chem week 8

adrenal anatomy

paired glands on upper pole of each kidney, outer cortex (90%) and inner medulla (10%)

zona glomerulosa

outer, 15% cells, synthesize aldosterone, main mineralocorticoid (salt), potassium excretion, bp reg, acid-base hoemostasis

zona fasciculata

middle, 75% cells, cortisol, main glucocorticoid (sugar), glucose homeostasis and bp

zona reticularis

inner, 10% cells, adrenal androgens DHEA and DHEA-S, small amount of estrogens (sex)

medulla

catecholamines (epinephrine, norepinephrine)

cholesterol

from LDL, common precursor for all steroid hormones, pregnenolone (1st & rate limiting step (mitochondria) stimulates by ACTH)

mineralocorticoid branch

progesterone> 11-deoxycorticosterone DOC> corticosterone> aldosterone

glucocorticoid branch

17-OH progesterone> 11-deoxycortisol> cortisol

adrenogen branch

17-OH pregnenolone> DHEA> androstenedione> testosterone

adrenal steroid biosynthesis enzymes

21, 11B, 17a, 3B-HSD, if block precursors upstream accumulate and are shunted into other branches, basis of CAH

CRH (hypothalamus) release

driven by diurnal rhythm, low cortisol and stress, ACTH (anterior pituitary)> cortisol (zona fasciculata, main neg feedback on CRH and ACTH)

ACTH in hypothalamic pituitary adrenal axis HPA

little effect on aldosterone which is controlled by RAAS and potassium)

blood glucose maintenance of cortisol

gluconeogenesis, lipolysis, protein muscle breakdown

cortisol supports bp with

anti-inflam and immunosuppressive effects

cortisol steroid hormone

transported bound to cortisol binding globulin (transcortin) & alb, small free fraction= active, enters target cell binds intracellular recep> gene transcription

cortisol diurnal variation

highest at 6-8 am 7-25, lowest midnight, record time of collection

estrogen (preg, oral contraceptive) effect on cortisol

high cortisol binding globulin> high total cortisol w/o true excess

ACE

angiotensin converting enzyme in the LUNG, renin way released from kidney

angiotensin II and high serum potassium

stimulates aldosterone release & vasoconstriction

aldosterone action in distal tubule and collecting duct

reabsorb Na and water, excrete K and H> raises bp

adrenal androgens DHEA and DHEA-S

weak, converted in peripheral tissues to testosterone (lots in women little in men) and estrogens

gonads

make less than 10% of DHEA-S> high DHEA-S indicates adrenal androgen source

excess DHEA and DHEA-S

ambiguous genitalia in female newborns, precocious puberty in kids, hirsutism and virilization in women

testing serum or plasma cortisol

immunoassay, usually at 8 am, synthetic glucocorticoids (prednisone, prednisolone) biotin and heterophile abs can cross react, dexamethasone will not

24 hr urine free cortisol UFC

reflects free cortisol over a full day, urine vol and creatinine confirm a complete collection, 3.5-45, falsely high with high fluid intake

late night salivary cortisol test

free cortisol at expected daily low point, high when normal nighttime drop is lost

ACTH plasma testing

EDTA, unstable peptide (collect in chilled tube, on ice, separate/ freeze asap), morn 7.2-63

low cortisol affect on ACTH

high= adrenal (primary) cause, norm-low= pituitary/hypothalamic cause

high cortisol affect on ACTH

low= adrenal source (independent), norm-high= pituitary or ectopic source (dependent)

ACTH (cosyntropin) stimulation test

confirms adrenal insufficiency, 8am, baseline cortisol and ACTH> 250 cosythropin (synthetic ACTH) IV> cortisol at 30 and 60 min

ACTH (cosyntropin) stimulation test interpretation

rise to 18 or more= norm, low-no rise= primary insufficiency, norm early or blunted later- adrenal shrink w/o ACTH stimulation= 2ndary insuff

metyrapone test

blocks 11B-hydroxylase> low cortisol> intact pituitary raises ACTH, 11-deoxy >7 cortisol <5, no rise in 11= pituitary/2ndary insuf

dexamethasone suppression test

potent synthetic glucocorticoid suppresses ACTH not measured by cortisol assays, low dose, high dose

dexamethasone suppression low dose test

1mg at 11pm, cortisol at 8 am, screens for Cushings syndrome, cortisol below 1.8, failure to suppress= suspect hypercortisolism

dexamethasone suppression high dose

8 mg overnight or 2mg every 6hrs for 48hrs, separates pituitary (partial suppression 50%+) from ectopic ACTH/adrenal tumors (no suppression)

aldosteronism screening results

aldosterone:renin ratio ARR, 30+ with plasma aldosterone concentration PAC >15 suggests primary aldosteronism, confirm by oral salt loading or IV saline infusion= primary= aldosterone failure to suppress

aldosteronism screening process

stop mineralocorticoid antagonists (spironolactone, eplerenone) collect in morning after awake for 2+ hrs and seated 5-25 min, unrestricted salt intake

DHEA-S testing

marks adrenal androgen production, ref interval depends on age

17-OHP

substrate of 21-hydroxylase, very high in classic 21 def, used in newborn screening

urinary 17-ketosteroids

older 24 hr urine measure of androgen metabolites from adrenals and gonads

adrenal cortex disorder locations

primary= adrenal gland, 2ndary= pituitary ACTH, tertiary= hypothalamus CRH (due to long term glucocorticoid therapy suppressing HPA axis)

primary adrenal insufficiency Addisons disease

autoimmune destruction of adrenal cortex, TB, histoplasmosis, hemorrhage, tumor, loss of cortisol aldosterone and adrenal androgens

primary adrenal insufficiency Addisons disease symp

fatigue, weight loss, anorexia, nausea, hypotension, salt craving, hyperpig from high ACTH (shares melanocyte hormone precursor)

primary adrenal insufficiency Addisons disease lab

low cortisol 8am <3 (hypoglycemia), high ACTH (no cortisol response when stimulates) and renin

loss of aldosterone in primary adrenal insufficiency Addisons disease

hypernatremia, hyperkalemia, mild metabolic acidosis

2ndary and tertiary adrenal insufficiency

low or inaprop norm ACTH (pit) or low CRH (hypothalamus)> low cortisol, aldosterone preserved by RAAS> sodium and potassium norm

acute adrenal insufficiency (adrenal crisis)

deathly loss of cortisol & aldosterone due to infec, surgery, or trauma with undx or undertreated adrenal insuf, stop long term glucocorticoids, draw cortisol and ACTH before treatment if possible

acute adrenal insufficiency (adrenal crisis) symp

bilateral adrenal hemorrhage, shock, hypotension, severe hyponatremia hyperkalemia hypoglycemia

bilateral adrenal hemorrhage

meningococcal sepsis, waterhouse-friederichsen syndrome, anticoag

cushing syndrome hypercortisolism sym

central obesity, moon face, buffalo bump, wide purple striae, bruising, proximal muscle weakness, hypertension, hyperglycemia, osteoporosis, menstrual irreg, hirsutism, hypokalemia (ectopic ACTH)

ectopic ACTH vs ACTH independent

nonpituitary tumors (small cell lung cancer), high ACTH and cortisol vs adrenal adenoma, carcinoma, nodular adrenal hyperlasia

cause of cushing syndrome disease

exogenous glucocorticoids

cushing disease

ACTH secreting pituitary adenoma, most common endogenous cause 70%

cushing syndrome workup step 1

confirm hypercortisolism (2 pos)- 24 hr UFC, late night salivary cortisol, low dose dexamethasone suppression

cushing syndrome workup step 2

locate the source- plasma ACTH low= adrenal, n-high= ACTH dependent

cushing syndrome workup step 3

pituitary vs ectopic, high dose dexamethasone suppression, inferior petrosal sinus sampling confirms pituitary source

pseudo-cushings

depression, alc, obesity, severe stress, mild cortisol elevation with norm diurnal rhythm retained

primary aldosteronism Conns syndrome

autonomous aldosterone secretion not suppressed by salt or vol, aldosterone producing adenoma or bilateral adrenal hyperplasia

primary aldosteronism Conns syndrome symp

hypertension (drug resistant), hypokalemia (not all pts), metabolic alkalosis, mild hypernatremia, stoke risk

primary aldosteronism Conns syndrome lab

high aldosterone, low renin, high ARR aldosterone:renin ratio

2ndary hyperaldosteronism

due to high renin (norm adrenal response), norm ARR, high renin distinguishes from primary hyperaldosteronism

causes of 2ndary hyperaldosteronism

low blood vol (HF, cirrhosis, nephrotic syndrome), renal artery stenosis, diuretics, dehydration or blood loss, renin secreting tumor

hypoaldosteronism

adrenal destruction, heparin therapy, low renin (diabetic kidney disease), hyperkalemia, mild metabolic acidosis

congenital adrenal hyperplasia CAH process

auto recess enzyme defect in cortisol synthesis> low cortisol> high ACTH> adrenal hyperplasia and precursor buildup

CAH 21-hydroxylase def

most common, high 17-OHP, low cortisol, low aldosterone (salt wasting: hyponatremia, hyperkalemia, hypotension), high androgens

CAH symp

common= ambiguous genitalia in female newborns, salt wasting crisis in infants, rare form= women with hirsutism, irreg menses, infertility

11B-hydroxylase def CAH

high 11-deoxycortisol and DOC, DOC acts as mineralocorticoid> hypertension> hypokalemia, virilization

17a-hyroxylase def CAH

high DOC and corticosterone> hypertension, hypokalemia, low cortisol and sex steroids> no virilization

3B-HSD def CAH

high DHEA, mild virilization

catecholamines

dopamine, norepinephrine, epinephrine, amine hormones acting on cell surface adrenergic receptors, stored in secretory vesicles

catecholamine pathway

phenylalanine> tyrosine> DOPA> dopamine> norepinephrine> epinephrine

PNMT (norepinephrine> epinephrine)

requires cortisol> adrenal medulla is main source of epinephrine

catecholamines release

within secs for fight or flight response (high heartrate, bp and glucose), 1-2 min half-life in blood

catecholamine removal

reuptake into vesicles, uptake in nonneuronal tissue (mostly liver) and degradation

COMT

epinephrine> metanephrine, norepinephrine> normetanephrine

MAO with COMT

vanillylmandelic acid VMA, end product of epinephrine and norepinephrine

dopamine becomes

homovanillic acid HVA

urine continents

largest fraction is VMA, metanephrines, and small amount of free catecholamines

pheochromocytoma and paraganglioma PPGL

rare catecholamine-secreting tumors of chromaffin cells, 90% in adrenal medulla (pheochromocytoma), extra adrenal (paragangliomas)

pheochromocytoma and paraganglioma symp

mostly benign, some familial (MEN 2, von Hippel-Lindae, neurofibromatosis type 1), headache, palpitations, sweating paroxysmal or sustained hypertension, anxiety or panic like episodes

testing for pheochromocytoma first line

plasma free metanephrines or 24 hr urine fractionated metanephrines & catecholamines, HPLC with electrochem detection/ tandem mass spec

plasma collection for pheochromocytoma

pt supine 30 min before draw (upright= false pos of normetanephrine)

24 hr urine collection of for pheochromocytoma

complete collection verified by col and creatinine, acid preservation often required

metanephrines testing

more sensitive than catecholamines bc made continuously in tumor

pheochromocytoma false pos

drugs (acetaminophen, labetalol, tricyclic antidepressants, MAO inhib, levodopa, sympathomimetics, cocaine)

pheochromocytoma results

more than 3x the upper ref limit suggest tumor, VMA and chromagrinin A are not first line (poor sensitivity)

neuroblastoma

malignant tumor of immature neural crest cells (neuroblasts) in adrenal medulla or sympathetic chain, common solid tumor before age 5

neuroblastoma tumor

releases catecholamines> high urine HVA & VMA measured together on random urine and reported per gram of creatinine to dx and monitor

time of day affects

cortisol and ACTH, emotional or physical stress and acute illness= high cortisol and catecholamines

posture and sodium intake affect

renin, aldosterone, and normetanephrine