ERM 1.2 Midterm

beta cell function? C-peptide function? excess?

• insulin → lower blood glucose via promote uptake (muscle, fat, liver) + stimulating glycogenesis, lipogenesis, protein synthesis

  • dec. lipolysis, GNG

• C-peptide released w/ endogenous insulin (via process/utilize)

  • low w/ exogenous insulin (since no processing)

• excess insulin → neuroglycemia + whipple triad (hypoglycemic Sx, <50 mg/dL blood glucose, fixed w/ glucose admin)

alpha cells function? delta cell function? excess?

• glucagon → raise glucose + FA via glycolysis, glycogenolysis, gluconeogenesis

  • glucagonoma → excess glucagon (5Ds: diabetes, depression, dec. weight, dermatitis, DVT)

• somatostatin → inhibit insulin > glucagon + GH (dec. glucose uptake via hypoglycemia)

  • somatostatinoma → excess somatostatin (achlorhydria, steatorrhea, hyperglycemia)

PP cell function? D1 cell + excess? enterochromaffin cell?

• pancreatic polypeptide → regulate GI enzyme + motility

• VIP → induce glycogenolysis = hyperglycemia + inc. GI fluid sec. (involved in sec. diarrhea)

  • excess → watery diarrhea, hypokalemia

• EC → serotonin synthesis

G cells function? fed state? fasting state?

• @ pyloric antrum, stimulate gastric acid secretion (digestion)

  • excess → peptic ulcers

• fed → source = carbs; inc. insulin, dec. glucagon

• fasting → source = glycogenolysis (liver), GNG (AA, glycerol), lipolysis (adipose tissue → FFA + glycerol); dec. insulin, inc. glucagon

type 1 DM etiology? susceptibility? symptoms? labs?

• failure of self-tolerance in T cells for pancreatic islet B-cell antigens → autoantibodies = leukocytic infiltration insulitis

  • type IV sensitivity

• MHC II HLADR3 or DR4 genes

• polyuria, polydipsia, polyphagia, weight loss despite hunger, infections, slow healing wounds, fatigue

• dec. C-peptide (no endogenous prod.), inc. ketones (DKA risk), HbA1c >6.5% + anti-islet antibodies

type 1 DM induced DKA?

• stress → E → inc. glucagon → lipolysis → FFA → ketones → acidosis, hyperkalemia (but lost so dec.= hypokalemia)

  • lymphocytic infiltration of pancreatic islets

• fruity breath, dehydration, coma, glucose (500-700 mg/dL), kussmal resp. (met. acidosis = deep/rapid→ dec. CO2)

type 2 DM etiology? cause? symptoms? labs?

• insulin resistance (dec. GLUT4) + B cell dysfxn (via B cell compensation)

  • result of lipotoxicity + glucotoxicity → truncal/visceral obesity + metabolic syndrome = risk factor (inc. adiponectin)

• fatigue, blurred vision, polyuria, polydipsia, polyphagia

• dec. incretin (GLP-1, GIP), amyloid deposition in islets

  • might see normal/high C-peptide (body makes insulin but there is insulin resistance)

• hyperosmolar hyperglycemic coma → severe dehydration, glucose >550 mg/dL (via infection of MI), NO ketones

chronic complications (NEG) of T1DM and T2DM?

• microvascular (pericyte + schwann take up glucose w/o insulin = sorbitol → osmotic damage)

  • retinopathy → non proliferative or proliferative (sorbitol in pericyte = BV rupture, cataracts, glaucoma)

  • nephropathy → albuminuria, glomerulosclerosis (proteinuria)

  • neuropathy → glove-stocking pattern, autonomic dysfxn (sorbitol in schwan cell)

• macrovascular → atherosclerosis (CAD, MI, stroke) or peripheral arterial disease (gangrene, RAD, claudication, ulcer)

diabetes screening?

• blood glucose conc., glucose tolerance, glycosylated Hbg level, fructosamine, urine glucose conc., urine protein conc., ketone bodies

• HbA1C inc.(via NEG) → check 3-4 months

  • other conditions affecting RBC turnover can effect A1C

  • ketone bodies → acetoacetate, B-hydroxybutyrate, acetone

insulin secretagogues? MOA? side effects?

• sulfonylureas + meglitinides

• inc. insulin sec. via inhibiting B cell K ATP channels (open Ca channels/Ca influx → insulin sec)

• hypoglycemia + weight gain

  • glucagon Tx hypoglycemia via Gs CPR

insulin analogs? MOA? side effects?

• types:

  • lispro, aspart, glulisine → rapid; used in CII (2-4 hrs)

  • regular → short (<8 hrs)

  • NPH → intermediate (10-20 hrs)

  • glargine, demerit, degludec → long (24 hrs)

• similar fxn as insulin (target = TKR); can be rapid to ultra long acting

• hypoglycemia + weight gain

sulfonylureas? MOA? side effects?

• 1st gen (-mide) or 2nd gen (glipizide, glyburide, glimepiride)

• close ATP-sensitive K channels → inc. insulin sec. independent of glucose levels (+ dec. glucagon sec.)

• hypoglycemia (esp. w/ metformin) + weight gain

biguanides? MOA? side effects?

• metformin

• insulin sensitizer → stim. AMPK + inhibit mit. GNG, dec. hepatic glucose prod. + inc. peripheral glucose uptake

• diarrhea, lactic acidosis (high lactate, low pH, deep/rapid breath = expel CO2., renal failure), weight loss (anorexia)

thiazolidinediones? MOA? side effects?

• pioglitazone

• activate nuclear PPAR-y → transcription of insulin-responsive genes (GLUT4)

• edema, heart failure, weight gain

GLP-1 agonists? MOA? side effects?

• exenatide, liraglutide

  • pramlintide → amylin analog (only dec. glucagon sec. + Tx T1/2DM)

• inc. glucose-dependent insulin sec., dec. glucagon sec., dec. gastric emptying (= anti hyperglycemic)

• pancreatitis, weight loss, GI (nausea, vomit, diarrhea)

DPP-4 inhibitors? MOA? side effects?

• sitagliptin, saxagliptin

• inc. endogenous GLP-1 + GIP (inc. insulin, dec. glucagon, dec. gastric emptying)

• nasopharyngitis, joint pain

a-glucosidase inhibitors? MOA? side effects?

• acarbose, miglitol

• dec. intestinal disaccharide absorption (manage postprandial blood glucose w/ T2DM)

• diarrhea, flatulence

SGLT2 inhibitors? MOA? side effects?

• canagliflozin, dapagliflozin

• inc. renal glucose excretion

  • SGLT2 → RA glucose @ PCT

• UTI, hypotension

adrenal zones? function?

• zona glomerulosa: aldosterone → Na retention, K/H sec., inc. BP (salt)

• zona fasciculata: cortisol → inc. ABIG (BP, insulin resistance, GNG), dec. FIB (fibroblasts, inflammation, bone formation) (stress)

  • inc. GNG → inc. proteolysis + lipolysis, hyperglycemia

• zona reticularis: DHEA, androstenedione → minor androgens, virilization (sex)

• medulla: epinephrine, norepinephrine → fight or flight

primary adrenal insufficiency (addison) defect? symptoms?

• adrenal cortex destruction via autoimmune adrenalitis, TB, AIDS or metastatic cancer → dec. cortisol (dec. Na, inc. K, hypovolemia), dec. aldosterone, inc. ACTH

  • if acute → DIC → AG necrosis → dec. cortisol → hypotension

• hyperpigmentation, hypotension, salt craving, weight loss, hyponatremia

secondary adrenal insufficiency defect? symptoms?

• exogenous steroid use, pituitary, hypothalamic disease → dec. ACTH + cortisol

• weakness, fatigue, dizziness, GI symptoms

adrenal crisis defect? symptoms?

• abrupt cessation of prednisone or acute cortisol deficiency → dec. cortisol

  • fix via inc. dexamethasone (glucocorticoid)

• shock, dehydration, coma, CV collapse

hypercortisolism (cushing) defect? symptoms?

• inc. cortisol (24-hr urine + midnight salivary cortisol), inc. or dec. ACTH

  • 1mg DST = inc. cortisol via endogenous cortisol (suppress in normal) w/ adrenal hyperplasia (ZF/ZR)

  • 8mg DST = dec. cortisol in cushing/pit. adenoma (pit. kinda listens), not suppressed in ectopic ACTH OR adrenal tumor (ACTH indep.)

  • exogenous → suppress ACTH + endogenous cortisol w/ cortical atrophy (ZF/ZR)

• HTN (via inc. a1 → inc. E), DM, moon face, buffalo hump, truncal obesity (inc. glucose → inc. insulin → inc. fat storage), striae (insulin impairs collagen), cortisol = inc. BIG + dec. FIB

  • inc. blood sugar via muscle breakdown = muscle weakness + thin extremities

primary hyperaldosteronism (conn) defect? symptoms?

• aldosterone-producing adenoma → inc. aldosterone + dec. renin (inc. Na + H2O follows; dec. K + H) → inc. BV @ kidney → dec. renin)

• 2ndary HTN, hypernatremia, hypokalemia (muscle cramping), met. alkalosis via K + H exc. (hypoventilation = want to inc. CO2)

secondary hyperaldosteronism defect? symptoms?

• dec. flow to kidney (e.g renal artery stenosis) → inc. renin (thinks low BP)→ inc. aldosterone (RAAS)

• HTN, edema

congenital adrenal hyperplasia (CAH) defect? symptoms?

• 21-H def. → dec. aldosterone, dec. cortisol, inc. androgen = Na wasting, hyperkalemia, hypovolemic; hypoglycemia; virilization

• 11 B-H def. → inc. aldosterone precursor, dec. cortisol, inc. androgen = HTN; hypoglycemia; virilization

  • Tx w/ metyrapone

• 17 a-H def. → inc. aldosterone precursor, dec. cortisol, dec. androgen = HTN; hypoglycemia; sexual infantilism

• hyperplastic adrenal gland

pheochromocytoma defect? symptoms?

• adrenal medulla tumor → inc. catecholamines, inc. metanephrines (vanillylmandelic acid)

  • can be @ bladder wall = episodic HTN w/ urination

• 5Ps (2ndary pressure, palpitations, perspiration, pain, pallor), brown tumor

MEN syndromes defect? symptoms?

• MEN1 (MENIN) → pit., parathyroid, pancreatic (PPP) = werner syndrome

  • headache/vision + prolactinoma/acromegaly, hypercalcemia/kidney stone

• MEN2A (RET) → med. thyroid carcinoma, pheochromocytoma, parathryoid

  • inc. calcitonin + mass effect, 5P

• MEN2B (RET) → med. thyroid carcinoma, pheochromocytoma, mucosal neuroma, marfanoid habitus

  • nerve tissue @ skin/mouth

function of adrenal gland secretions?

• mineralocorticoids (aldosterone) → Na-retaining

• glucocorticoids (cortisol) → bind cytoplasmic receptors

• adrenal androgens (DHEA) → inc. GNG, protein + lipid catabolism, body resistance to stress

adrenal gland drugs function?

• anti-inflammatory (inhibit leukocyte migration, prod/release of cytokine, PG, leukotrienes) + immunosuppressant

• stabilize lysosomal membrane + cause VC

• avoid cessation after long term admin → taper dose for withdrawal

corticosteroid indications? contraindications?

• stressful incident → begin glucocorticoid or inc. corticoid dose if on (e.g dexa) → suppress ACTH

• CI for corticosteroid → peptic ulcer, heart disease, HTN, infectious disease (varicella, TB), psychoses, diabetes, osteoporosis, glaucoma

prednisone MOA? use? AE/interaction?

• glucocorticoid agonist (Nf-kB)

• anti-inflammatory, immunosuppressant, organ transplant, hematologic cancer

• adrenal suppression/atrophy, growth inhibition, muscle wasting, osteoporosis, Na retention, glucose intolerance, behavior changes

  • exogenous glucocorticoid dec. CRH, corticotropin, cortisol; mineralocorticoid aldosterone mostly regulated by RAAS

mifepristone MOA? use? AE/interaction?

• glucocorticoid receptor antagonist

  • etomidate = cortisol antagonist → don’t give to addison

• medical abortion

• vaginal bleeding, abdominal pain, GI upset, diarrhea, headache

fludrocortisone MOA? use? AE/interaction?

• mineralocorticoid agonist (immunosuppressant)

• adrenal insufficiency (addison); supplements hydrocortisone (cortisol/glucocorticoid + mineralocorticoid) → Tx CAH

• Na + H2O retention w/ K excretion, CHF, signs + symptoms of glucocorticoid excess

spironolactone MOA? use? AE/interaction?

• mineralocorticoid receptor antagonist

• aldosteronism (conn), hypokalemia, HTN, post MI

• hyperkalemia, gynecomastia, menstrual irregularities

ketaconazole, fluconazole MOA? use? AE/interaction?

• steroid synthesis inhibitors

• cushing syndrome (inc. cortisol)

• hepatic dysfxn, drug interaction (CYP450), gynecomastia

phenoxybenzamine, phentolamine MOA? use? AE/interaction?

• irr vs reversible

• a-blocker (follow w/ B-blocker)

• pheochromocytoma

• reflex tachy, dizziness, headache, orthostatic hypotension, nasal congestion

fibrocystic changes characteristics?

• non-proliferative

• hormone-driven development of blue domed cysts, fibrosis, apocrine metaplasia (non malignant); ductal epithelial hyperplasia

  • sclerosing adenosis/calcification (2x risk)

mastitis characteristics?

• non-proliferative

• lactation-related (postpartum); S. aureus (abscess = mass) or strep infection (cellulitis)

  • microscopy → neutrophilic exudate + liquefactive necrosis

  • symptoms → pain, erythema, fever, purulent discharge

• Tx via drain + antibiotic (dicloxacillin)

fat necrosis characteristics?

• non-proliferative (mimic cancer)

• inter-lobular stroma; trauma related

  • stages: acute (hemorrhage, fat necrosis), late (giant cells, painless mass/calcification), heal (scarring)

duct ectasia characteristics?

• non-proliferative (mimics cancer);@ lactiferous sinus + large duct

• multiparous, post-menopausal (50-60)

• periductal inflammation/fibrosis (plasma cell, lymphocytes) + dilation of subareolar duct (foamy histiocytes)

• symptoms → irregular palpable peri areolar mass, nipple discharge (inflammatory debris → green/brown), retraction

squamous metaplasia of lactiferous duct/SMOLD (zuska) characteristics?

• non-proliferative

• recurrent subareolar abscess or periductal mastitis (via keratinizing squamous metaplasia of nipple ducts = granulomatous response)

  • ass. w/ smoking

  • nipple retraction + fistula tract at areolar edge

ductal/epithelial hyperplasia characteristics?

• proliferative (1.5-2x risk)

• proliferation of epithelial (luminal) + myoepithelial cells distend/fill lumen → irregular, slit-like lumen

  • gynecomastia → inc. ducts (lobule form. absent)

papilloma characteristics?

• proliferative (1.5-2x risk); @ lactiferous sinus + large duct

  • fibrovascular projection w/ epithelial + myoepithelial (benign/intraductal)

• pre-menopausal

• large duct → solitary + blood-stained nipple discharge

• small duct → multiple, peripheral ducts, small palpable mass; densities or calcification on mammogram

sclerosing adenosis characteristics? complex sclerosing lesion?

• proliferative (1.5-2x risk)

• proliferation of acini + stroma → acini are compressed + distorted via dense stroma (mimics cancer= palp. mass, calcification)

  • myoepithelial cells

• radial scar closely mimics malignant lesion

  • central nidus of small tubules entrapped in dense fibrous stroma

  • myoepithelial cells

proliferative with atypia breast disorders?

• inc. risk for malignant transformation 4-5x (w/o atypia only 1.5-2x)

• atypical ductal hyperplasia (ADH) → histo resemblance to DCIS (dec. ME, calcification)

  • highest risk of breast cancer

• atypical lobular hyperplasia (ALH) → histo resemblance to LCIS (dyscohesive cells)

neoplastic breast disorders cause? survival? imaging?

• 30% (BRCA1/2 mut; also ovarian/pancreatic); 70% (sporadic → inc. estrogen = faster proliferation of breast cells → inc. mut. chance)

• ER+/PR+ (highest rate) > HER2+ > triple negative (aggressive)

• mammography guided needle biopsy (40+ pt, older = more adipose = easier to see); US guided needle biopsy (premenopausal women)

benign neoplasm conditions? characteristics?

• intra-lobular stroma (phyllodes can be periductal)

• fibroadenoma (pre-menopausal) → ER sensitive (changes size during cycle); mobile + well-circumscribed

• phyllodes tumor (post-menopausal) → recur locally, leaf-like architecture (cellular stroma w/ inc. mitosis); pleomorphism w/ atypia of ductal or stromal elements

  • can be malignant

ductal carcinoma in situ (DCIS) type? characteristics? invasive ductal carcinoma (IDC)/invasive carcinoma of no special type?

• malignant neoplasm; term. duct

• confined, microscopic; ME absent/reduced

  • patterns → calcification, comedo carcinoma, cribiform, papillary

  • paget (@ lactiferous sinus + large duct) → DCIS extension w/in ductal system to nipple epidermis (eczematous lesion + palpable mass)

• firm + irregular w/ desmoplasia (chalky), spiculated margins, calcification → advanced (skin dimple, retraction, peau d’orange)

invasive ductal carcinoma (IDC) categorization? characteristics?

• medullary → soft/fleshy, well-circumscribed; syncytium-like sheets of large cells w/ pleomorphic nuclei + prominent nucleoli

• colloid/mucinous → soft/rubbery, gelatinous (good prognosis)

• inflammatory → erythema swelling, warmth, peau d’orange; extensive plug of lymphovascular space of dermis, diffusely infiltrative, bloody discharge

• tubular → ME cells absent (excellent prognosis)

lobular carcinoma in situ (LCIS) type? characteristics? invasive lobular carcinoma (ILC)?

• malignant neoplasm; lobular unit

• confined, microscopic; uniform dyscohesive cells (loss of E-cadherin/CDH1)

  • always incidental finding (no mass/calcifcation)

• loss of E-cadherin/CDH1; single file infiltration; bilateral + multicentric w/in same breast

tamoxifen MOA? AE?

• selective estrogen receptor modulator (SERM)

  • ER antagonist in breast (block ER+ cancer), partial agonist in bone/endometrium (dec. resoprtion + inc. uterine thickening)

• thromboembolic disorder, endometrial cancer

fulvestrant MOA? AE? anastrozole? exemestane?

• competitive estrogen receptor antagonist/degrader

• selective nonsteroidal reversible aromatase inhibitors (inhibit androgen → estrogen)

• irreversible aromatase inhibitor

• osteoporotic fracture, thrombophlebitis

trastuzumab MOA? AE? atezolizumab?

• inhibits RAS-MAPK + PI3K-AKT path → inc. HER2 degradation → dec. cancer cell proliferation

  • dilated cardiomyopathy

• monoclonal antibody against PDL1 → inc. RBP → inc. T cell killing of tumor cells (triple negative)

  • peripheral edema

palbociclib MOA? AE? -parib?

• cyclin-dependent kinase (CDK4/6) inhibitor (halts G1/S)

• poly-ADP-ribose polymerase (PARP) inhibitor

• myelosuppression, edema