Unit 3 Endocrine Flashcards
definition of Integrative Health and Medicine
healing-oriented practice that incorporates the relationship between the provider and the whole person
emphasizes evidence and makes use of all appropriate therapeutic approaches to achieve optimal health and healing
IHM utilization
most used by elderly American women w/ higher education and income
72% pts didn’t report IHM use to health care provider
Why pts use IHM and what pts believe
dissatisfied w/ results of conventional therapy
lack of disease curing of conventional therapy
dramatic reports from media
pt empowerment
focused on spiritual and emotional wellbeing
pts believe: natural is better than synthetic herbs not considered drugs herbs don't have side effects herbs are regulated, standardized, and safe used for 1000s of yrs
Dietary Supplement and Health Education Act DSHEA 1994
evaluates the evaluation of vitamins, herbs, AAs, and other botanicals
regulates herbal supplements more like food than meds
products can’t be put on same shelf as OTC or meds
prior to 1994- all products were grandfathered
manufactures and FDA with the DSHEA
manufacturers:
don’t need to register or get FDA approval
responsible for product safety
ensure product label is truthful and not misleading
FDA:
takes action if product is unsafe once on the market
monitors safety (ADR MedWatch Reporting)
monitors product info
higher quality supplement requirements
label contains the REQUIRED disclaimer: “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent disease”
label MAY include structure-function claim (claim for use)
manufacturer follows Good Manufacturer Practices
Label contains Supplement Seal of Approval (GMPs, CL, USP, NSF) if applicable
dislipidemia tx options- 2
fish oil/omega 3 fatty acid
plant sterols and stanols
fish oil/ omega 3 fatty acid info
dislipidemia tx option
dec the fishy taste by freezing, take w/ food, or enteric coated product
GRAS
pregnancy limit to 12oz/week
–avoid shark, swordfish, and tilefish due to high Hg
tx option for pts who can’t take Niacin (gout, flushing rxn)
Not effective in lowering TC or LDL
omega Quant HS- Omeg-3 Index test
Krill Oil- Dr Oz
inc risk of bleeding in combo w/ Rx, OTCs, or other supplements
DHA/EPA potency- amount varies in commercial products
use both in primary and secondary prevention per the AHA recommendations
plant sterols and stanols info
dislipidemia tx option
takes 2-3 weeks to be effective
cholesterol rises back to baseline in 2-3 weeks when discontinued
sterol equally effective to stanol
GI side effects
drug interaction w/ Zetia
weight loss tx options- 4
Ephedra
Bitter Orange
Calcium
Alli
Ephedra info
weight loss option
moderate weight loss benefits
FDA received many serious/fatal case reports
product has been banned from market
potential risk outweighs benefit
Bitter orange info
weight loss option
manufacturers switch to bitter orange due to Ephedra FDA ban
often products contain caffeine
GRAS
no evidence that this supplement is safer than Ephedra!
Calcium supplement info
weight loss option
supplement alone does not equal to a low-fat dietary intake of Ca
Alli info
weight loss option
take a MVI qd 2 hrs before or after dose
due to risk of LIVER INJURY, inform pt signs and symptoms
FDA approved for long-term weight loss
pts w/ BMI >=27 have seen benefits
diabetes tx options- 2
Chromium
Vanadium
Chromium info
diabetes tx option
several salt forms
-Picolinate, Nicotinate, Polynicotinate, and Chloride
Chromium Picolinate most often used in studies
no reliable method to dx deficiency
caution in renal and hepatic dysfunc
mix data on effectiveness
Vanadium info
diabetes tx option
avg diet contains 6-18mcg qd
–only 5% is abs
kidney toxicity
effective ONLY in T2DM
inc risk of bleeding when used in combo w/ Rx, OTC, or supplements
hypertension tx options- 2
Garlic
Coenzyme Q-10
Garlic supplement info
HTN tx option
when using fresh product needs to sit for 10min chopped up prior to use for best results
GRAS
discontinue 2-3 weeks prior to surgery
products marketed as odorless may not contain Allicin
0.65-1.3% Allicin for standardization (measure potency)
Coenzyme Q-10 info
HTN tx option
some meds can lower CoQ10 levels (statins, BBs, diuretics)
inc risk of bleeding
inc T4/T8 labs in normalized pts
take w/ fatty meal for best abs
basics of MRI
3 properties of protons in magnetic fields:
T1 relaxation rate: protons align (anatomy)
T2: loss of magnetization (anatomy, pathology)
proton density
no ionizing radiation- EM fields in radio frequency range
contrast agent detects “leaky capillaries”
imaging in any plane
MRI pituitary imaging sequences
MRI (CT only if contraindicated)
high resolution sagittal and coronal pre and post contrast T1-weight images
high resolution Coronal T2 weighted images
1st time studies usually incl whole brain (for assoc or incidental pathology)
pituitary gland imaging
ant pituitary gland:
enhances (no BBB), low T2 signal
secretes: Prolactin, GH, ACTH, LH, FSH, TSH
intermediate (septum)
usually slightly brighter on T2
posterior pituitary gland
sometimes bright on T1, does not fat saturate
secretes oxytocin, vasopressin
basic structures
adenohypophysis (anterior pituitary)
- outside cell predominance: GH and PRL
- inside cells: TSH and ACTH
neurohypophysis (posterior pituitary)
pituitary septum
tuber cinerum
infundibulum
Rathke cleft cyst
benign cyst
secretes protein
bright on T1**
only go after these when we think HAs can be attributed to it
lymphocytic hypophysitis
infundibulum is large (>5mm)
T1 vs T2 imaging
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
craniopharyngioma adamantinomatous type
young (2yo girl)
classic: calcification
other types of craniopharyngiomas
low-grade benign tumors; recurring; stick to adjacent soft tissue
hamartoma of tuber cinerum
pt presents w/ gelatinous (??) laughing seizures
contrast does not enhance the tissue
hamartoma of tuber cinereum
pt presents w/ gelatinous (??) laughing seizures
contrast does NOT enhance the tissue
meningioma
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
endocrine gland histo general
in contact w/ basal lamina and secrete through it
fenestrated endothelia
pituitary gland histo/general info
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
neurology in hypothalamus and pituitary
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
blood flow of pituitary
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
anterior pituitary histo/general info
clumps of cells and capillaries w/ endothelial cells
can secrete FLAT PiG
FSH, LH, ACTH, TH, PRL, GH
posterior pituitary histo/general info
lots of ends of axons w/ granules of hormones that get secreted into local vessels
-Herring bodies
secretes ADH, oxytocin
cells of median eminence releasing hormone
TSH-RH, DRH, GHRH
adrenal gland histo/general info
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
adrenal gland bloodflow
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
adrenal gland layers and products
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)
thyroid gland histo/general
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
parathyroid glands histo/general info
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
endocrine pancreas cells
islet of Langerhans cells
clumps of cells
pituitary gland embryology
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
adrenal gland embryology
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
thyroid and parathyroid gland embryology
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
parathyroids, thyroid embryology
vascular embryology
parathyroids and thyroid come from endoderm
vasculature comes from mesoderm
paracrine vs autocrine cells
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**
classify hormones based on chemical structure tyrosine derivatives peptides proteins steroids
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
classify hormones based off func
water and mineral
E
growth
reproduction
water and mineral
ADH, aldo
Energy
Insulin, GH
growth
IGF, testosterone
reproduction
Estrogens, testosterone
2 ways of measuring hormones in the blood
bioassays
immunoassays
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
Hormone Receptors
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
hormone regulation general info
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
hormone regulation
serum glucose conc
serum glucose conc
when glucose is low you activate glucagon from alpha cells
when it is high, you activate insulin from beta cells
hormone regulation
pulsatile action
circadian rhythm
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
hormone regulation
HPT axis
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
hypothalamus pituitary communication ysstem
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
pathways of peptide hormones (+ Dopamine) TRH CRH GnRH GHRH Somatostatin PTH
TRH–> thyrotrophs –> TSH
CRH- corticotrophs- ACTH
GnRH - gonadotrophs - LH, FSH
GHRH- somatotrophs- GH
somatostatin - somatotrophs- dec GH
PTH - Dopamine - dartotrophs- dec prolactin
GPCRs cAMP actions and ex
Gs
Gi
Gq
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)
prolactin and JAKSTAT
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
prolactin effects on mammary gland
mammogenesis (growth of gland)
lactogenesis (prep of gland for prod)
galactopoiesis (synthesis of milk components)
prolactin regulation
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)
hypoprolactin
rare
consequence of low pituitary function
Sheehan’s syndrome- failure to lactate, ischemic infarct of pituitary from postpartum bleeding/hemorrhage
GH basics
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
2 major effects of growth hormone
metabolic
need E sources that allow you to invest in growth
growth
need growth itself
GH actions
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
GH growth effects
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
regulation of GH
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
GH dysregulation
hyper and hypo
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
GH stimulation and suppression
stimulation: sleep low glucose exercise stress puberty high AA/protein GHRH glucagon alpha-adrenergic
suppression somatostatin high glucose aging FFAs
Excess GH diseases
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)
GH deficiency
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
high prolactin
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
low prolactin
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
high FSH/LH
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
low FSH/LH
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
high TSH
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
low TSH
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
high ADH
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
low ADH
Diabetes Insipidus
ACTH
assess adrenal gland- cortisol and DHEA-S
hypothalamic-pituitary-target organ axis and defect nomenclature
peripheral:
primary disorder
target organ
central:
secondary disorder (pituitary gland)
tertiary disorder (hypothalamus)
Prolactinomas
basic
F vs M
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
Dx and Tx of prolactinoma
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
cortisol function, production, timing, binding
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
chronic cortisol excess
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
hypercortisolism
ACTH dependent vs ACTH independent
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)
Cushing’s syndrome
non-specific signs/symptoms
specific signs/symptoms
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)
3 screening tests for Cushing’s Syndrome
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)
pseudo-cushing’s disease
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)
central adrenal insufficiency
etiology
clinical presentation
basal tests
stimulation tests
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
hypopituitarism
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)
apoplexy
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
ADH deficiency
common w/ metastatic tumors (breast, lung, GI) or craniopharyngiomas, but not pituitary adenomas
management of hypopituitarism
-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
posterior pituitary gland
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)
volume regulation of ADH
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)
osmotic demyelination syndrome
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
Diabetes insipidus DI
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
Nephrogenic vs neurogenic DI
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
post-op/trauma related DI
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%)
outpatient DI diagnosis
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
water deprivation test
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
central DI treatment
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
sella region masses overview
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
anterior and posterior pituitary histology
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
pituitary adenoma
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)
invasive pituitary marcoadenoma
> 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
pituitary blastoma
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
abnormal pituitary adenoma
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
lineage of pituitary tumors
all start w/ same lineage
Rathke pouch stem cell–>
then delineate based on transcription factors
ACTH adenomas
85% of ACTH adenomas are micro adenomas and often missed on imaging
most prolactinomas in premenopausal women are microadenomas
non-secretors/weak secretors pituitary tumors
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))
hormone negative pituitary adenoma
clinically nonfunctioning AND show now IHC(+) for the hormones GH, PRL, FSH, LH, TSH, ACTH
most of these are SF-1 (+), indicating gonadotroph lineage
GH adenoma
densely granulated and sparsely granulated
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
mixed pituitary adenoma
something that makes a mix of 2 hormones
ex. mixed GH-PRL adenoma
has both prolactin and GH overproductions
prolactinoma
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)
acidophil stem cell adenoma
usually presents w/ prolactinemia but discordance between large size of adenoma and relatively modest serum PRL elevation
aggressive, need to follow closely
ACTH/ corticotrophin adenoma
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
frequency of seller region masses
PITUITARY ADENOMAS
craniopharyngiomas
hypophysitis
spindle cell oncocytomas
frequency of seller region masses
PITUITARY ADENOMAS
craniopharyngiomas
hypophysitis
spindle cell oncocytomas
craniopharyngioma,
adamantinomatous and papillary
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
pituicytoma
from posterior pituitary
looks similar to a pituitary adenoma, but TTF1 staining/marker makes the diagnosis
metastatic breast carcinoma to anterior pituitary gland
metastasis is not common, but most commonly happens via breast cancer
estrogen receptor is positive in the metastatic breast cancer
GH tumor treatment goals
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!!
general treatment of pituitary tumors
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
2 surgical approaches for pituitary tumors
depends on surgeon preference
transnsasal microscopic approach
2-D
transnasal endoscopic approach
3-D
risks of pituitary tumor surgery
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)
GH pharm basics
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
PRL pharm basic-
inhibited by DA
ADH pharm basics
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
applications of hypothalamic-pituitary hormones
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
GH/Somatropin drug uses
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)
Growth hormone releasing hormone GHRH pharmacology
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
Somatostatin SST pharmacology
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
Somatostatin pituitary uses
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
somatostatin non-pituitary uses
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)
Somatostatin adverse rxns
transient deterioration in glucose tolerance
HYPERGLYCEMI
then subsequent improvement
abdominal cramps, loose stools
cardiac effects incl sinus brady and conduction disturbances
Prolactin pharm
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
Dopamine agonists for hyperprolactinemia
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
ADH-Vasopressin pharm
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)
posterior pituitary disease pharm for central DI
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
posterior pituitary disease pharm for peripheral DI
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
posterior pituitary hyperfunction pharm
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)
cholesterol hormone pathways
cholesterol–> pregnenalone
pregnenalone–> aldosterone
pregnanlone–> (17-alphahydroxylase)–> 17-OH-pregnenalone –> (17,20-lysae)–> dehydroepiadnosterone DHEA
17-OH-pregnenolone–> cortisol
DHEA–> sex steroids
cortisol info and its effects
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
cortisol regulation
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
addison’s disease
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
secondary hypo function of adrenal cortex
problem with pituitary
low cortisol
low ACTH (there’s the problem)
same/nl aldo (adrenal gland isn’t damaged)
primary, secondary, tertiary problem w/ cortisol hyperfunction
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
adrenal medulla chromaffin cells
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
EPI actions
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)
thyroid hormone TH
basic structures
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)
thyroid hormone TH synthesis
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
TH levels in the blood
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
TH function
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
regulation of TH
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
thyroid dysfunction basics
hypo vs hyperthyroidism
primary and secondary
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)
thyroid dysfucntion- what causes Type 1 or Type 2 deiodinase to not function
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
T4 and T3 number info
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
causes of increased total T4 and total T3
causes of increased free T4 and free T3
causes of decreased total for free T4 and T3
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)
TSH testing
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
symptoms of
Hyperthyroidism and hypothyroidism
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
diagnosis of hyperthyroidism or thyrotoxicosis
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
thyrotoxicosis specifics- how to tell if it’s also true hyperthyroidism
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)
etiology of hyperthyroidism:
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
Graves findings
Graves exophthalmos- bulging eyes
pretrial myxedema- doughy feeling
Graves treatment
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
destructive thyroiditis clinical course
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
subclinical hypothyroidism
small decrease in free T4 = LARGE increase in TSH
etiology of hypothyroidism
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
Hashimoto’s Thyroiditis
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
when to treat hypothyroidism
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
myxedema coma
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!
aldosterone, cortisol, androgens, NE/EPI released in response to:
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
adrenal hormone functions aldosterone cortisol androgens NE/EPI
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
primary adrenal insufficiency vs secondary
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
adrenal insufficiency clinical features
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
adrenal crisis
emergency!
N/V, fever, syncope, hypotension, tachy
give stress dose steroids
–hydrocortisone 100mg IV every 8 hrs
Addison’s disease info
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
testing for primary adrenal insufficiency-
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)
testing for secondary adrenal insufficiency
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
treatment of adrenal insufficiencies
primary and secondary
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
Aldosterone regulation and RAAS system
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)
causes of hyperaldosteronism
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
signs and symptoms of primary aldosteronism
screening
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
testing for hyperaldosteronism
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)
treatment of hyperaldosteronism
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
licorice causing pseudohyperaldosteronism
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
Hypercortisolemia
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
ACTH dependent hypercortisolemia:
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)
ACTH independent hypercholesterolemia
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)
Dx of hypercortisolism
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
Treatment for hypercortisolism
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
most common cause of hypercortisolism
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
neuroendocrine tumors
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
excessive production of metanephrines/normetanephrines
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
screening for pheochromocytoma/paraganglioma tumor:
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)
interfering meds w/ screening for pheo/paraganglioma neuroendocrine tumors
Acetaminophen SSRIs Serotonine NE inhibtors Marijuana and other illicit drugs among others
will give you false positives
after a positive neuroendocrine screening for pheo/paraganglioma
treatment
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
pheochromocytoma rule of 10s
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
MEN2 info
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
genetic testing for pheo/para
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
malignant pheochromocytoma
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%
adrenal incidentalomas- prevalence
evaluation
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?)
determining whether an adrenal incidentaloma is secreting or non-secreting
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
determining whether an adrenal incidentaloma is benign or malignant
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!)
management of adrenal incidentaloma
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
giving glucocorticoid/ CORTISOL in pharmacologic doses
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
giving mineralocorticoid/ALDOSTERONE in pharmacologic doses
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
mineralocorticoid vs glucocorticoid pharm acitivty
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
metabolism of glucocorticoids (cortisol and prednisone)- liver, kidney, fetus
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)
adrenocortical insufficiency pharm tx-
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!)
pharm tx of Cushing’s syndrome
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**
adrenal enzyme inhibitors
Ketoconazole and metyrapone
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)
diuretic agents on plasma electrolytes
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
CCBs and selectivity
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
RAAS antagonists
ACEI’s- give you a cough because of the increased bradykinin
-pril
ARB
-sartan
both decrease BP!
pharm tx of pheochromacytoma
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)
Calcium’s importance in body
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
PO4’s importance in body
bone high E compds- ATP membrane phospholipids regulation DNA, RNA
Calcium regulation
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
3 types of cells that regulate Ca and PO4 in and out of bone
surface osteoblasts
osteocytes- differentiated osteoblasts within canaliculi
osteoclasts- in matrix (phagocytic)
3 main Ca exchange processes
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
PO4 equilibrium
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
PTH and its triggering
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
PTH function
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
Hyperparathyroidism info
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
hypoparathyroidism info
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
Calcium mineral info
major mineral
intake require >100mg/day
1200-1500g in body total; mot abundant
Ca hydroxyapatite- 99% of Ca (bone, teeth)
metabolic: signal transmitter
Ca homeostasis and intestinal Abs
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
Ca abs and habitual intake
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)
Ca abs through life cycle
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
Calcium requirements with pregnancy and lactation
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
DRIs of Ca during lifetime
high risk groups
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)
Calcium supplements
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
non-nutrtiitonal factors assoc w/ BMD
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
Nutritional factors sassy w/ BMD
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
how to optimize bone health
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
3 Ca regulating hormones
3 Ca reguationg organs
hormones:
PTH
1,25 (OH)2 Vit D
Calcitonin
Organs:
intestine
bone
kidney
PTH effects on Ca- 3 mech’s
inc bone resorption
kidney:
decreases Ca excretion (and increases excretion of PO4)
–makes active Vit D, which indirectly helps gut
Gut: inc Ca abs
Vit D metabolism
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
Calcitonin effects
made in parafollicular C cells in thyroid gland
causes decreased bone resorption and lower serum Ca
the 3 major cell types in body that have Ca sensor regulator
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
hypercalcemic disorders
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)
classification of primary hyperparathyroidisms
clinical features:
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)
Dx primary hyperparathyroidism
serum Ca
serum PO4
tx
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
MEN1 and MEN2A associations
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!
secondary hyperparathyroidism
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
hypercalcemia of malignancy
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
diagnose hypercalcemia of malignancy
Ca
PTH
PTH-RP
high serum Ca
low serum PTH
high serum PTH-RP (or other mediator)
diagnose familial hypcalciuric hypercalcemia
Ca phos PTH urine Ca Ca/CC
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
causes of hypocalcemia
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
features of hypocalcemia
paresthesias- numbness/tingling
muscle cramps
muscle weakness
Ckvostek’s sign (Facial nerve)
Trousseau’s sign (BP cuff)
dx nutritional Vit D deficiency
-osteomalacia
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
how to get a Vit D disorder
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
dx hypoparathyroidism
Ca
PO4
PTH
low Ca
high PO4
low PTH
pseudohypoparathyroidism
Ca
Phos
PTH
signs
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
bone remodeling
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
osteoporosis
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)
risk factors for fragility fractures
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
abnormal bone remodeling
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
low bone mass DDx
not always osteoporosis!!
need an H and P exam
ex meds- glucocorticoids
SSRIs, anticonvulsants
osteomalacia and rickets
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
phosphate disorders
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!!!
Paget’s disease of bone
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
Paget’s disease clinical features and course
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
Paget’s Disease Dx
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
prevalence of endocrine disorders in US
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
thyroid neoplasm types
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)
Thyroid adenoma
benign neoplasm
solitary nodule
follicular/Hurthle cell
DDx:
hyperplastic nodule follicular ca
careful evaluation of the capsule!!
thyroid follicular/Hurthle Cell carcinoma
thyroid follicular/Hurthle cell carcinoma: 2 types: minimally invasive --vascular or capsular invasion!!!!!! widely invasive --more extensive invasion!!!!!
thyroid papillary carcinoma
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
thyroid gland anaplastic carcinoma
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
thyroid gland medullary carcinoma
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 +
thyroid gland lymphomas
background autoimmune thyroiditis
large fleshy masses (skeletal muscle looking)
DDx: anaplastic ca of thyroid
Positive LCA, usually B-cell
gene rearrangement
thyroid gland
sarcomas and metastatic
sarcomas: blank?
metastatic: melanoma renal lung breast head/neck colon
approach to pt w/ thyroid nodules
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
proto-oncogene
oncogene
tumor suppressor gene definitions
mutations
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
radiology- anatomy of thyroid
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
imaging modalities of thyroid
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
ultrasound thyroid imaging
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”
lymph node assessment in thyroid imaging
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
CT of the neck- nl thyroid
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
MRI thyroid imaging
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
Iodine scan of thyroid imaging
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
evaluating a cold vs hot thyroid nodule w/ I-123
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
I-131 scan in the dx and treatment of:
hot lymph nodes
hot lungs
nl low-level salivary gland activity
how to reliably differential between benign and malignant thyroid disease
thyroid nodule evaluation
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
The imaging test of choice to evaluate a thyroid lesion size, location, and simple cyst vs not simple cyst is
What is the imaging testof choice to evaluate a patient with hyperthyroidism?
ultrasound
iodine scan
to find out whether or not you should recommend something
search for guidelines based on: quality of evidence benefits vs harms applicability (cost, resource) pt values and preferences
IOM (NAM) Standards- 8
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
Appraisal of Guidelines for Research and Evaluation AGREE
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
US Preventive Services Task Force USPSTF
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
evaluating the body of evidence for each key question
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
forrest plot omega-analysis
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
pros and cons of the review process for screening
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
define evidence based medicine
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
systematic review vs traditional literature reviews
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
pyramid of EBM resources
start w/ summaries and guidelines (guidelines decision analyses)
then reappraised research (systematic reviews)
then nonpreappraised research (primary studies)
critical appraisal of systematic reviews
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?
meta-analysis pros and cons
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
PTH actions pharm
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
loop diuretics vs thiazide diuretics on plasma Ca
loop diuretics:
decrease plasma Ca
thiazide diuretics:
increase plasma Ca
Vitamin D actions pharm
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
Vit D preparations pharm
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
med options for treating hyperparathyroidism pharm
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!!!
Vitamin D analogs pharm
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
calcitonin regulation on pharm
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
estrogen actions on bone pharm
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!!
glucocorticoid actions on bones pharm
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!!
bone formation review
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
Adverse Rxns of Warfarin on bones pharm
Warfarin is a Vitamin K antagonist
can cause GI problems, but also OSTEOPOROSIS
contraindicated in pregnancy (crosses placenta)
osteoporosis tx strategy pharm
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
actions of anti-resorptive agents pharm
anti-osteoclast
increase OPG synthesis
-estrogen
Raloxifine
decrease RANK-L
Denosumab
decrease OC activity
BISPHOSPHONATES
-ex. Alendronate
Bisphosphonates pharm
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
SERM meds in tx of osteoporosis pharm
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
estrogens treating osteoporosis pharm
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!
Denosumab pharm
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
Calcitonin pharm
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
Teriparatide pharm
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
Sclerotin pharm
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
thyroid development
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
arrested thyroid migration
lingual, sublingual, or ectopic thyroid gland anywhere around the neck
-not enough cells, can’t grow to nl size
fetal hypothyroidism
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
congenital hypothyroidism
causes
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)
thyroid dysgenesis
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
thyroid dyshormonogenesis
accounts for 10-15% of congenital hypothyroidism
auto recessive
Goiter may be present
mutations in genes coding for proteins involved in TH synthesis
Pendred syndrome
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
TSH resistance
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
congenital central hypothyroidism
hypothalamic or pituitary deficiency
usually occurs in setting of multiple pituitary hormone deficiencies
need to eval other pituitary hormones and obtain cranial MRI
signs/symptoms of congenital hypothyroidism
baby usually appears entirely nl for a few weeks
large posterior fontanel prolonged jaundice macroglossia umbilical hernia hypotonia feeding difficulties hoarse cry
newborn screening and dx of congenital hypothyroidism
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
what to measure w/ thyroid hormones
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
assessing T3 uptake
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)
treatment of congenital hypothyroidism
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! :)
Levothyroixine pharm
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
drug effects on plasma-protein binding
ones that increase and decrease binding
increase binding:
Estrogens/ SERMS
Decrease binding:
anticonvulsants
phenytoin-carbamazepine
T4–> T3 conversion inhibition by drugs pharm
the activating enzyme (type 1 or 2 deiodinase) is inhibited by:
glucocorticoids
beta blockers
(amiodarone)
propylthiouracil (in higher doses)
treat myxedema pharm
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
levothyroxine alternatives
Liothyronine
Liotrix
Thyroid USP
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
treatment of graves disease pharm
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
methimazole and Propylthiouracil “PTU” pharm
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
super saturated KI - SSKI
and Lugol’s soln (KI)
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!
radioactive iodine I-131 pharm
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
thyroid storm treatment pharm
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
diabetes and mood
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
hypercortisolism and psych
psych symptoms may predate physical symptoms
depressive- most common anxiety hypomanic/manic symptoms psychosis memory problems
Calcium levels and psych
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
Addison’s and Acromegaly psych
Addisons:
apathy, anhedonia, fatigue, depression
Acromegaly:
irritability/mood lability
depressive symptoms
personality changes***
thyroid and psych problems
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
pregnancy and psych
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
worrisome growth intro
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)
how to calculate midparental target height
boys:
(mom’s height + 5” + father’s height) / 2
girls:
(mom’s height + father’s height - 5”) / 2
when do children start their growth spurts
skeletal maturation
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
causes of short stature/abnormal growth
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
familial short stature
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
constitutional growth delay
“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)
failure to thrive
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
nutritional growth retardation
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
hormonal causes of worrisome growth
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
GH/IGF-1 abnormalities in growth
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
syndromic shot stature
chromosomal
skeletal dysplasia and other genetic syndromes
Turner syndrome- haploinsufficiency of SHOX gene
Prader-Wili- GH deficient
Noonan syndrome- abnl GH post-receptor signaling
Turner syndrome
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
small for gestational age
< 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
MEN syndromes
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
