for fetus/breastfeeding

Answer 321

complex action, transient effect of high doses inhibits T4-T3 synthesis (via elevated intracellular Iodide) inhibits T4-T3 release (via elevated plasma Iodide)- blocks TG proteolysis rapid onset- used in severe thyrotoxicosis (THYROID STORM) -also used to decrease size and vascularity of hyperplastic gland prior to surgery ADRs: acneform rash, rhinorrhea, metallic taste, swollen salivary glands disadvantages: variable effects (some have no response) rapid reversal of inhibitory effect when withdrawn potential to prod new T3- worsen hyperthyroidism!

Answer 322

admin orally, rapidly abs, and concentrates in thyroid beta-radiation causes slow inflammatory process that destroys parenchyma of gland over weeks-months ``` advantages: easy admin effective low cost no pain ``` ``` disadvantages: slow onset and time to peak radiation thyroiditis- CV complications in elderly may worsen opthalmopathy major complication is HYPOthyroidism ``` NOT FOR PREGNANT or nursing women no radiation-induced genetic damage, leukemia, or neoplasia surgery- less common as I-131 is becoming better benefit:risk ratio -50-60% of pts require thyroid supplementation after surgery due to iatrogenic hypothyroidism

Answer 323

control symptoms inhibit release of preformed thyroid hormones block T4-->T3 conversion meds: PROPANOLOL- controls CVS symptoms AND blocks T4-->T3 NaI or KI admin to slow hormone release --best way to decrease release!! PTU slows hormone release AND blocks T4-->T3 hydrocortisone protects against shock AND blocks T4-->T3 AND modulates immune response

Answer 324

depression is 2-3x greater than general public -worsens control of blood sugar bipolar also increases risk of DM2 -higher obesity -treatments (ex mood stabilizers) sleep apnea worsens w/ insulin resistance

Answer 325

psych symptoms may predate physical symptoms ``` depressive- most common anxiety hypomanic/manic symptoms psychosis memory problems ```

Answer 326

``` hyperparathyroidism with hypercalcemia*** common: irritability, low mood, apathy, lethargy severe: delirium, psychosis, catatonia, coma ``` ``` hypocalcemia: common: anxiety, paresthesias, irritability severe: psychosis, manic symptoms, tetany, seizures ``` you can have psychosis w/ both types of hypo and hyper calcemia

Answer 327

Addisons: apathy, anhedonia, fatigue, depression Acromegaly: irritability/mood lability depressive symptoms personality changes***

Answer 328

hypothyroidism: depression lethargy (major issue)!! forgetfulness (can be confused w/ dementia!!!) psychosis (later stages after physical symptoms) ``` subclinical hypothyroidism: treatment-resistant depression supplementation can improve depressive symptoms w/o evidence of hypothyroidism --can worsen depression in bipolar --supplementaion is still controversial ``` hyperthyroidism: anxiety**** depressive disorder**** pts who become manic when thyrotoxic usually have underlying mood disorder or positive FHx for bipolar

Answer 329

some pregnancies are followed by postpartum thyroiditis- which may result in permanent hypothyroidism postpartum depression= major depressive episode, severe, w/ permpartum onset ----may be due to thyroid disease thyroiditis: hyper ---> hypo most recover to euthyroid state may be confused w/ postpartum depression, or Graves disease relapse Sheehan syndrome is rare

Answer 330

poor growth may be 1st/only sing of underlying health problem consequences of missed dx incl permanent height deficits always measure height/weight and plot them! (double check measurements) --WHO growth chart is preferable growth can be worrisome about: height (<2 SD's or 3.5" below mid parental target) growth velocity (abnl slow linear growth or dropping across 2 major percentile lines)

Answer 331

boys: (mom's height + 5" + father's height) / 2 girls: (mom's height + father's height - 5") / 2

Answer 332

girls- avg puberty age is 10-10.5 (breasts, not period) -big growth spurt at onset boys- 11 -growth spurt mid-puberty skeletal maturation - skeletal maturation correlates w/ time of epiphyseal closure - greater bone age delay = longer time before the plates fuse closed - height predictions can be made using height and bone age--not accurate in growth disorders or pubertal tempo

Answer 333

normal/physiologic Familial short stature constitutional growth delay Pathological: Nutritional** Endocrine: - -Hypothyroid*** - -GH deficiency*** - -Cushing - -Rickets Chromosomal: Turner*** Down Prader-Wili skeletal dysplasias Small for gestational age*** drugs glucocorticoids stimulants

Answer 334

nl growth velocity and height within nl limits for parents' heights initially have decrease in growth rate between 6-18mo, then maintain a single trajectory **no further fall off after first 2 yrs

Answer 335

"late bloomer" growth deceleration during first 2 yrs followed by nl growth paralleling lower percentile skeletal maturation is delayed **catch-up growth achieved by late puberty and delayed fusion of growth plates generally end up along lower-normal of family range reassurance of nl growth pattern can tx boys w/ testosterone if bone age >=11.5 to avoid compromising final height (kickstart puberty) can tx girls w/ estrogen (not as common)

Answer 336

infants or toddlers <2yo w/: deceleration of weight gain to <3% or fall across 2 major centile lines non-organic causes most common- poor nutrition and psychosocial factors may look like constitutional growth delay, but this is a primary WEIGHT issue- weight falls off before height

Answer 337

linear growth stunting form poor weight gain in children >2yo may be 2/2 systemic illness (Celiac, IBD), stimulant meds sometimes hard to distinguish from constitutional growth delay and constitutional thinness

Answer 338

generally, weight is spared (may appear chubby, not underweight)- short fatties hypothyroidism (often acquired) -growth response is good w/ meds ``` GH/IGF-1 abnormalities *Abnl growth velocity w/ exclusion of other causes Congenital- -hypothalamic-pituitary malformations ---holoprosencephaly (forebrain) ---Schizencephaly (cleft problems) ---Isolated cleft lip or palate ---Septo-optic dysplasia (midline brain abnl; blindness, developmental delay) ---optic nerve hypoplasia ---empty sella syndrome Acquired: Trauma CNS infection/meningitis Hypophysitis (autoimmune at pituitary stalk) CNS tumors- craniopharyngioma, germinoma Cranial irridation- for other cancers ``` Cushing (commonly from steroids) Rickets

Answer 339

Abnl growth velocity w/ exclusion of other causes Congenital- - hypothalamic-pituitary malformations - --holoprosencephaly (forebrain) - --Schizencephaly (cleft problems) - --Isolated cleft lip or palate - --Septo-optic dysplasia (midline brain abnl; blindness, developmental delay) - --optic nerve hypoplasia - --empty sella syndrome ``` Acquired: Trauma CNS infection/meningitis Hypophysitis (autoimmune at pituitary stalk) CNS tumors- craniopharyngioma, germinoma Cranial irridation- for other cancers ``` ``` decreased muscle build increased subQ fat, esp around trunk face immature for age** prominent forehead, depressed mid face M small penis other midline facial defects may have hx of prolonged jaundice, hypoglycemia in newborn period ``` evaluate: Bone age random, single GH not useful IGF-1: may be low in malnutrition regardless of GH status IFGBP-3 less affected by nutrition, may be better in young children stimulating test: Clonidine, Arginine, Glucagon, L-dopa --look for peak of 10= nl

Answer 340

chromosomal skeletal dysplasia and other genetic syndromes Turner syndrome- haploinsufficiency of SHOX gene Prader-Wili- GH deficient Noonan syndrome- abnl GH post-receptor signaling

Answer 341

most common sex chromosome abnormality of Females complete or partial absence of 1 X chromosome virtually all have short stature final height ~20cm less than target height if untreated Haploinsufficiency of SHOX genes are responsible for skeletal and growth abnormalities GH therapy has been shown to sig improve growth and final adult height starting tx early is important- best potential for growth ``` clinical findings: may be subtle so dx is often delayed skeletal: short stature increased carrying angle short neck micro or retognathia lymphatic obstruction: lymphedema low hairline "trident sign" webbed neck cardiac- bicuspid aortic valve, coarctation renal- horseshoe kidney ovarian insufficiency hypothyroidism/Celiac otitis media (ear infections) hearing loss non-verbal learning disability ```

Answer 342

< 2 SD's for birth weight or length etiologies: maternal- infection, nutritional deficiencies, uterine abnormalities, smoking, alcohol, drugs placental fetal most healthy infants born SGA achieve catch-up by 2yo 10-15% remain short -final height may also be compromised by early/rapid puberty GH tx is FDA-approved for SGA who fail to catch u by 2yo may inc final height by ~3in

Answer 343

``` MEN1 AD Menin gene Pituitary adenoma Parathyroid adenoma or hyperplasia Pancreatic endocrine neoplasm/islet cell tumor ``` ``` MEN2A AD RET gene Medullary thyroid carcinoma and C cell hyperplasia Parathyroid hyperplasia Pheochromocytoma ``` ``` MEN2B AD RET gene Medullaryy thyroid carcinoma and C cell hyperplasia Pheochromocytoma Diffuse ganglioneuromatosis of GI tract Marfanoid body habitus ```

Unit 3 Endocrine Flashcards

(367 cards)