endocrine notes (harrisons)

8/18/2019 Endocrine Notes (Harrisons)

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309 Approach to Endocrine Diseases

• ANP – from the heart; induce natriuresis in kidney

• EPO – made in kidney to stimulate erythropoiesis in BM

• Leptin - produced by adipose tissue

• ushin!"s #isease – impaired inhibition of A$% but not

completely resistant as e&idenced by A$% suppressionof hi!h dose de'amethasone test

• MEN ( – triad of parathyroid) pancreatic islet and pituitary

tumors

• MEN * – predisposed to medullary thyroid A)

hyperparathyroidism and phrecromocytoma• Acti&ate mutations of L% rc

o Mcune Albri!ht syndrome – early in

de&elopmento +% secretin! tumors and acrome!aly –

occur only in somatotropes

• %ormone resistance – defecti&e hormone action

despite increase hormone le&els

• ushin!"s syndrome – central fat distribution) striae)

pro'imal muscle ,eakness) obesity) plethora) hpn)!lucose intolerance

• %ypothyroidism –mental slo,in!) fati!ue) dry skin

• mmuonassays – most impt dia!nostic tool in

endocrinolo!y; use ab to detect specific hormones

• .rinary hormone secretion - assessment of ahormone that &ary ,ithin the day/

o *0 hr urinary free cortisol – measures

unbound1biolo!ically acti&e hormone

• cortisol – increase 2 fold bet,een midni!ht and da,n

• reproducti&e hormones – &ary durin! mens

• #ecrease P$% ,ith hypercalcemia –

mali!nancy1!ranulomatous disease

• A$% ,ith hypercotisolemia – hyperfunctionin!

adrenal adenoma

• A$% stimulation test – for adrenal insufficiency

• Metyrapone inhibition – cortisol synthesis

• lomiphene inhibition – estro!en feedback

•

3creenin!o $ype * #M – be!innin! a!e 02 e&ery 4 years

hi!h risk; 5P+ (*0m!1dl; 6P+ 7*88m!1dlo %yperlipidemia – cholesterol screenin! e&ery

2 yrso +ra&es"s #se – $3%) free $0

o $hyroid nodule1neoplasia – PE of thyroid and

5NABo PO3 – testosterone) #%EA3

o 9it # def – *2-O% serum &it #

400 Mechanism of Hormone Action

• lasses of %ormones

o Amino acid – dopamine) catecholamines) thyroid

hormoneo 3mall neuropeptide – +n6%) $6%) somatostatin)

&asopressino Lar!e neuropeptide – insulin) P$%) L%

o 3teroids – estro!en : cortisol

o 9itamin deri&ati&e – 9it/ A : #

• Membrane 6eceptors

o +P6 – almost all

o 6c $yrosine inase – nsuline

o ytokine 6c-linked kinase – +%) P6L

• %ormone precursor

o POM – A$%

o Pro-!luca!on) insulin) P$%

• Pro-hormone con&ersion

o $estosterone dihydrotestosterone

o $0$4

• holesterol – steroid hormones

• 3tored in secretory !ranules – +n6%) insulin) +%; ,ith

stimulus ,ill be released from the !ranules

• #iffusion as they synthesi days; ?( month to reach steady

state; sin!le daily doseo $4 –%5= ( day; administered *-4' a day

o 3ynthetic !lucocorticoids – &ary

#e'amethasone- lon!er half-life

!reater suppression of A$%o Protein hormones – short half life 7*8mins

o P$% – short half allo,s the use of P$%

determination intraoperati&ely in to confirmsuccessful remo&al of adenoma

• %ormones in association ,ith serum bindin! proteins

o Ad&= hormonal reser&oir) pre&ent rapid

de!radation of unbound hormones) restricthormone access to certain sites

o #isad&= reate dia!nostic problems

o Li&er dse : meds – estro!en inc $B+)

salsalate displace $0 from $B+o 5or self corrections= e'cept= 3%B+ dec in

insulin resistance or andro!en e'cess unbound testosterone leadin! to hirsutism;testosterone does not result feedbackcorrection bec estro!en is the primaryre!ulator of reproducti&e a'is

• %ormone de!radation

o ((B-hydro'ysteroid dehydro!enase –

inacti&ates !lucocorticoids in renal tubular

cellso #eiodenases – con&ert t$0 to $0 and

inacti&ates $4o yp*@b( – de!rades retinoic acid that

pre&ents promodial !erm cells in male toenter meiosisfemale o&ary

• %ormone action throu!h receptors

o Membrane rc – bind to peptide hormones

and catecholamineso Nuclear rc – bind to small molecules that can

diffuse such as steroids and &it #/

• 5unctions of hormones

o +ro,th and differentiation

o Maintenance of homeostasis

o 6eproduction• Positi&e feedback control

o Estro!en mediated mid cycle L% sur!e –

risin! estro!en stimulate L% secretion

• Paracrine re!ulation – factors released by one cell act

on adacent cell E'/ 3omatostatin secreted by # cellsinhibit insulin secretion from B cells

• Autocrine – action of factors from ,hich it is produced

E'/ 5+- acts on many cells from ,1c it ,as producedlike chondrocytes) breasts) and !onadal cells

• %ormonal rhythms

o Menstrual cycle – * days; follicular

maturation : o&ulation


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o ircadian rhythm –pituitary hormones

A$% and cortisol – peak early

mornin!) nadir at ni!ht ushin!s – increased midni!ht

cortisol le&els %PA a'is susceptible to

suppression by !lucocorticoidsadministered at ni!ht as they bluntthe early mornin! rise of A$%

+lucocorticoid replacement= mimic

diurnal pattern; administer lar!edoses in the AM than in PMo +n6% pulse freCuency

ntermittent pulses – reCd to

maintain pituitary sensiti&ity ontinuous e'posure – causes

pituitary !onadotropedesensiti


3/27

o Pulsatile and e'hibits circadian rhythm; peak=

@am nadir at ni!hto ncreased= stress) e'ercise) acute illness) and

insulin-induced hypo!lycemiao Action=

maintain metabolic homeostasis and

mediate neuroendocrine response induce streoido!enesis

• +onadotropins 53% : L%F

o (8G of AP cells

o ,ith B-subunits like $3% and %+F – confersspecificity

o 3timulation= +n6% by brain kisspeptin

3ecreted in discrete pulses e&ery @8-

(*8mins Pulses prime !onadotropin

responsi&eness ontinuous +n6% – induces

desensiti


4/27

• Normal bone a!e in short child – !enetic cartila!e

dysplasia or !ro,th plate do

*H Deficiency in .hildren

o solated +% deficiency – short stature)

micropenis) increased fat) hi!h pitched &oice andhypo!lycemia due to unopposed insulin

o diopathic +% deficiency – dia!nosis made after

molecular defects e'cludedo +%6% mutations – se&ere proportionate

d,arfism associated ,ith lo, basal +% le&els

that cannot be stimulatedo +% insensiti&ity – Laron"s 3yndrome – +%

insensiti&ity) !ro,th failure) normal or hi!h +%le&els) dec +%BP) lo, +5- le&els

o Nutritional short stature – caloric depti&ation and

malnutrition) uncontrolled #M) 65 producecytokines -? e'acerbates the block in +%mediated si!nal transduction; short stature ,1normal or ele&ated +% and lo, +5- le&els

o Psychosocial short stature – emotional and social

depri&ation ,ith delayed speech) discordanthyperpha!ia

• Presentation and #'

o 5amily h'

o 3hort stature – e&aluated if pt"s hei!ht is ?43#

belo, the mean for a!e or if !ro,th rate hasdecelerated

o 3keletal maturation – measured by radiolo!ic

bone a!e; based on ,rist bone !ro,th failureo 5inal hei!ht – predicted ,ith standardi


5/27

D$A/E%E( $!($P$D&(hap 080

403 Anterior Pituitary %umor (yndromesHypothalamic Pituitary and #ther (ellar Masses

• E&aluation of 3ellar Masses

(/ Local Mass Effectsa/ #orsal sellar diaphra!m – least resistance

to soft tissue e'pansionb/ %eadaches – cmmon feature of small

intrasellat tumorsc/ 5eatures of 3ellar Mass Lesions= $able 084-

(*/ M6

a/ Pituitary !land hei!ht

• children – @mm-mm

• pre!naoncy : puberty – (8-(*mm

• adult – flat1sli!htly conca&e

• pre!nancy1adolescent – con&e'

pituitary enlar!ementFb/ pituitary bri!ht spot – hi!h phospholipid

content in posterior pituitaryc/ 3ellar masses – incidental findin!s

• Absence of hormone hypersecretion –

monitor ,ith M6 annually

• 6esection – macroadenomas ,ith

in&asi&e and pressure effects4/ Ophthalmolo!ic E&aluation

a/ Optic tracts conti!uous to e'pandin! pituitarymass

b/ perimetry – test &isual fields in those ,ithsellar mass lesions impin!in! optic chiasm

c/ Bitemporal hemianopia – compression ofoptic chiasm

d/ %omonymous hemianopia – postchiasmalcompression

e/ Monocular temporal field loss – prechiasmalcompression

f/ #iplopia – oculomotor ner&e palsy due to

in&asion of car&ernous sinus0/ Laboratory n&esti!ationa/ 3creenin! $ests for 5unctional Pituitary

Adenomasb/ Pituitary adenoma suspected in M6) initial

hormonal e&aluation

• Basal P6L

• +5-

• *0-hr urinary cortisol1o&erni!ht oral

de'amethasone (m!F suppression test

• a-53% and L%

• thyroid function test

c/ %istiolo!ical e&aluation – aftertransphenoidal sur!ery

2/ $reatmenta/ $ransphenoidal 3ur!ery

• #esired sur!ical approach for pituitary

tumors than transfrontal

• A&oids cranial in&asion and brain tissue

manipulation

• 3ur!ical decompression and resection –

for e'pandin! pituitary mass

• 3E= #) N dama!e) nasal septal

perforation) &isual disturbancesb/ 6adiation

• $otal of 728+y 2888 radF is

!i&en as (8-c+y (8-radFdi&ided in @,ks

@/ 3ellar Masess= %ypothalamic Lesionsa/ Anterior : preoptic re!ions= ause

parado'ical &asoconstriction) tachycardia)hyperthermia

b/ Posterior re!ions= periodic hypothermiasyndrome – episodes of 748) s,eathin!)&asodilation) &omitin! and bradychardia

c/ 9entromedial re!ion= hyperpha!ia andobesity

d/ Preoptic nuclei – dama!e to osmorc polydipsia and hypodipsia

e/ ryaniopharny!omas – beni!n) suprasellarcystic masses that present ,ith headaches)&isual field deficits and hypopituitarism) a!eof *8 ,ith si!n of inc P

>/ Pituitary Adenomas and %ypersecretion %ormonesa/ Pituitary Adenomas – most common cause

of pituitary hormone hypersecretion andhypose'retion in adults

b/ Beni!n neoplasms that arise from one of the2 AP cell types=

c/ lassification of Pituitary Adenomas $able084-4

d/ +enetic 3yndromes assoc ,ith pituitarytumors $able 084-0

/ %yperprolactinomaa/ Most common pituitary hormone

hypersecretion in both men and ,omenb/ Prolactinomas – most common cause of

P6L le&els ?*88u!1Lc/ Etiolo!y $able 084-2d/ Presentation=

• amenorrhea) !alatorrhea) and infertility

– hallmarks in ,omen

• de&elops before menarche – primary

amenorrhea

• hyperestro!enemia – &ertebral bone

density reduced

• men= diminished libido) infertility) and

&isual loss

• +alactorrhea – inaapropriate dischar!e

of milk; abnormal if ? @ mos afterchildbirth) d1c of bf

e/ Lab=

• Basal) fastin! mornin! P6L le&els

assess for hypersecretion

• E'clude hypothyroidism – e'cluded by

measurin! $3% and $0 le&elsf/ $'=

• #opamine a!onists

• Dithdra, dru!s causin!

hyperprolactenemia

• Psych pts= dose titration of neuroleptic

a!ents

• 6esol&es after thyroid replacement in

hypothyroidism and renal transplant ptsunder!oin! dialysis

• 6esection of mass

J/ Prolactinomaa/ Most common pituitary tumor; half of all f'nin!

pituitary tumorsb/ Microadenomas - 7(cm; nonin&asi&e; 5=M ratio=

(=(c/ Macroadenomas -?(cm; in&asi&e and impin!es;

5=M ratio= *8=(d/ Presentation= same ,ith hyperprolatinemia


6/27

e/ P6 le&els ? *88u!1L) if less than (88microadenoma

f/ $'=

• Asymptomatic microadenoma – no t';

monitor P6L and M6

• 3ymptomatic microadenoma

o Medical= #opamine a!onists

aber!oline 8/2-(/8mf t,ice

,eeklyF – #* rc affinity; suppressP6L for (0 daysafter sin!le oral

dose; 3E= headaches) &isual d1o;but less 3E than bromocriptine Bromocriptine 8/@*2-(/*2m! at

bedtime ,1 snacks; !radual dailydose of */2m! tid – short actin!;preferred in pre!nancy; restorefertility in ,omen ,ithhyperprolactinemia

3E= constipation) nasal stuffiness)

dry mouth) ni!htmares) insomnia)and &erti!o

o Mn!t Approach ,ith Ele&ated

Prolactin le&els= 5i! 084-4(8/ Acrome!aly

a/ Etiolo!y= usually result of somatotrophe

adenoma1pituitary cause -JGb/ +%6% mediated acrome!aly – most common

cause is chest or abdominal carcinoid tumor c/ Presentation=

• +% and +5- hypersecretion – indolent

clinically dia!nosed for (8 yrs or more

• Acral bony o&er!ro,th= frontal bossim!)

increased hand and foot si2!F

e/ $'=o 3ur!ical resection of +%-secretin!

adenomaso 3omatostatin analo!ues – adu&ant t'

for preop shrinka!e

• Ocreotide acetate 3K 28u! tid to

(288u!1d

• 3E= + nausea) abdominal

dscomofrt) fat malabsorption/#iarrhea) flatulence) suppress!allbladder contractility leadin! toasymptomatic cholesterol !allstone

o +% rc anta!onists Pe!&isomant daily

3K (8-*8m!) normali8G of pts

,ith endo!enous cause of 3

• atro!enic hypercortisolism – most common

cause of cushin!oid fechronic cortisol

featuresb/ Presentation= $ypical features of chronic cortisole'cess

• $hin skin) central obesity) hpn) plethoric

moon facies) purple striae) easy bruisability)!lucose intolerance) dm) !onodal dysnf'n)hyperandro!enism) psych disturbances

• %ema features= leukocytosis) lymphopenia)

eosinophilia

• mmune suppression

• Ectopic tumor source= rapid de&t of features

of hypercotisolism assoc ,ith skinhyperpi!mentation and se&er myopathy) hpnhypokalemic alkalosis) !lucose intolerance)edema

• $able 084/- >

c/ Lab=

• *0-hr urone free cortisol .5F

• failure to suppress after an o&erni!ht (-m!

de'amethasone suppression test – cortisolnadir le&els at ni!ht ele&ated midni!htserum samples

• Basal A$% le&els – distin!uish A$%

independent adrenal1e'o!enous!lucocorticoidsF from A$%-dependentpituitary ectopic A$% fold hi!her F

• #ynamic testin! based on !lucocorticoid

feedback or A$% stimulation in response to6% or cortisol reduction

• #ifferentia dia!nosis of A$%-dependent

ushin! 3yndrome $able 084-d/ $reatment

• 3electi&e transphenoidal sur!ery – t' of

choice ,ith postop sytomatic A$%deficiency lo, dose cortisol replacement

• Pasireotide @88-J88u!1d 3K – t' for A$%-

secretin! pituitary tumors ,hen s' notuseful1successful

• etocona


7/27

o O'ytocin – postpartum milk letdo,n in response

to sucklin!

• # – production of lar!e urine; impairs urinary e'cretion)

predispose to hyponatremia

• 9asopressin

o re!ulated primarily by the effecti&e osmotic

pressure of body fluids mediated by osmorc ,1care sensiti&e to chan!es in plasma sodium*8mosmo1L or (42meCL

o Action= reduce ,ater e'cretion by promotin!

concentration of urine

increasin!hydroosmotic permeability of cellsthat line #$and M# of kidney

o Dater diuresis – lack of reabsorption; e'cretion of

8/*mL1k! per min of ma'immaly dilute urine and3+ -(/888 and osmolarity of 28mosmol1L

o $hirst – ensure adeCuate intake to pre&ent

dehydrationo O'ytocin

Act on mammary ducts to facilitate milk

letdo,n ; initiate or facilitate labor bystimulatin! contraction of uterine smmuscle

Deficient of A,P (ecretion(/ #iabetes nsipidus

• #ecrease of >2G or more in the secretion or action of

A9P usually results in #; syndrome characteri


8/27

d/ parathyroid – loc at posterioir pole of the thyroide/ thyroid medullary cells= produce calcitonin – a

lo,erin! hormone; in&ol&e in medullary canf/ $3% – re!ulates increase demand in $3%; most useful

marker of thyroid hormone action; establish the setpoint in %PA

!/ B-sub unit – uniCue to $3%h/ $hyroid hormones – dominant re!ulator of $3%

production*/ $hyroid %ormone 3ynthesis

a/ $! – thyroid hormones are deri&ed

b/ 3teps=• odine Metabolism and $ransport idodide

uptake is the critical first step in the thyroidhormone synthesis

o Mutation of pendrin !enre – Pendrad

syndrome – defecti&e or!anification ofiodine) !oiter) and sensorineuraldeafness

• Or!anification) ouplin!) 3tora!em and 6elease

4/ odine deficiencya/ pre&alent in mountainous re!ionsb/ increased pre&alence of !oiter c/ se&ere deficiency= cretinism – mental and !ro,th

retardation

d/ o&ersupply of iodine

inc/ autoimmine thyroiddse

0/ $3% Actiona/ 6e!ulates thyroid !land f'n throu!h +P6b/ +5-) $+5-B) endothelinsc/ odine deficiency – inc thyroid bld flo, and

upre!ulates N3 more efficient iodine uptaked/ Dolff-haikoff effect – e'cess iodide transiently

inhibits thyroid iodide or!anificatione/ haracteristics of $4 and $0= $able 082-*

2/ Abnormalities in $hyroid %ormone Bindin! Proteinsa/ H-linked $B+ deficiency -? &ery lo, le&els of total

$0 and $4) unbound le&els are normal) ptseuthyroid and normal$3%

b/ Pre!nany1$akin! OP estro!enF ele&ated$B+ inc $0 and $4 le&els) unbound normal

c/ Euthyroid hyoerthyro'inemia – inc $0 and $0 butunbound are norm

d/ 3alicylates and salsalate – displace thyroidhormones from circuatin! bindin! proteins

@/ #eiodenasesa/ con&erts $0 to $4b/ $ype ( – thyroid) li&er) and kidneys) lo, affinity to

$0c/ $ype * – hi!her affinity to $0) pituitary !land)

bro,n fat) and thyroid- re!ulate $4concentrations locally) - impt in le&othyro'inereplacement; enhance $0 to $4 con&ersion

d/ $ype 4 – inacti&ates $0 to $4 – most impt sourceof re&erse $4m includin! sick euthyroidsyndrome muscle and li&er

>/ Physical E'aminationa/ Palpate the thyroidb/ .$Q – method of choice to determine accurately

thyroid si


9/27

• Adult= tiredness) ,eakness) dry skin) feelin! cold)

,ei!t !ain ,ith poor appetite) dry coarse skin)puffy hands and feet) bradycardia

• #' : $'= NB3) measure $3% and $0; (8-(2u!1k!

per day) $0 reCts !reat durin! the first year fornomal K le&els

• Autoimmune %ypothyroidsim

o %ashimoto"s1 +oitrous thyroiditis) atrophic thyroiditis

o 3ubclinical hypothyroidism – minor symptoms

o O&ert1clinical hypothyroidism – $3% ? (8m.1L

o Pre&alence= !enetics; chonic e'posure to hi!h iodinediet; mean a!e of dia!nosis= @8y1o

o %ashimotos= Marked lymphocytic infiltration of thyroid

,ith !erminal center formation) atrophy of thyroidfollicles ,ith o'yphil metaplasia

o Atrophic thyroiditis – e'tensi&e fibrosis) lymphocyte

infiltration less pronounced) thyroid follicles absent;represents end sta!e %ashimotos

o %LA-#r polymorphisms

o Antoboides to $PO and $+ – useful markers for

thyroid autoimmunity; no effect on fetal thyroid; $-cellmediated inury

o Antibodies to $3%-6 – pre&ent bindin! of $3% –

Asians thyroid atrophy

o

linical Manifestations= $able 082-@; puffy eyes andthick skino %ashimotos= usually present ,ith !oiter irre!ular

and firm; palpated at pyramidal lobe &esti!ialremanant of thyro!lyossal duct

o Atrophic thyroiditis1Late sta!e %ash= dry dec

s,eatin!) thinnin! of epidermis) and hyperkeratosis of stratum corneum) skin thickenin! ,1o pittin! edemamysedemaF) puffy face ,ith edematous eyelids andpretibial edema) pallor: yello,-yin!ed skin carotene accumulation) brittle nails) fry hair) ,t !ain –modest and due to fluid retention ) dec) libidio)oli!o1amenorrhea) fertility dec) prolactin mod inc--+alactorrhea) myocardial comtractility and P6reduced dec 39 and brady) diastolic hpn) cool

e'termities blood flo, di&erted from the skin)carpal tunnel and entrapment synromes – impairmuscle function) stiffness) crmaps) slo, rela'ation oftendon refle'es

o Lab E&aluation=

• normal $3% – secondary cause; pituitary dse

check $0; if lo, rule out dru! effects) euthyroidsyndrome) pituitary tumor

• $3h ele&ated – !et $0; but $0 inferoir and cannot

detect subclinical hypothy

• Establish ori!in= $PO ab

• 5NAB – confirm the presence of autoimmune

thyroiditis

• E&aluation of %ypothyroidsim – 5i! 082->

!/ Other causes of hypothyroidismo atro!enic hypothyroidism= first 4-0 months of

radioiodine t'o odine deficiency – responsible for endemic !oiter and

cretinism in childreno hronic e'cess iodine – parado2-

(*2

• adult less @8 y1o ,ith no heart dse= 28-(88un!

le&o

• $3% response measured * months after

• Effects= slo, to appear or relief until 4-@ mos

• 3E= risk of atrial fibrillation and bone density

• $akin! ?*88uf of le&o a day ,ith ele&ated $3%

poor compliance1adherence to t'

• $0 lon! half life – miss a dose) can take * doses

at onceo 3ubliclinical %ypothy= biochemical e&idence of

hypothyroidism but no apparent clinical features• No recommended t'

• E'cept= onsider in ,omen ,ish to !et pre!nant

or $3% belo, (8m.1L le&o) positi&e $PO ab),ith heart dse) ,ith su!!esti&e symptoms)positi&e $POab) e&idence of heart dse/

• 3ustained ele&ation $3% for 4mos before t' is

!i&en

• 3tart lo, dose= *2-28u! 1d

o 3pecial $' onsideration

• Domen ,ith hi!h risk of hypothy= must be euthyroid

prior to conception and pr!anacy maternalhypothy affect neural de&t and cause pretermdeli&ery/

o ncrease le&o dose up to 28G ,ith $3%7*/2m.1L (st trimF) 4/8m.1L durin!*nd14rd tri/

• Elderly= *8G less thyro'ine; those ,ith A#=

startin! dose (*/2-*2u!1d emer!ency sur!ery –pt must be euthyroid first

• My'edema oma – reduced LO) assoc ,ith

sei


10/27

o Most serious manifestation compress optic ner&e

papilledema blindnesso $hyroid demopathy1pretibial my'edema – shins;

oran!e skin appearance) noninflamed) induratedo $hyroid acropachy – form of clubbin!

• Lab E&aluation=

o $3% suppressed) $4 and $0 increased

o *-2G $4 to'icosis

o $0 to'icosis – ele&ated $0 and normal $4; due to

iodine e'cess

o Lack features of diffuse !oiter and ophtalmopathy=radionuclide scan –+ra&e"s – hi!h uptake;thyroiditis) ectopic thyroid tissue) and factititiousthyto'icosis – lo, uptake

o 3cinto!raphy – preferred dia!nostic test

o $6Ab – assess autoimmune acti&ity

o E&alutaion of $hyroto'icosis 5i!ure 082-J

• $reatment;

o Anti-thyroid dru!s

P$.) arboma


11/27

follicles lo, uptakeF pro!ress to !ranulomas ,ithfibrosis thyroid returns to normal normal uptakeF

• #isruption phase= release of $! and thyroid hormones

in$0 and $0) suppressed $3%

• 31s'= painful and enlar!ed thyroid ,ith fe&er) complains of

sorethroat

• Labs and ourse= thyto'ic t0 and t0 inc) $3%

suppressed hypothyroid reco&ery ,ithdra, thyro'inereplacementF

o onfirmed by increased E36 and radioiodine

uptakeo 5NAB – distin!uish unilateral in&ol&ement

• $'= aspirin) !lucocorticoids 08-28 m! prednisoe; thyroid

f'n monitoered e&ery *-0,ks(ilent %hyroiditis

• Painless thyroiditis or silent thyroiditis

• ommon is postpartum thyroiditis; common ,ith $ype (

#M

• Normal E36 and presence of $PO ab

• $hyroto'ic symptoms= no !lucocorticoids propranolol

.hronic %hyroiditis

most common cause= %ashimoto"s thyroiditis – firm hard

!oiter

6eidel"s thyroiditis – middle a!ed ,omen; painless hoiter

,ith compression of trachea) esopha!us) neck &eins) LN;hard nontender !oiter; 5NAB

(ic Euthyroid (yndrome

Lo, $4 syndrome) normal $0 and $3%

$0 co&ersion to $4 &ia peripheral deiodination impaired

leadin! to increased re&erse $4) ,ith decreased clearance

9ery sick pts fall in $0 and $4 lo, $0 syndromeF

decreased tissue perfusion) muscle) and li&er e'pressionof of type 4 deiodinease

Amiodarone

type 4 antiarrhythmic a!ents

assoc ,ith hi!h iodine intake; stored in adipose tissue;

persists for more than @ months

Rod-Basedo, phenomenon – thyrpid hormone systhesis

e'cessi&e as a result of increased iodine e'posurePregnancy

• ncrease in %c!

• Estro!en induced rise in $B+

• Alterations in immune system

• ncreased thryroid metab in placenta

• nc urinary iodide e'cretion

*oiter

• Enlar!ed thyroid !land

• +ra&es" – !oiter results from $3%-6 mediated effects of

$3

• %ashimoto"s – lymphocytic infiltration and immune system

induced thyroid enlar!ement

• Nodular dse – disordered !ro,th of thyroid cells; ,ith de&t

of fibrosisDiffuse nonto2ic 5simple6 goiter

• #iffuse enlar!ement ,1o nodules

• +oitro!ens

• ommon in ,omen

• $hyroid hormones preser&ed= asymptomatic

• PE= symemetrically endlar!ed nontender soft !land ,1o

nodules lateral lobeF

• Abnormalities in hormone synthesis=

o odide transport N3F

o $! synthesis) or!anification and couplin! $POF

o 6e!eneration of iodide dehalo!enaseF

• 3ubsternal !oiter – obstruct thoracic outlet

• Pemberton"s si!n – faintness ,1 facial con!estion and

e'ternal u!ular &enous obstruction ,hen arms raisedabo&e the head

• Labs

o odine def= lo, t0) normal t4 and $3%) refelectin!

enhanced con&ersiono 3ubclinical thyro'icosis= lo, $3%) normal $4 and

$0 older pts and undia!nosed !ra&esF; elderlytreated to pre&ent atrial fibr and bone loss

o $PO ab – autoimmuneo Lo, urinary iodine le&els 728u!1LF – d' of iodine

def

• $'= odine replacement

!onto2ic Multinodular *oiter

• ommon in ,omen; increase pre&alence ,ith a!e

• %yperplastic response to locally produced !f and

cytokines

• Asymptomatic) euthyroid

• Lead to compressi&e symptoms tracheal and &enous

con!estion= respi distress) plethora

• 3udden pain – hemorrha!e in nodule

• #'= architecture distorted= &aryin! si


12/27

alcitonin- Medullary $

• P$ – most common type of thyroid ca; ,ell- differentiated

• 5ollicular – common in iodine deficient re!ions; D#

• $hyroid lymphoma – arise in back!round of %ashimotos

• M$ – MEN syndrome

• $'= 3ur!ery) $3% suppression

407 Disorders of Adrenal .orte2a/ 4 hormones= !luco cortisolF) mineralo aldosteroneF)

andro!en #%EA3F

b/ anatomy• @-(( !rams

• abo&e the kidneys

• ori!inate in uro!enital rid!e and separate from !inads

and kidneys by @th AO+c/ re!ulatory control of steroido!enesis

!luco and andro!ens – %PA

mineralo – 6AA3 system

hypothalamus produce 6% in response to stress

A$% – released by cortcotrope cells of pituitary;

pi&otal re!ulator of cortisol synthesis; released inpulsatile fashion that follo,s a circadian rhythmsuprachiasmatic nucleusF; rise in am prior toa,akenin! and lo, le&els in the e&enin!

+lucocorticoid e'cess – dia!nosed by de'amethsanesuppression test; de'a – synthetic !lucocorticoid thatsuppress 6% and A$% by bindin! to !luco rctherefore do,nre!ulation of cortisol synthesis

#e'amethasone test

o Establish ushin!s"s and dd' of cortisol

e'cesso AutonomousAdrenal noduleF – A$% is

already supressedl de' little effecto A$% producin! pituitary adenoma – de'a

ineffecti&e in lo, doses but inducesuppression at hi!h doses

o Ectopic source – resistant to de'a

suppression

A$% stimulationo 5irst line test

o Assess !lucocorticoid deficiency

o Administer cosyntropin 8/*2 m! 91m)

collect bld samples at 8)48) @8 min forcortisol N= ?*8u!1dl 48-@8 min after admin

nsulin tolerance test $$F

o Alternati&e

o nect insulin to induce hypo!lycemia

stron! si!nal that tri!!ers hypothalamicrelease and acti&ation of entire %PA a'is;admin re! insulin 8/(./l! 9 : collect bldsamples at 8) 48) @8 (*8 mins for !lucose)

cortisol and +%; then after pt achie&edsymptomatic hypo!ly !lucose 708m!1dlF!i&e oral or 9 !lucose; N= cortisol ?*8u!1dland +% ?2/(u!1L

o = A#) 9#7 sei


13/27

?*8G at 02-28min after6% (88u! 9

• %i!h dose #EH test

cortisol suppression?28G after C@h * m! #EHfor * days

o ushin!s dse=

6% test andhi!h dose de' F transphenoidal

s'o Ectopic A$%

prod= 6% testand hi!h dose#E' ne!ati&e do inferioirpetrosal sinussamplin!petrosal1peripher al A$% ratio ?*at baselin) ?4 at*-2 min after6% (88u! 9

f

positi&e=

transpehnoidal s'

f

ne!ati&e=bilateraladrenalectomy

3uppressed 72 p!1ml A$%

independent

• #o $

o f bilateral

micro1macronodular adrenal

hyperplasia orunilateral adrenalmass adrenalectomy

h/ $reatment=

• 3ee abo&e

• Oral a!ents=

o Metyrapone – inhibits cortisol synthesis at the

le&el of B-hydro'ylase; 288m!$# to @!o etocona28pmol1L and

aldosterone ?pmol1Lo onfirmation

3aline infusion test *L saline o&er 0hr

9F 3odium loadin!

5ludrocortisone suppression

o $ adrenals

.nilat adrenal mass=

• 708yo – adrenalectomy

• ?08yo – do adrenal &ein

samplin!o if positi&e=

adrenalectomyo if ne!ati&e= M6

anta!onists) amiloride Bilateral adrenal mass - #ru! t'

Normal adrenal morpholo!y

• 5amily h' of early onset hpn

• 3creen for +6%

o f positi&e= #e'a

8/(*2-8/2m!1d

• Medical t' prior sur!ery= 3pirinolactone or more selecti&eepleronone mineralocorticoid rc anta!onist= (*/2 to 28m!bid up to 088m!1d to a&oid postsur!icalhypoaldosteronism control bp and normali


14/27

secondary A – only !lucocorticoid is deficient bec/

Adrenals intact 6AA3 ,orks

Adrenal andro!en – disrupted by both primary and

secondary %P dses – additional manifetsations in thyroid) !onadsm

+%) and prolactin) &isual impaitment E'o!enous !lucocorticoids abruptly stopped= cushin!oid

hronic adrenal insufficiency – nonspecific s1' fati!ue;

distin!uishin! feature= hyperpi!mentation in skin e'posedto increased friction or stress

3econdary A – alabaster-like palness due to lack of A$%secretion

%ypnatremia – char/ Biochemical feature in primary A

due to mineralo def primaryF and diminished inhibition of A#% release by cortisol lead to 3A#% secondaryF

%yperkalemia – 08G

Acute adrenal insufficiency – prolon!ed pd of nonspecific

complaints obser&ed in primary A due to loss of both+:M secretion/

auses of Primary Adrenal nsufficiency=

o Autoimmune poly!landular syndrome AP3( :

*Fo Autoimmune adrenalitis

o A%

o

Adrenoleukodystrophyo #ru! induced= mitotanem ketoconaO%P

o Adrenal $

f F= adrenal infection $BF

nfiltration lymphomaF

%emorr!ae

A% (>O%P incF

f -F= Autoimmune adrenalitis

Adrenoleukodystrophy

men) 9L5A incF 3econdary A lo,-normal A$%)

normal renin) normal aldosteroneF

+lucocorticoid replacement

o M6 pituitary

f positi&e= %P mas

lesion f ne!= h' of

e'o!enous!lucocorticoid t')trauma) considerisolated A$% def

• Acute A – reCuires immediate rehydration by saline

infusion at (L/hr ,ith continuous cardiac monitorin!; +replacement (88 m! hydrocort bolus; M replacementinitiated once hydrocort dose reduced to 728m! bec

hi!her doses of hydocort stimulates M rc• +lucocorticoid 6eplacement – t' of chronic A; (2-*2m!

hydrocort; prednisone and de'a lon! actin!; notpreferred bec they result in inc !luco e'posure

• 3tress rt dose adustment in + replacement

• Mineralocorticoid replacement= for primary A initiated at

(88-(28u! fludrocortisone; measure BP for adeCuacy oft'; serum renin and electrolytes measured re!ularly; reninnot used as monitorin! tool in pre!nancy bec ofphysiolo!ic rise

• Adrenal andro!en replacement= for ,omen ,ith features

of Andro!en def= once daily admin of *2-28m! #%EA)measured by #%EA3) androstenedione) and testosteroneshb! *0 hr after the last #%EA dose

.ongenital Adrenal Hyperplasia

• Measured by the steroids accumulatin! before the distinct

enO%P – useful marker for o&ert'

o M replacement= renin- re!ularly monitorer

40 Pheocromocytoma

• atecholamine producin! tumors deri&ed from 3N3 and

P3N3 restricted at the adrenals

• Mean a!e of d'= 08yo

• lassic rules of ten= (8G bilateral) e'tra-adrenal and

mali!nant

• Etiolo!y=


15/27

o Pheochromyctoma= reflects black colored

stainin! caused by chromaffic o'idation ofcatecholamines

o Para!an!lioma= catecholamine producin! tumors

in the skull base and neck tumors to all othersitesF

• linical 5eatures= the !reat masCuerader

o Palpitations) headache) profuse s,eatin!

classic triad hpn likely dia!nosis

o May be asymptomatic for years

o #ominant si!n= %PN

episodic1sustainedo atecholamine crisis – lead to %5) PE) arythmias)

and intracranial hemorrha!eo %ormone release di&er!ent inter&als= an'ious)

plae) tachycar) palpitations

• #'=

o Biochemical testin!

atecholamines= epi) NE) dopamine

El&ated plasma and urinary

catecholamines and metanephrinesleak of O-methylated metabolitesF–cornerstone of d'

.rinary test for metanephrines and

cathecholamines – ,idely a&ailable and

used for initial e&aluation 6efractionated metanephrines :

catecholamines – most sensiti&e Plasma metanephrines – most sensiti&e

and less susceptible to false positi&eelea&tions from stress

E'clude dru! rt factors= ,ithdra,al of

le&odopa) sympathomimemtics)diuretics) $A) alpha and beta blockers

6pt test or clonidine suppression test –

measurement of plasmanormetnephrine 4 hr after oral admin of488u! clonidine

o ma!in!=

$* ,ei!hted M6 ,ith !adolinium –

optimal for detectin!pheocrhomocytomas

MB+ scinti!raphy) 5#+ PE$ – selecti&e

uptake for para!an!liomas ,ithhereditary syndromes

• $reatment=

o omplete tumor remo&al – ultimate therapeutic

!oalo Preop= Bp must be belo, (@81J8mmh+

o ntraop= Nitroprusside intraophyppertensi&e

crisiso Laparoscopy and retroperistoneoscopy –

standard approach in pheochromocytoma s'o Adrenocorticotropic hormone test – ne'clude

cortisol def ,hen bilateral adrenal corte' sparin!s'

• Mali!nant pheochromycytoma – restricted to tumors ,ith

distant mets lun!s) bones) li&erF

• n pre!anancy – remo&ed by 0-@th month of !estation

• Associated syndromes=

o Neurofibromatosis type ( N5(F – multiple

neurofibromas) cafT au lait spots) a'illaryfrecklin! of the skin) Lisch nodules of iris

o MEN type * – best kno,n pheocrhomocytoma

associated syndrome Men*A – M$) pheo)

hyperparathyroidism

Men*B – M$) pheo) mucosal

neuromas) marfanoid habitus) lackshyperpara

o 9on %ippel Lindau syndrome 9%LF – predispose

to retinal and cerebellar hamn!ioblastomas inbrainstem and 3

41 Diaetes Mellitusa/

Normal+lucose

$olerance

+$ #Mriteria for

#'F

6andomblood !lucoseconcentratiion

3ymptomsof #M *88m!1dl

5P+ 7(88 m!1dl (88-(*2m!1dl

?(*@m!1dl

*-h O+$$ 7(08 m!1dl ?(08-(JJm!1dl

?*88m!1dl

%bA( 72/@ 2/>U@/0 ?@/2

b/ $ypes

• $ype ( complete or near total insulin deficiency1 beta cell

destruction; commonly de&elops before the a!e of 48 butany a!e

• $ype * insulin resistance) impaired insulin secretion)increased !lucose tolerance; preceded by impaired fastin!tolerance

• +estational #M – !lucose intolerance durin! pre!anancyl;

re&ert to normal postpartum but ha&e substantial risk inthe ne't (8-*8 yrs

• Other causes=

o Maturity onset diabetes of the youn! and

mono!enic diabetes – early onset of hyper!ly7*2yo and impaired insulin secretion

o Pancreatic e'ocrine dse) 5

o Endocrinopathies= acrome!aly) ushin!s

o 5ulminant diabetes – rt to &irla infections of islets

• $ype * #M – risin! rapidly due to obesity and reduced

acti&ity le&els• Epidemiolo!y

o hina – hi!hest pre&alence of #M

o 3candina&ia – hi!hest $ype (

o Pacific slands and ME

• 5P+ and %bA( – screenin! test for $ype * #M

recommended

• A#A recommends=

o 3creenin! all indi&iduals ?02yo e&ry 4 hrs

o 3creenin! at early a!e if o&er,ei!ht BM?*2 and

ha&e additional risk factor for #Mo 6isk 5actors=

5amily h'

Obesity

Physical inacti&ity

6ace1ethnicity

%' of +#M and deli&ery of ?0k! baby

%PN

%#L chole 742 and tri!ly? *28m!1dl

PO3

%' of 9#

• +lucose homeostasis – balance bet,een hepatic !lucose

production and peripheral !lucose uptake and utili


16/27

• +luca!on – secreted by pancreatic alpha cells) stimulates

!lyco!enolysis and !luconeo!enesis

• 3kelteal ms –maor portion of postprandial !lucose

• Brain – insulin-independent fashion

• nsulin= produced by beta cells; pro-insulin

• 9-peptide – cleared more slo,ly than insulin; useful

marker of insulin secretion and allo,s discrimination ofendo!enous and e'o!enous sources of insulin

• +lucose – key re!ulator of insulin secretion

• +lucose le&els >8m!1dl stimulate insulin synthesis

• ncretins – released from neuroendocrine cells of the +tract follo,ed by food in!estion and amplify !lucosestimulated insulin secretion and suppress !luca!onsecretion

• +LP( – most potent incretin release from L cells of 3)

stimulates insulin secretion only ,hen bld !lucose le&el isabo&e the fastin! le&els

%ype $ DM mmune beta cell destruction

ommon before the a!e of *8yo

Nonimmune mechanism – ketosis prone

Many African American and Asian

$emporal ourse=

o Dith !enetic predisposition tri!!ered by

infection initiates autoimmune process !radual decline in beta cell mass

o Pro!ressi&e impairment in insulin release ,hen

8G of the beta cell mass destroyedo %oneymoon phase – first (-* yrs after onset of

diabetes and insulin reCts Pathophysiolo!y

o Other islet cell types= spared from autoimmune

destruction Apha cells – !luca!on

#elta – somatostatin

PP cells – pancreatic polypeptide

producin!o Pancreatic islets ha&e infiltration of lymphocytes

insulitisF beta cells destroyed isletsbecome atrophic

En&ironmental 5actors

o $ri!!ers of autoimmune process= &iral co'sackie)

rubella) entero&irusF) bo&ine milk %ON)nitrosourea

%ype DM nsulin resistance and abnormal insulin secretion

Latinos – !reater insulin resistance

East Asians and 3outh Asians – more beta cell

dysfunction etosis prone – obese

etosis resistant – lean

3tron! !enetic component

haracteri


17/27

not ha&e absolute insulin def but ha&eautoimmune markers +A#) AFsu!!esti&e of $ype (

Lab Assessment= dia!nostic criteria and de!ree of

!lycemic controlDiaetes Managemento O&erall !oals

Eliminate symptoms of hyper!ly

6educe lon! term micro1macro&ascular complications

Normal lifestyle

o

3ymptoms resol&e ,hen plas)a !lucose is 7*88m!1dlo omprehensi&e diabetes care

Optimal and indi&iduali


18/27

Osmolality 488-4*8 448-48

etones 1-

Bicarb 7(2 Normal to sli!htlydec

Arterial p% @/->-4 ?>/4

Pco* *8-48 Normal

Anion !ap nc Normal -sli!htly inc

Diaetic =etoacidosisa/ 3ymptoms= n/&) thirst) polyuria) abd pain resemble

acute pancreatitis1ruptured &iscus) 3OB

b/ Physical 5indin!s= tachycardia) dehydration) hypotensiondue to &ol depletion) kaussmaul"s respiration and fruityodor breath *" to met acidosis and inc acetone classicsi!nsF) lethar!y) coma) cerebral edema maornonmetabolic1 serious complication of #A common inchildren

c/ Precipitatin! e&ents= inadeCuate insulin admin) infectionpneumonia) .$) A+E) sepsisF) infarction) cocaine)pre!nancyF

d/ Pathophysiolo!y=

• both insulin deficiency and !luca!on e'cess necesary

for #A to de&elop

• dec ratio of insulin to !luca!on ratio promotes

!luconeo!enesis) !lyco!enolysis) and ketone bodyformation in the li&er

• cytokines and -reacti&e protein – markers if inflamincreased

• ketosis results form marked inc in free fatty acid

release from adipocytes

• hyper!luco!onemia alters hepatic metab to fa&or

ketone body formation thru acti&ation of carnitinepalmitoyltransferase – an en


19/27

near optic ner&e/macula &ietrous hemorrha!e)fibrosis) and retinal detachment

• Macular edema – fluorescein an!io!raphy and optical

coherence tomo!raphy detect

• $'=

o most effecti&e therapy= pre&ention

o !lycemic control and BP control

o Laser –preser&e &ison

Panretinal – proliferati&e retinopathy

5ocal – macular edema

'enal .omplications of DM

#M nephropathy= leadin! cause of #) E36#

6t to chronic hyper!lycemia

Effects of soluble !ro,th factors +5) an!iotensin )

endothelin; !lomerular hyperfiltrration1hyperperfusion)increase !lomerular capillary pressure

3rtuctural chan!es in !lomerulus= inc EM) BM

thickeinin!) mesan!ial e'pansion) fibrosis

3mokin! – accelerates declin in renal f'n

ourse

o (st yrs= !lomerular hyperperfusion and renal

hypertrophy; inc +56;o (st 2 yrs= thickenin! of BM) !lomerular

hypertrophy) masan!ial &ol e'pansiono 2-(8 yrs= albuminuria= microalbumineria – 48-

*JJm!1dl in *0 hr collection or creatine sptcollection; macroalbuminuria ?488m!1*0h

o Macroalbuminuria E36#

Annual microalbuminuria measurement= albumin to

creatinine ratio in spot urine

$'=

o impro&ed !lycemic control) strict BP control and

AE inhibitor or A6N3o hemodialysis – freCuent complications=

hypotension) difficult &ascular access) andpro!ression to retinopathy

o renal transplant – preferred byt reCuires chronic

immunosuppressiono combined pancreas-kidney transplant –

nomo!lycemia and freedom from diabetes!europathy

due to chronic hyper!lycemia

6isk factors= BM) smokin!) 9#) and inc tri!ly

Polyneuropathy= most common form is distal symmetric

polyneuropathy freCuently ,ith distal sensory loss andpain; senstation of numbness) tin!lin! sensation) andsharpness) burnin! pain; neuropathic pain= lo,ere'tremities present at rest and ,orsens at ni!ht; PE=sensory loss) loss of #$6) abnormal position sense

#iabetic polyradiculopathy- se&ere disablin! pain in the

distribution of one or more ner&e roots; intercostal1truncal pain thora' or abdomen; femoral1lumbr ner&e hipand thi!h pain; assoc ,ith diabetic amyotrophy – muscle,eakness in hip fle'ors and e'tensors

Monneuropathy – dysfunction of isolated cranial or

peripheral ner&e; pain and ,eakness in sin!le ner&e;occur at entrapment sites carpal tunnel syndrome; thirdcranial ner&e -? diplopia

Autonomic neuropathy

o 9= restin! tachycardia and orthostatic

hypotensiono +astroparesis and bladder emptyin!

abnormalitieso %yperhidrosis of upper e' and anhidrosis of lo,er

e'n dry crackin! feet ulcerationo %ypo!lycemia una,areness

$'=

o A&oid neuroto'ins

o 9it B supplementations

o heck feet daily; foot,ear precautions

o Painful diabetic neuropathy= dulo'etine :

pre!abalin*A(%'#$!%E(%$!A-8*E!$%#&'$!A'" D"()&!.%$#!

• #elayed !astric emptyin! !astroparesisF) - anore'ia) n1&)

early satiety) and abdominal bloatin! altered + motilitydiarrhea : constipationF $'= small freCuent meals) lo, fat: fiber

• ystopathy – inability to sense full bladder and failure to

&oid completely urinary hesistancy) dec &oidin! freC)incontinence) .$; $'= schedule &oidin! or self-catheteri


20/27

• Necrobiosis lipodica diabeticurom – youn! ,omen;

etythematous plaCue that !radually de&elops irre!ularmar!ins,ith atrophic centers and central ulceration

• 9itili!o – type ( #M

• Acanthosis ni!ricans – hyperpi!mented &el&ety plaCues

seen on neck) a'illa) or e'tensor surfaces

• +ranuloma annulare – erythematous plaCues on e'tr and

trunk

• 3lecroderma -8 skin thickenin! of back or neck at site of

pre& superficial infections

• Lipoatrophy/hypertrophy – - insulin inection sites

40 Hypoglycemia

• M= dru!s to treat #M) e'posure to alcohol

• Dhipple"s $riad= (F symptoms consistent ,ith

hypo!lycemia) *F a lo, plasma !lucose concentrationmeasured ,ith a precise method not a !lucose moni-torF)and 4F relief of symptoms after the plasma !lucose le&elis raised/

• #ecrease in insulin secretion is the f irst defense a!ainst

hypo!lycemia/

• +uca!on is the second defense a!ainst hypo!lycemia/

• Epinephrine is the third defense a!ainst hypo!lycemia/

• ortisol and !ro,th hormone play no role in defense

a!ainst acute hypo!lycemia/• 3hift to hi!her-than- normal !lucose le&els in people ,ith

poorly controlled diabetes) ,ho can e'perience symptomsof hypo!lycemia ,hen their !lucose le&els decline to,ardthe normal ran!e pseudohypo!lycemiaF/ On the otherhand) thresholds shift to lo,er-than-normal !lucose le&elsin people ,ith recurrent hypo!lycemia

• 3i!ns : 3ypmtoms

o Neuro!lycopenic manifestation - beha&ioral

chan!es) confusion) fati!ue) sei


21/27

6isk 5actors

• O&er,ei!ht1Obesity - central adiposity is a key feature of

the syndrome

• 3edentary lifestyle - Physical inacti&ity is a predictor of

9# e&ents and the related risk of death/

• A!in! - lder than a!e 28) and at ?@8 years of a!e ,omen

are more often affected than men/ $

• #M - eat maority I>2GF of patients ,ith type * diabetes

or impaired !lucose tolerance ha&e the metabolicsyndrome/

• 9# - ndi&iduals ,ith the metabolic syndrome are t,ice

as likely to die of cardio&ascular disease as those ,ho donot) and their risk of an acute myocardial infarction orstroke is three- fold hi!her/

• Lipodystrophy

Etiolo!y

• nsulin 6esistance

o most accepted and unifyin! hypothesis to

describe the pathophysiolo!y of the metabolicsyndrome is insulin resistance)

o An early maor contributor to the de&elopment of insulin

resistance is an o&erabundance of circulatin! fatty acido inhibition of lipolysis in adipose tissue is the most sensiti&e

path,ay of insulin action/o Leptin resistance - reduces appetite) promotes ener!y

e'penditure) and enhances insulin sensiti&ity/• ncreased Daist ircumference

o D – most freCuently applied dia!nostic criteria

• #ylipidemia

o %ypertri!lyceredemia - e'cellent marker of the

insulin-resistant condition/o reduction in %#L cholesterol/

• Adiponectins

• Proinflammatory cytokines

• linical 5eatures

o Not assoc ,ith s1s'

o ,aist circumference may be e'panded and blood

pressure ele&ated/

o lipoatrophy or acanthosis ni!ricans

• Associated #ses= 9#) $ype * #M

• Associated ondition= NA5L#) PO3) O3A)

%yperuricemia

• O3A - associated ,ith obesity) hypertension) increased

circulatin! cytokines) impaired !lucose tolerance) andinsulin resistance; ontinuous positi&e air,ay pressuretreatment

#ru!s MOA 3amplesuffi'

Ad&anta!e 13E

Bi!uanides

6educe hepatic !luc prodand impro&es peripheral!lucose utili


22/27

ues

+LP-( rca!onists

Enhance +LP( rc si!nalin! E'anatide-tideF

No hypo!lync insulin secretion)suppress !luca!on) slo,!astric emptyin!

Nausea6enal dseM$

A-!lucosidase inhibitors

6educe postprandialhyper!lycemia by delayin!!lucose absoption

#iarrhea) flatulence) abdominaldistention

A&oid simultaneous admin ,ithbile acid resins and abtacidsi ,ith B#) !astroparesis) orserum crea ?*m!1d

$hia


23/27

function/

• Estradiol - decrease osteoclast number and decrease

bone resorption/

• remodelin! and replacin! pre&iously calcified cartila!e

endochondral bone formationF or) in a fe, bones) isformed ,ithout a cartila!e matri' intramembranous boneformationF/

• Ne, bone) relati&ely hi!h ratio of cells to matri' and is

characteri


24/27

• n patients in ,hom (\-hydro'ylation is impaired)

metabolites that do not reCuire this acti&ation step are thetreatment of choice/ $hey include ()*2O%F

*#

4calcitriol

Z6ocaltrol[) 8/*2–8/2 ]!1dF and (\-hydro'y&itamin #*

%ectorol) */2–2 ]!1dF/ f the path,ay reCuired foracti&ation of &itamin # is intact) se&ere &itamin #deficiency can be treated ,ith pharmacolo!ic repletioninitially 28)888 . ,eekly for 4–(* ,eeksF) follo,ed bymaintenance therapy 88 . dailyF/ Pharmacolo!ic dosesmay be reCuired for maintenance therapy in patients ,ho

are takin! medications) such as barbiturates or phenytoin)that accelerate metabolism of or cause resistance to()*2O%F

*#

44 Disorders of Parathyroid *land and .alciumHomeostasis

• parathyroid hormone P$%F) ,hich is the primary re!ulator

of calcium physiolo!y

• P$% acts directly on bone) ,here it induces calcium

release; on the kidney) ,here it enhances calciumreabsorption in the distal tubules; and in the pro'imal renaltubules) ,here it synthesi–0/2

mmol1L (0/–(/8 m!1dLF) can be a medical emer!ency;coma and cardiac arrest can occur/

Primary Hyperparathyroidism

• !enerali


25/27

thyroid) as ,ell as hyperparathyroidism; MEN *B hasadditional associated features such as multiple neuromasbut usually lacks hyperparathyroidism/

• hyperparathyroidism a, tumor %P$-R$F syndrome occurs

in families ,ith parathyroid tumors sometimescarcinomasF in association ,ith beni!n a, tumors/

• Adenomas are most often located in the inferior parathy-

roid !lands)

• alcium &alues of 4/2–4/> mmol1L (0–(2 m!1dLF are

freCuent ,ith carcinoma and may alert the sur!eon to

remo&e the abnormal !land ,ith care to a&oid capsularrupture; parathyroid carcinoma is often not a!!ressi&e/

• Many patients ,ith hyperparathyroidism are

asymptomatic/ Manifestations of hyperparathyroidismin&ol&e primarily the kidneys and the skeletal system

• 6enal stones are usually composed of either calcium

o'alate or calcium phosphate/ n occasional patients)repeated episodes of neph- rolithiasis or the formation oflar!e calculi may lead to urinary tract obstruction)infection) and loss of renal function/ Nephrocalcinosis mayalso cause decreased renal function and phosphateretention/

• distincti&e bone manifestation of hyperparathyroidism is

osteitis fibrosa cystica) %o,ship"s lacunaeF

• #ual-ener!y '-ray absorptiometry #EHAF of the spine

pro&ides reproducible Cuantitati&e estimates ,ithin a fe,percentF of spinal bone density/ 3imilarly) bone density inthe e'tremities can be Cuanti- fied by densitometry of thehip or of the distal radius at a site chosen to be primarilycortical/

• Asymptomatic primary hyperparathyroidism is defined as

biochemi- cally confirmed hyperparathyroidism ele&atedor inappropriately normal P$% le&els despitehypercalcemiaF ,ith the absence of si!ns and symptomstypically associated ,ith more se&ere hyperparathy-roidism such as features of renal or bone disease/

• 3ur!ical e'cision of the abnormal parathyroid tissue is the

defini- ti&e therapy for this disease/

• $he hypercalcemia is dependent on continued lithium

treatment) remittin! and recurrin! ,hen lithium is stoppedand restarted/

• 5amilial %ypocalcemic %ypercalcemia- the primary defect

is abnormal sensin! of the blood calcium by the

parathyroid !land and renal tubule) causin! inappropriatesecretion of P$% and e'cessi&e reabsorption of calcium inthe distal renal tubules/

• $reatment of the hypercalcemia of mali!nancy is first

directed to control of tumor;

• P$%rP is the responsible humoral a!ent in most solid

tumors that cause hypercalcemia/

• many patients ,ith sCuamous cell carcinoma of the lun!

de&elop hypercalcemia/

• linical suspicion that mali!nancy is the cause of the

hypercalcemia is hei!htened ,hen there are other si!ns or symptoms of a para- neoplastic process such as ,ei!htloss) fati!ue) muscle ,eakness) or une'plained skin rash)or ,hen symptoms specific for a particular tumor are

present/ 3Cuamous cell tumors are most freCuently asso-ciated ,ith hypercalcemia) particularly tumors of the lun!)kidney) head and neck) and uro!enital tract/

• n patients ,ith sarcoid- osis and other !ranulomatous

diseases) such as tuberculosis and fun!al infections)e'cess ()*2O%F

*# is synthesi mmol1L Z(4–(2 m!1dL[F must be mana!eda!!ressi&ely; abo&e that le&el) hypercalcemia


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endocrine notes (harrisons)

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