¡Descarga RESUMEN ENDOCRINOLOGÍA STEPS y más Guías, Proyectos, Investigaciones en PDF de Endocrinología solo en Docsity!
`
ENDOCRINE
`
ENDOCRINE
EMBRYOLOGY
SEC TION III
`
ENDOCRINE
EMBRYOLOGY
Thyroid development^ A
Thyroid diverticulum arises from floor of primitive pharynx and descends into neck. Connected to
tongue by thyroglossal duct, which normally disappears but may persist as cysts or the pyramidallobe of thyroid. Foramen cecum is normal remnant of thyroglossal duct. Most common ectopic thyroid tissue site is the tongue (lingual thyroid). Removal may result in
hypothyroidism if it is the only thyroid tissue present. Thyroglossal duct cyst
A
presents as an anterior midline neck mass that moves with swallowing
or protrusion of the tongue (vs persistent cervical sinus leading to pharyngeal cleft cyst in lateralneck). Thyroid follicular cells
B
derived from endoderm.
Parafollicular cells arise from 4th pharyngeal pouch.
Foramen cecum
Internal carotid arteryExternal carotid arterySuperior thyroid artery
Hyoid bone
Thyrohyoid membrane
Thyroglossal ductThyroid cartilage
Thyroid Trachea
Brachiocephalic artery
Inferior thyroid artery Thyrocervical trunkLeft subclavian artery
B
ENDOCRINE
`
ENDOCRINE
ANATOMY
`
SEC TION III
`
ENDOCRINE
ANATOMY
Pituitary gland
A
nterior pituitary(a
denohypophysis)
Secretes FSH, LH, ACTH, TSH, prolactin,
GH, and
β
-endorphin. Melanotropin (MSH)
secreted from intermediate lobe of pituitary.Derived from oral ectoderm (Rathke pouch).
α
subunit—hormone subunit common to TSH, LH, FSH, and hCG.
β
subunit—determines hormone specificity.
Pro
opiomelanocortin derivatives—
β
-endorphin,
A
CTH, and
M
SH. Go
pro
with a
BAM
FLAT P
e
G
F
SH,
L
H,
A
CTH,
T
SH,
P
RL,
G
H.
B
- FLAT
:^
B
asophils—
F
SH,
L
H,
A
CTH,
T
SH.
Acid P
i
G
Acid
ophils —
P
RL,
G
H.
Posterior pituitary
neuro
hypophysis)
Stores and releases vasopressin (antidiuretic
hormone, or ADH) and oxytocin, bothmade in the hypothalamus (supraoptic andparaventricular nuclei) and transported toposterior pituitary via neurophysins (carrierproteins). Derived from
neuro
ectoderm.
Adrenal cortex andmedulla
Adrenal cortex (derived from mesoderm) and medulla (derived from neural crest).
Zona
G
lomerulosa
ANATOMY
Preganglionic sympathetic fibers
Epi, NE
CORTEX MEDULLA
Zona
R
eticularis
Zona
F
asciculata
ACTH, CRH Angiotensin II
Cortisol Aldosterone
ACTH, CRH
DHEA
1 ˚
REGULATION BY
Glucocorticoids Catecholamines
HORMONE Androgens
CLASS
1 ˚^ HORMONE PRODUCED
HISTOLOGY
Superior surface
of kidney
Adrenal gland
Capsule
Mineralocorticoids
Chromaffin cells
GFR
corresponds with
s alt (mineralocorticoids),
s ugar (glucocorticoids), and
s ex (androgens).
Endocrine pancreascell types
Islets of Langerhans are collections of
α
β
, and
δ
endocrine cells. Islets arise from pancreatic buds. α
= gluc
α
gon (peripheral)
β
= insulin (central) δ
= somatostatin (interspersed)
Capillary
α
cell β
cell δ
cell
`
ENDOCRINE
`
ENDOCRINE
PHYSIOLOGY
SEC TION III
`
ENDOCRINE
PHYSIOLOGY
Hypothalamic-pituitary hormones
HORMONE
FUNCTION
CLINICAL NOTES
ADH
q
water permeability of distal convoluted tubuleand collecting duct cells in kidney to
q
water
reabsorption
Alcohol consumption
p r
ADH secretion
p
polyuria and dehydration
CRH
q
ACTH,
q
MSH,
q
β
-endorphin
r
in chronic glucocorticoid use
Dopamine
r
prolactin,
r
TSH
Also called prolactin-inhibiting factorDopamine antagonists (eg, antipsychotics) can
cause galactorrhea due to hyperprolactinemia
GHRH
q
GH
Analog (tesamorelin) used to treat
HIV-associated lipodystrophy
GnRH
q
FSH,
q
LH
Suppressed by hyperprolactinemiaTonic GnRH analog (eg, leuprolide) suppresses
hypothalamic–pituitary–gonadal axis. Pulsatile GnRH leads to puberty, fertility
MSH
q
melanogenesis by melanocytes
Causes hyperpigmentation in Cushing disease,
as MSH and ACTH share the same precursormolecule, proopiomelanocortin
Oxytocin
Causes uterine contractions during labor.Responsible for milk letdown reflex in response
to suckling.
Modulates fear, anxiety, social bonding, mood,
and depression
Prolactin
r
GnRH Stimulates lactogenesis.
Pituitary prolactinoma
p
amenorrhea,
osteoporosis, hypogonadism, galactorrhea Breastfeeding
p q
prolactin
p r
GnRH
p
delayed postpartum ovulation (natural contraception)
Somatostatin
r
GH,
r
TSH
Also called growth hormone inhibiting hormone
(GHIH)
TRH
q
TSH,
q
prolactin
q
TRH (eg, in 1°/2° hypothyroidism) mayincrease prolactin secretion
p
galactorrhea
HypothalamusAnteriorpituitary
CRH
GnRH
TRH
Somatostatin
GHRH
DA
ACTH
Basophils (basophilic)
Acidophils (eosinophilic)
LH
FSH
TSH
GH
Prolactin
ENDOCRINE
`
ENDOCRINE
PHYSIOLOGY
`
SEC TION III
Growth hormone^ Sleep, hypoglycemia, stress,
puberty, exercise
Growthhormone IGF-
Anteriorpituitary
Posteriorpituitary
Somatostatin
Amino acid uptakeProtein synthesis
Amino acid uptakeProtein synthesis
Glucose uptakeLipolysis
DNA and RNA synthesisChondroitin sulfateCollagenCell size and number
Aging, obesity,hyperglycemia
GHRH
Also called somatotropin. Secreted by anterior
pituitary. Stimulates linear growth and muscle mass
through IGF-1 (somatomedin C) secretion byliver.
q
insulin resistance (diabetogenic).
Released in pulses in response to growth
hormone–releasing hormone (GHRH). Secretion
q
during sleep, hypoglycemia, stress,
puberty, exercise. Secretion
r
with aging, obesity, hyperglycemia,
somatostatin, somatomedin (regulatorymolecule secreted by liver in response to GHacting on target tissues). Excess secretion of GH (eg, pituitary adenoma)
may cause acromegaly (adults) or gigantism(children). Treatment: somatostatin analogs(eg, octreotide) or surgery.
Antidiuretic hormone
Also called vasopressin.
SOURCE
Synthesized in hypothalamus (supraoptic and
paraventricular nuclei), stored and secreted byposterior pituitary.
FUNCTION
Regulates b
ood pressure (V
1 -receptors) and
serum osmo
l a
l ity (V
2
-receptors). Primary
function is serum osmolality regulation (ADH r
serum osmolality,
q
urine osmolality) via
regulation of aquaporin channel insertion inprincipal cells of renal collecting duct.
ADH level is
r
in central diabetes insipidus (DI),
normal or
q
in nephrogenic DI.
Desmopressin (ADH analog) is a treatment for
central DI and nocturnal enuresis. Vasopress
in is a potent
vasopress
or that can be
used to increase organ perfusion in septic shock.
REGULATION
Plasma osmolality (1°); hypovolemia.
ADH
ADH serum osmolality
serum osmolality
serum volume
serum volume
Posteriorpituitary(storage)
Medullary collecting duct
Aquaporin channels
urine osmolality^ urine volume
Hypothalamus
`
ENDOCRINE
`
ENDOCRINE
PHYSIOLOGY
SEC TION III
Parathyroid hormone
SOURCE
Chief cells of parathyroid
FUNCTION
q
free Ca
2+
in the blood (1° function)
q
Ca
2+
and PO
4 3–
absorption in GI system
q
Ca
2+
and PO
4 3–
from bone resorption
q
Ca
2+
reabsorption from DCT
r
PO
4
3–
reabsorption in PCT
q
1,25-(OH)
2
D
3
(calci
tri
ol) production by
activating 1
α
-hydroxylase in
PCT
tri
to make
D
3
in the
PCT
PTH
q
serum Ca
2+
r
serum PO
4 3–
q
urine
PO
4 3–
q
urine cAMP
q
RANK-L (receptor activator of NF-
κ
B ligand)
secreted by osteoblasts and osteocytes; bindsRANK (receptor) on osteoclasts and theirprecursors to stimulate osteoclasts and
q
Ca
2+
p
bone resorption (intermittent PTH release
can also stimulate bone formation) PTH
P
hosphate-
T
rashing
H
ormone
PTH-related peptide (PTHrP) functions
like PTH and is commonly increased inmalignancies (eg, squamous cell carcinoma ofthe lung, renal cell carcinoma)
REGULATION
r
serum Ca
2+
p q
PTH secretion
q
serum PO
4 3−
p q
PTH secretion
r
serum Mg
2+
p q
PTH secretion
rr
serum Mg
2+
p r
PTH secretion
Common causes of
r
Mg
2+
include diarrhea,
aminoglycosides, diuretics, alcohol usedisorder
Ca
2+
is the major regulator of PTH release
1,25-(OH)
2
D
3
Fourpara-thyroidglands
Feedbackinhibitionof PTHsynthesis
Vitamin D activity
PTH activity ↑ Ca
2+
and
PO
4 3–
↑
PO
3– 4
↑
PTH released into circulation
25-OH D
3
Bone
Intestines
1,25-(OH)
2 D
3
1
α
-hydroxylase
↑ Ca
2+
and
↑
PO
3– 4
↑
↓ ionized Ca
2+
,^ ↑ PO
3– 4
, or
1,25-(OH)
2 D
3
↑ Ca
2+
and
↑
PO
3– 4
released from bone
↑ absorption ofCa
2+
and PO
3– 4
Renal tubular cells
↑
1,25-(OH)
2
D synthesis
3
Urine
Ca
2+
,^ ↑
PO
3– 4
Reabsorption:
↑
Ca
2+
,^
PO
3– 4
↑
↑
↑
ENDOCRINE
`
ENDOCRINE
PHYSIOLOGY
`
SEC TION III
Calcium homeostasis
Plasma Ca
2+
exists in three forms:
Ionized/free (~ 45%, active form)
Bound to albumin (
Bound to anions (
Ionized/free Ca
2+
is 1° regulator of PTH;
changes in pH alter PTH secretion, whereaschanges in albumin concentration do not
Ca
2+
competes with H
to bind to albumin
q
pH (less H
p
albumin binds more
Ca
2+
p r
ionized Ca
2+
(eg, cramps, pain,
paresthesias, carpopedal spasm)
p
q
PTH
r
pH (more H
p
albumin binds less Ca
2+
p q
ionized Ca
2+
p
r
PTH
Calcitonin
SOURCE
Parafollicular cells (C cells) of thyroid.
Calcitonin opposes actions of PTH. Not
important in normal Ca
2+
homeostasis
Calcit
on
in t
on
es down serum Ca
2+
levels and
keeps it in b
on
es
FUNCTION
r
bone resorption.
REGULATION
q
serum Ca
2+
p q
calcitonin secretion.
Parafollicular cells(C cells) of thyroid
Peripheral blood
Ca
2+
Osteoclast
Calcitonin lowers serum Ca
2+
by inhibiting osteoclastic
bone resorption
Ca
2+ serum Ca
2+
calcitonin
Decreasedresorption
Ca
2+
Glucagon
SOURCE
Made by
α
cells of pancreas.
FUNCTION
Promotes glycogenolysis, gluconeogenesis, lipolysis, ketogenesis. Elevates blood sugar levels to
maintain homeostasis when bloodstream glucose levels fall too low (ie, fasting state).
REGULATION
Secreted in response to hypoglycemia. Inhibited by insulin, amylin, somatostatin, hyperglycemia.
`
ENDOCRINE
`
ENDOCRINE
PHYSIOLOGY
SEC TION III
Insulin
SYNTHESIS
S
S
Insulin
C-peptide
Proinsulin
Preproinsulin (synthesized in RER of pancreatic
β
cells)
p
cleavage of “presignal”
p
proinsulin
(stored in secretory granules)
p
cleavage of proinsulin
p
exocytosis of insulin and C-peptide
equally. Both insulin and C-peptide are
q
in endogenous insulin secretion (eg, type 2 DM, insulin
secretagogues, insulinoma), whereas exogenous insulin lacks C-peptide. Insulin is synthesized in pancreas and cleared by both liver and kidneys.
FUNCTION
Binds
in
sulin receptors (tyrosine kinase
activity
in
ducing glucose uptake (carrier-
mediated transport)
in
to insulin-dependent
tissue
and gene transcription.
Anabolic effects of insulin:
q
glucose transport in skeletal muscle and adipose tissue
q
glycogen synthesis and storage
q
triglyceride synthesis
q
Na
retention (kidneys)
q
protein synthesis (muscles)
q
cellular uptake of K
and amino acids
r
glucagon release
r
lipolysis in adipose tissue
Unlike glucose, insulin does not cross placenta.
In mothers with diabetes, excess glucose cancross placenta and
qq
fetal insulin.
Insulin-dependent glucose transporters:
GLUT4: adipose tissue, striated muscle(exercise can also
q
GLUT4 expression)
Insulin-independent transporters:
GLUT1: RBCs, brain, cornea, placenta
GLUT
bi
directional):
β
islet cells, liver,
kidney, GI tract (think
^2
-way street)
GLUT3: brain, placenta
GLUT
f ructose): spermatocytes, GI tract
SGLT1/SGLT2 (Na
-glucose cotransporters):
kidney, small intestine
Brain prefers glucose, but may use ketone bodies
during starvation. RBCs utilize only glucose, asthey lack mitochondria for aerobic metabolism. BRICK LIPS
(insulin-independent glucose
uptake):
B
rain,
R
BCs,
I
ntestine,
C
ornea,
K
idney,
L
iver,
I
slet (
β
) cells,
P
lacenta,
S
permatocytes.
REGULATION
Glucose is the major regulator of insulin release.
q
insulin response with oral vs IV glucose due
to incretins (eg, glucagonlike peptide 1 [GLP-1], glucose-dependent insulinotropic polypeptide[GIP]), which are released after meals and
q
β
cell sensitivity to glucose. Release
r
by
α
2
q
by
β
2
stimulation (
= regulates
in
sul
in
Glucose enters
β
cells
p q
ATP generated from glucose metabolism
closes K
channels (target
of sulfonylureas)
and depolarizes
β
cell membrane
. Voltage-gated Ca
2+
channels open
p
Ca
2+
influx
and stimulation of insulin exocytosis
ATP-sensitive K +^ channels close
K
Insulin
GLUT
Glycolysis^ Glucose
Exocytosisof insulingranules Depolarization
ATP/ADP ratio
IntracellularCa
2+
Glucose
ATP
Voltage-gatedCa
2+ channels open
GLUT
Glucose
InsulinInsulin Tyrosine phosphorylation
Vesicles containing
GLUT
Glycogen, lipid, protein
synthesis
Cell growth,
DNA synthesis
Insulin-dependent glucose uptake
Bloodvessel
Insulin secretion by pancreatic
cells
ENDOCRINE
`
ENDOCRINEPHYSIOLOGY
`
SEC TION III
Adrenal steroids and congenital adrenal hyperplasias
Cholesterol desmolase 21-hydroxylation 11 Aldosterone synthase
β
-hydroxylation
ZONA GLOMERULOSA Mineralocorticoids
ZONA FASCICULATA Glucocorticoids
Adrenal cortex
Peripheral tissue
ZONA RETICULARIS Androgens
Estrogens, DHT
Cholesterol (via StAR
a)
Pregnenolone Progesterone11-deoxycorticosterone Corticosterone Aldosterone
17-hydroxypregnenolone 17-hydroxyprogesterone11-deoxycortisol Cortisone
Glycyrrhetinic acid
Cortisol
Dehydroepiandrosterone (DHEA)
Anastrozole,
letrozole, exemestane
Finasteride
AndrostenedioneTestosterone
Dihydrotestosterone(DHT)
Angiotensin II 3 β
-hydroxysteroid dehydrogenase
Estrone Estradiol
Aromatase Aromatase
17
α
-hydroxylase
17,20-lyase 17,20-lyase
17
α
-hydroxylase
ACTH
5 α
-reductase
C
A
B C
Metyrapone
a Rate-limiting step.
Ketoconazole,
spironolactone, abiraterone
ENZYME DEFICIENCY
MINERA
LO
CORTICOIDS
!K
"^
BP
CORTISOL
SEXHORMONES
LABS
PRESENTATION
α
-hydroxylase
a
q
r
q
r
r
r
androstenedione
XY: atypical genitalia,
undescended testes XX: lacks 2° sexual
development
21-hydroxylase
a
r
q
r
r
q
q
renin activity q
17-hydroxy-progesterone
Most commonPresents in infancy (salt
wasting) or childhood(precocious puberty) XX: virilization
β
-hydroxylase
a
r
aldosterone q
11-deoxycorti-costerone(results in q
BP)
r
q
r
q
r
renin activity
Presents in infancy
(severe hypertension)or childhood(precocious puberty) XX: virilization
a All congenital adrenal enzyme deficiencies are autosomal recessive disorders and most are characterized by skin hyperpigmentation (due to
q
MSH production, which is coproduced and secreted with ACTH) and bilateral adrenal gland
enlargement (due to
q
ACTH stimulation).
If deficient enzyme starts with 1, it causes hypertension; if deficient enzyme ends with 1, it causes virilization in females.
`
ENDOCRINE
`
ENDOCRINEPATHOLOGY
SEC TION III
`
ENDOCRINEPATHOLOGY
Syndrome of inappropriateantidiuretic hormone secretion
Characterized by excessive free water retention,
euvolemic hyponatremia with continuedurinary Na
excretion, urine osmolality >
serum osmolality. Body responds to water retention with
r
aldosterone and
q
ANP and BNP
p q
urinary
Na
secretion
p
normalization of extracellular
fluid volume
p
euvolemic hyponatremia.
Treatment: fluid restriction (first line), salt
tablets, IV hypertonic saline, diuretics,ADH antagonists (eg, conivaptan, tolvaptan,demeclocycline). SIADH causes include (
HEELD
-up water):
H
ead trauma/CNS disorders
E
ctopic ADH (eg, small cell lung cancer)
E
xogenous hormones (eg, vasopressin, desmopressin, oxytocin)
L
ung disease
D
rugs (eg, SSRIs, carbamazepine, cyclophosphamide)
ADH
ADH
serum L osmolality
serum osmolality L
serum volume L
Posteriorpituitary(storage)
SIADH
Medullary collecting duct
Aquaporin channels
ADH antagonists
Lithium
Nephrogenic DI
Central DI
urine osmolality L urine volume L
Hypothalamus
Primary polydipsia anddiabetes insipidus
Characterized by the production of large amounts of dilute urine +/– thirst. Urine specific gravity
< 1.006. Urine osmolality usually < 300 mOsm/kg. Central DI may be transient if damage isbelow hypothalamic median eminence or in the posterior pituitary (ADH in hypothalamus canstill be secreted systemically via portal capillaries in median eminence). Primary polydipsia
Central DI
Nephrogenic DI
DEFINITION
Excessive water intake
r
ADH release
ADH resistance
CAUSES
Psychiatric illnesses,
hypothalamic lesionsaffecting thirst center
Idiopathic, brain injury
(trauma, hypoxia, tumor,surgery, infiltrative diseases)
Hereditary (ADH receptor
mutation), drugs (eg,lithium, demeclocycline),hypercalcemia, hypokalemia
SERUM OSMOLALITY
r
q
q
ADH LEVEL
r
or normal
r
Normal or
q
WATER RESTRICTION
a^
Significant
q
in urine
osmolality (> 700 mOsm/kg)
No change or slight
q
in urine
osmolality
No change or slight
q
in urine
osmolality
DESMOPRESSIN ADMINISTRATION
b
Significant
q
in urine
osmolality (> 50%)
Minimal change in urine
osmolality
TREATMENT
Water restriction
Desmopressin (DDAVP)
Manage the underlying cause;
low-solute diet, HCTZ,amiloride, indomethacin
a No water intake for 2–3 hours followed by hourly measurements of urine volume and osmolality as well as plasma Na
concentration and osmolality. b Desmopressin (ADH analog) is administered if serum osmolality > 295–300 mOsm/kg, plasma Na
145 mEq/L, or urine
osmolality does not increase despite
q
plasma osmolality.
ENDOCRINE
`
ENDOCRINEPATHOLOGY
`
SEC TION III
Hypopituitarism
Undersecretion of pituitary hormones due to
Nonsecreting pituitary adenoma, craniopharyngioma
Sheehan syndrome
—ischemic infarct of pituitary following severe postpartum hemorrhage;
pregnancy-induced pituitary growth
p q
susceptibility to hypoperfusion. Usually presents with
failure to lactate, amenorrhea, cold intolerance (anterior pituitary hormones mainly affected).
Pituitary apoplexy
—sudden hemorrhage of pituitary gland, often in the presence of an existing
pituitary adenoma. Usually presents with sudden onset severe headache, visual impairment (eg,bitemporal hemianopia, diplopia due to CN III palsy), and features of hypopituitarism
Brain injury
Radiation
Treatment: hormone replacement therapy (glucocorticoids, thyroxine, sex steroids, human growth
hormone)
Acromegaly
Excess GH in adults. Typically caused by pituitary adenoma.
FINDINGS
Large tongue with deep furrows, frontal
bossing, coarsening of facial features withaging
A
, deep voice, diaphoresis (excessive
sweating), hypertrophic arthropathy, impairedglucose tolerance (insulin resistance), HTN,LVH, HFpEF (most common cause of death).
q
GH in children
p
gigantism (
q
linear bone
growth due to unfused epiphysis). A
cromegaly in
a
dults,
g
igantism in j(
g
)uniors.
A
Baseline
DIAGNOSIS
q
serum IGF-1 (GH levels unreliable as theyfluctuate throughout the day); failure tosuppress serum GH following oral glucosetolerance test; pituitary mass seen on brainMRI.
TREATMENT
Pituitary adenoma resection. If not cured,
treat with octreotide (somatostatin analog),pegvisomant (GH receptor antagonist), ordopamine agonists (eg, cabergoline).
`
ENDOCRINE
`
ENDOCRINEPATHOLOGY
SEC TION III
Hypothyroidism vs hyperthyroidism
Hypothyroidism
Hyperthyroidism
METABOLIC
Cold intolerance,
r
sweating, weight gain
r
basal metabolic rate
p
r
calorigenesis),
hyponatremia (
r
free water clearance)
Heat intolerance,
q
sweating, weight loss
(q
synthesis of Na
/K
-ATPase
p
q
basal
metabolic rate
p
q
calorigenesis)
SKIN/HAIR
Dry, cool skin (due to
r
blood flow); coarse,
brittle hair; diffuse alopecia; brittle nails;puffy facies and generalized nonpitting edema(myxedema) due to
q
GAGs in interstitial
spaces
p
q
osmotic pressure
p
water retention
Warm, moist skin (due to vasodilation); fine hair;
onycholysis (
A
); pretibial myxedema in Graves
disease
B
OCULAR
Periorbital edema
C
Ophthalmopathy in Graves disease (including
periorbital edema, exophthalmos), lid lag/retraction (
q
sympathetic stimulation of
superior tarsal muscle)
GASTROINTESTINAL
Constipation (
r
GI motility),
r
appetite
Hyperdefecation/diarrhea (
q
GI motility),
q
appetite
MUSCULOSKELETAL
Hypothyroid myopathy (proximal weakness,
q
CK), carpal tunnel syndrome, myoedema (small lump rising on the surface of a musclewhen struck with a hammer)
Thyrotoxic myopathy (proximal weakness,
normal CK), osteoporosis/
q
fracture rate (T
3
directly stimulates bone resorption)
REPRODUCTIVE
Abnormal uterine bleeding,
r
libido, infertility
Abnormal uterine bleeding, gynecomastia,
r
libido, infertility
NEUROPSYCHIATRIC
Hypoactivity, lethargy, fatigue, weakness,
depressed mood,
r
reflexes (delayed/slow
relaxing)
Hyperactivity, restlessness, anxiety, insomnia,
fine tremors (due to
q
β
-adrenergic activity),
q
reflexes (brisk)
CARDIOVASCULAR
Bradycardia, dyspnea on exertion (
r
cardiac
output)
Tachycardia, palpitations, dyspnea, arrhythmias
(eg, atrial fibrillation), chest pain and systolicHTN due to
q
number and sensitivity of
β
-adrenergic receptors,
q
expression of cardiac
sarcolemmal ATPase and
r
expression of
phospholamban
LABS
q
TSH (if 1°) r
free T
4
Hypercholesterolemia (due to
r
LDL receptor
expression)
r
TSH (if 1°) q
free T
3
and T
4
r
LDL, HDL, and total cholesterol
B
A
C
ENDOCRINE
`
ENDOCRINEPATHOLOGY
`
SEC TION III
Hypothyroidism
Hashimoto thyroiditis
Also called chronic autoimmune thyroiditis. Most common cause of hypothyroidism in iodine-
sufficient regions. Associated with HLA-DR3 (differs by ethnicity),
q
risk of primary thyroid
lymphoma (typically diffuse large B-cell lymphoma). Findings: moderately enlarged,
nontender
thyroid. May be preceded by transient hyperthyroid
state (“Hashitoxicosis”) due to follicular rupture and thyroid hormone release. Serology:
antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies.
Histology: Hürthle cells
A
, lymphoid aggregates with germinal centers
B
Postpartum thyroiditis
—mild, self-limited variant of Hashimoto thyroiditis arising < 1 year after
delivery.
Subacute
granulomatousthyroiditis
Also called de Quervain thyroiditis. Usually, a self-limited disease. Natural history: transient
hyperthyroidism
p
euthyroid state
p
hypothyroidism
p
euthyroid state. Often preceded by viral
infection. Findings:
q
ESR, jaw pain, very
tender
thyroid (de Quer
vain
is associated with
pain
Histology: granulomatous inflammation
C
Riedel thyroiditis
Also called invasive fibrous thyroiditis. May occur as part of IgG
4 -related disease spectrum (eg,
autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis). Hypothyroidism occursin
(^1)
⁄^3
of patients. Fibrosis may extend to local structures (eg, trachea, esophagus), mimicking
anaplastic carcinoma. Findings: slowly enlarging, hard (rocklike), fixed,
nontender
thyroid.
Histology: thyroid replaced by fibrous tissue and inflammatory infiltrate
D
Congenital
hypothyroidism
Formerly called cretinism. Most commonly caused by thyroid dysgenesis (abnormal thyroid gland
development; eg, agenesis, hypoplasia, ectopy) or dyshormonogenesis (abnormal thyroid hormonesynthesis; eg, mutations in thyroid peroxidase) in iodine-sufficient regions. Findings (
P
’s):
p
ot-bellied,
p
ale,
p
uffy-faced child
E
with
p
rotruding umbilicus,
p
rotuberant
tongue
F
, and
p
oor brain development.
Other causes
Iodine deficiency (most common cause worldwide; typically presents with goiter
G
), iodine excess
(Wolff-Chaikoff effect), drugs (eg, amiodarone, lithium), nonthyroidal illness syndrome (alsocalled euthyroid sick syndrome;
r
T
3
with normal/
r
T
4
and TSH in critically ill patients).
A
D G
F
E
Before treatment
After treatment
C
B
`
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
SEC TION III
Diagnosingparathyroid disease
6
4
8
10
12
Ca
2+
(mg/dL)
PTH (pg/mL)
14
16
18
20
50 10 250
2
Normal
Hypoparathyroidism (surgical resection,
autoimmune)
1° hyperparathyroidism (hyperplasia, adenoma,
carcinoma)
2° hyperparathyroidism
(vitamin D deficiency,
↓
Ca
2+
intake,
chronic kidney disease)
PTH-independent
hypercalcemia
(excess Ca
2+
intake, cancer,
↑
vitamin D)
3° hyperparathyroidism (chronic kidney disease)
Hypoparathyroidism
Due to injury to parathyroid glands or their blood supply (usually during thyroid surgery),
autoimmune destruction, or DiGeorge syndrome. Findings: tetany, hypocalcemia,hyperphosphatemia. Ch
vostek sign—tapping of facial nerve (tap the
Ch
eek)
p
contraction of facial muscles.
Tr
ousseau sign—occlusion of brachial artery with BP cuff (cuff the
Tr
iceps)
p
carpal spasm.
Pseudohypoparathyroidism type 1A
—autosomal dominant, maternally transmitted mutations
(imprinted
GNAS
gene). GNAS1-inactivating mutation (coupled to PTH receptor) that encodes
the G
s^
protein
α
subunit
p
inactivation of adenylate cyclase when PTH binds to its receptor
p
end-organ resistance (kidney and bone) to PTH.
Physical findings: Albright hereditary osteodystrophy (shortened 4th/5th digits
A
, short stature,
round face, subcutaneous calcifications, developmental delay). Labs:
q
PTH,
r
Ca
2+
q
PO
4 3–
Pseudopseudohypoparathyroidism
—autosomal dominant, paternally transmitted mutations
(imprinted
GNAS
gene) but without end-organ resistance to PTH due to normal maternal allele
maintaining renal responsiveness to PTH. Physical findings: same as Albright hereditary osteodystrophy.Labs: normal PTH, Ca
2+
, PO
4 3–
A Lab values in hypocalcemic disorders DISORDER
Ca
2+
PO
4 3!
PTH
ALP
25"OH# VITAMIN D
1,25"OH#
2 VITAMIN D
Vitamin D deficiency
r
r
q
q
r
q
2° hyperpara-
thyroidism (CKD)
r
q
q
q
r
Hypoparathyroidism
r
q
r
r
Pseudohypo-
parathyroidism
r
q
q
q
r
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
`
SEC TION III
Hyperparathyroidism
Primary
hyperparathyroidism A
Usually due to parathyroid adenoma or
hyperplasia.
Hypercalcemia
, hypercalciuria
(renal
stones
), polyuria (
thrones
hypophosphatemia,
q
PTH,
q
ALP,
q
urinary
cAMP. Most often asymptomatic. May presentwith
bone
pain, weakness, constipation
groans
”), abdominal/flank pain (kidney
stones, acute pancreatitis), neuropsychiatricdisturbances (“
psychiatric overtones
Osteitis fibrosa cystica
—cystic
bone
spaces
filled with brown fibrous tissue
A
(“brown
tumor” consisting of osteoclasts and depositedhemosiderin from hemorrhages; causesbone pain). Due to
q
PTH, classically
associated with 1° (but also seen with 2°)hyperparathyroidism. “
Stones
,^
thrones
,^
bones
groans
, and
psychiatric overtones
Secondary
hyperparathyroidism
2° hyperplasia due to
r
Ca
2+
absorption
and/or
q
PO
4 3 −
, most often in chronic
kidney disease (causes hypovitaminosis Dand hyperphosphatemia
p r
Ca
2+
Hypocalcemia
, hyperphosphatemia in
chronic kidney disease (vs hypophosphatemiawith most other causes),
q
ALP,
q
PTH.
Renal osteodystrophy
—renal disease
p
2° and
3° hyperparathyroidism
p
bone lesions.
Tertiary
hyperparathyroidism
Refractory (autonomous) hyperparathyroidism
resulting from end-stage renal disease. qq
PTH,
q
Ca
2+
Familial hypocalciurichypercalcemia
Autosomal dominant. Defective G-coupled Ca
2+
-sensing receptors in multiple tissues (eg,
parathyroids, kidneys). Higher than normal Ca
2+
levels required to suppress PTH. Excessive renal
Ca
2+
reabsorption
p
mild hypercalcemia and hypocalciuria with normal to
q
PTH levels.
`
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
SEC TION III
Diabetes mellitus
ACUTE MANIFESTATIONS
P
olydipsia,
p
olyuria,
p
olyphagia (
3 P
’s), weight loss, DKA (type 1), hyperosmolar hyperglycemic
state (type 2). Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen in patients on
glucocorticoid therapy (steroid diabetes).
CHRONIC COMPLICATIONS
Nonenzymatic glycation:
Small vessel disease (hyaline arteriolosclerosis)
p
retinopathy, neuropathy, nephropathy.
Large vessel disease (atherosclerosis)
p
CAD, cerebrovascular disease, peripheral vascular
disease. MI is the most common cause of death.
Osmotic damage (sorbitol accumulation in organs with aldose reductase and
r
or absent sorbitol
dehydrogenase):
Neuropathy: motor, sensory (glove and stocking distribution), autonomic degeneration (eg,GERD, gastroparesis, diabetic diarrhea).
Cataracts.
DIAGNOSIS
TEST
DIAGNOSTIC CUTOFF
NOTES
HbA
1c
Reflects average blood glucose
over prior 3 months (influencedby RBC turnover)
Fasting plasma glucose
126 mg/dL
Fasting for > 8 hours
2-hour oral glucose tolerance test
200 mg/dL
2 hours after consumption of 75 g
of glucose in water
Random plasma glucose
200 mg/dL
Presence of hyperglycemic
symptoms is required
available insulin
lipolysis
proteolysis
gluconeogenesis
glycogenolysis
tissue glucose uptake
plasma
free fatty acids
muscle mass, weight loss
Hyperglycemia,
glycosuria
ketogenesis,
ketonemia, ketonuria
Vomiting
Anion gap
metabolic acidosis
Hyperventilation, Kussmaul respiration
Osmotic diuresis
plasma osmolality
Loss of water,
Na, and K
thirst
Hypovolemia Circulation failure,
tissue perfusion
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
`
SEC TION III
Type 1 vs type 2 diabetes mellitus
Type 1
Type 2
1° DEFECT
Autoimmune T-cell–mediated destruction of
β
cells
q
resistance to insulin, progressive pancreatic β
-cell failure
INSULIN NECESSARY IN TREATMENT
Always
Sometimes
AGE "EXCEPTIONS COMMON#
< 30 yr
40 yr
ASSOCIATION WITH OBESITY
No
Yes
GENETIC PREDISPOSITION
Relatively weak (50% concordance in identical
twins), polygenic
Relatively strong (90% concordance in identical
twins), polygenic
ASSOCIATION WITH HLA SYSTEM
Yes, HLA-DR
and -DR
^3
= type
No
GLUCOSE INTOLERANCE
Severe
Mild to moderate
INSULIN SENSITIVITY
High
Low
KETOACIDOSIS
Common
Rare
β
&CELL NUMBERS IN THE ISLETS
r
Variable (with amyloid deposits)
SERUM INSULIN LEVEL
r
q
initially, but
r
in advanced disease
CLASSIC SYMPTOMS OF POLYURIA,
POLYDIPSIA, POLYPHAGIA, WEIGHTLOSS
Common
Sometimes
HISTOLOGY
Islet leukocytic infiltrate
Islet amyloid polypeptide deposits
Hyperglycemic emergencies
Diabetic ketoacidosis
Hyperosmolar hyperglycemic state
PATHOGENESIS
Insulin noncompliance or
q
requirements
due to
q
stress (eg, infection)
p
lipolysis and
oxidation of free fatty acids
p q
ketone bodies
β
-hydroxybutyrate > acetoacetate).
Insulin deficient, ketones present.
Profound hyperglycemia
p
excessive osmotic
diuresis
p
dehydration and
q
serum osmolality
p
HHS. Classically seen in older patients with type 2 DM and limited ability to drink. Insulin present, ketones deficient.
SIGNS/SYMPTOMS
DKA
is
D
eadly:
D
elirium/psychosis,
K
ussmaul
respirations (rapid, deep breathing),
A
bdominal
pain/nausea/vomiting,
D
ehydration. Fruity
breath odor due to exhaled acetone.
Thirst, polyuria, lethargy, focal neurologic
deficits, seizures.
LABS
Hyperglycemia,
q
H
r
HCO
3
q
anion gap
metabolic acidosis),
q
urine and blood ketone
levels, leukocytosis. Normal/
q
serum K
, but
depleted intracellular K
due to transcellular
shift from
r
insulin and acidosis. Osmotic
diuresis
p q
K
loss in urine
p
total body
K
depletion.
Hyperglycemia (often > 600 mg/dL),
q
serum
osmolality (> 320 mOsm/kg), normal pH (noacidosis), no ketones. Normal/
q
serum K
r
intracellular K
COMPLICATIONS
Life-threatening mucormycosis, cerebral
edema, cardiac arrhythmias.
Can progress to coma and death if untreated.
TREATMENT
IV fluids, IV insulin, and K
(to replete intracellular stores). Glucose may be required to prevent
hypoglycemia from insulin therapy.
`
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
SEC TION III
Hyperaldosteronism
Increased secretion of aldosterone from adrenal gland. Clinical features include hypertension,
r
or normal K
, metabolic alkalosis. 1° hyperaldosteronism does not directly cause edema due
to aldosterone escape mechanism. However, certain 2° causes of hyperaldosteronism (eg, heartfailure) impair the aldosterone escape mechanism, leading to worsening of edema.
Primary
hyperaldosteronism
Seen in patients with bilateral adrenal hyperplasia or adrenal adenoma (Conn syndrome).
q
aldosterone,
r
renin. Leads to treatment-resistant hypertension.
Secondary
hyperaldosteronism
Seen in patients with renovascular hypertension, juxtaglomerular cell tumors (renin-producing),
and edema (eg, cirrhosis, heart failure, nephrotic syndrome).
q
aldosterone,
q
renin.
Neuroendocrinetumors
Heterogeneous group of neoplasms originating from neuroendocrine cells (which have traits similar
to nerve cells and hormone-producing cells). Most neoplasms occur in the GI system (eg, carcinoid, gastrinoma), pancreas (eg, insulinoma,
glucagonoma), and lungs (eg, small cell carcinoma). Also in thyroid (eg, medullary carcinoma)and adrenals (eg, pheochromocytoma). Neuroendocrine cells (eg, pancreatic
β
cells, enterochromaffin cells) share a common biologic
function through amine precursor uptake decarboxylase (APUD) despite differences inembryologic origin, anatomic site, and secretory products (eg, chromogranin A, neuron-specificenolase [NSE], synaptophysin, serotonin, histamine, calcitonin). Treatment: surgical resection,somatostatin analogs.
Neuroblastoma^ A
Most common solid extracranial tumor in children (typically < 4 years old). Usually arises in
adrenal medulla, but may occur anywhere along the sympathetic chain. Originates from
n
eural
crest cells. Most common presentation is abdominal distension and a firm, irregular mass that can cross the
midline (vs Wilms tumor, which is smooth and unilateral). Less likely to develop hypertensionthan with pheochromocytoma (
n
euroblastoma is
n
ormotensive). Can also present with
opsoclonus-myoclonus syndrome (“dancing eyes-dancing feet”). q
HVA and VMA (catecholamine metabolites) in urine. Homer-Wright rosettes (neuroblastssurrounding a central area of neuropil
A
) characteristic of neuroblastoma and medulloblastoma.
Bombesin and
N
SE
. Associated with amplification of
N
oncogene.
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
`
SEC TION III
Pheochromocytoma
ETIOLOGY^ A
Most common tumor of the adrenal medulla
in adults (black arrow in
A
; red arrow points
to bone metastases). Derived from chromaffincells (arise from neural crest). Rare. May be associated with germline mutations (eg,
NF-1, VHL, RET
[MEN 2A, 2B]).
Rule of 10
’s:
malignant
bilateral
extra-adrenal (paraganglioma;
eg, bladder wall, organ of Zuckerkandl) 10%
calcify
kids
SYMPTOMS
Most tumors secrete epinephrine,
norepinephrine, and dopamine, which cancause episodic hypertension. May also secreteEPO
p
polycythemia.
Symptoms occur in “spells”—relapse and remit.
Episodic hyperadrenergic symptoms (
5 P
’s):
P
ressure (
q
BP)
P
ain (headache) P
erspiration P
alpitations (tachycardia) P
allor
FINDINGS
q
catecholamines and metanephrines (eg,homovanillic acid, vanillylmandelic acid) inurine and plasma.
Chromogranin, synaptophysin and NSE
TREATMENT
Irreversible
α
-antagonists (eg,
phenoxybenzamine) followed by
β
-blockers
prior to tumor resection.
α
-blockade must be
achieved before giving
β
-blockers to avoid a
hypertensive crisis.
A
before
B
Phe
noxybenzamine for
phe
ochromocytoma.
`
ENDOCRINE
`
ENDOCRINE
PATHOLOGY
SEC TION III
Multiple endocrineneoplasias
All
MEN
syndromes have autosomal
dominant
inheritance.
The X-
MEN
are
dominant
over villains.
SUBTYPE
CHARACTERISTICS
MEN
P
ituitary tumors (prolactin or GH) P
ancreatic endocrine tumors—Zollinger-Ellison syndrome, insulinomas, VIPomas, glucagonomas(rare) P
arathyroid adenomas Associated with mutation of
MEN
(tumor suppressor, codes for menin, chromosome 11),
angiofibromas, collagenomas, meningiomas
MEN2A
P
arathyroid hyperplasia Medullary thyroid carcinoma—neoplasm of parafollicular C cells; secretes calcitonin; prophylactic
thyroidectomy required P
heochromocytoma (secretes catecholamines) Associated with mutation in
RET
(protooncogene, codes for receptor tyrosine kinase, chromosome 10)
MEN2B^ A
Medullary thyroid carcinoma P
heochromocytoma Mucosal neuromas
A
(oral/intestinal ganglioneuromatosis)
Associated with marfanoid habitus; mutation in
RET
gene
Pituitary Pancreas
Parathyroid
Medullary thyroid carcinoma Pheochromocytoma
Parat
hyroi
d
Parat
hyroi
d
Mucosalneuromas
MEN1 = 3 P’s
MEN2A = 2 P’s, 1 M
MEN2B = 1 P, 2 M’s
ENDOCRINE
`
ENDOCRINEPATHOLOGY
`
SEC TION III
Pancreatic islet cell tumors
Insulinoma
Tumor of pancreatic
β
cells
p
overproduction of insulin
p
hypoglycemia.
May see Whipple triad: low blood glucose, symptoms of hypoglycemia (eg, lethargy, syncope,
diplopia), and resolution of symptoms after normalization of plasma glucose levels. Symptomaticpatients have
r
blood glucose and
q
C-peptide levels (vs exogenous insulin use).
10% of cases
associated with MEN1 syndrome. Treatment: surgical resection.
Glucagonoma
Tumor of pancreatic
α
cells
p
overproduction of glucagon.
Presents with
6 D
’s:
d
ermatitis (necrolytic migratory erythema),
d
iabetes (hyperglycemia),
D
VT,
d
eclining weight,
d
epression,
d
iarrhea.
Treatment: octreotide, surgical resection.
Somatostatinoma
Tumor of pancreatic
δ
cells
p
overproduction of somatostatin
p r
secretion of secretin,
cholecystokinin, glucagon, insulin, gastrin, gastric inhibitory peptide (GIP). May present with diabetes/glucose intolerance, steatorrhea, gallstones, achlorhydria.Treatment: surgical resection; somatostatin analogs (eg, octreotide) for symptom control.
Carcinoid tumors^ A
Carcinoid tumors arise from neuroendocrine cells, most commonly in the intestine or lung.
Neuroendocrine cells secrete 5-HT, which undergoes hepatic first-pass metabolism andenzymatic breakdown by MAO in the lung. If 5-HT reaches the systemic circulation (eg, afterliver metastasis), carcinoid tumor may present with
carcinoid syndrome
—episodic flushing,
diarrhea, wheezing, right-sided valvular heart disease (eg, tricuspid regurgitation, pulmonicstenosis), niacin deficiency (pellagra),
q
urinary 5-HIAA.
Histology: rosettes
A
, chromogranin A
, synaptophysin
Treatment: surgical resection, somatostatin analog (eg, octreotide) or tryptophan hydroxylase
inhibitor (eg, telotristat) for symptom control. Rule of thirds
metastasize
present with 2nd malignancy
are multiple
Zollinger-Ellisonsyndrome
Constellation of symptoms due to acid hypersecretion resulting from gastrin-secreting tumor
(gastrinoma) in duodenum or pancreas
p
multiple, recurrent ulcers in duodenum/jejunum
(often refractory to proton pump inhibitors) and malabsorption. Presents with abdominal pain,heartburn, steatorrhea, weight loss. Positive secretin stimulation test (
q
gastrin levels after secretin
administration, which normally inhibits gastrin release). Chromogranin A
. May be associated
with MEN1.
`
ENDOCRINE
`
ENDOCRINEPHARMACOLOGY
SEC TION III
Thionamides
Propylthiouracil, methimazole.
MECHANISM
Block thyroid peroxidase, inhibiting the oxidation of iodide as well as the organification and
coupling of iodine
p
inhibition of thyroid hormone synthesis.
P
TU also blocks 5
′-deiodinase
p
r
P
eripheral conversion of T
4
to T
3
CLINICAL
USE
Hyperthyroidism.
P
TU used in
P
rimary (first) trimester of pregnancy (due to methimazole
teratogenicity); methimazole used in second and third trimesters of pregnancy (due to riskof PTU-induced hepatotoxicity). Not used to treat Graves ophthalmopathy (treated withglucocorticoids).
ADVERSE EFFECTS
Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity.PTU use has been associated with ANCA-positive vasculitis.Methimazole is a possible teratogen (can cause aplasia cutis).
Levothyroxine, liothyronine
MECHANISM
Hormone replacement for T
4
levo
thyroxine; levo = 4 letters) or T
3
lio
thyronine; lio = 3 letters).
Avoid levothyroxine with antacids, bile acid resins, or ferrous sulfate (
r
absorption).
CLINICAL USE
Hypothyroidism, myxedema. May be misused for weight loss. Distinguish exogenous
hyperthyroidism from endogenous hyperthyroidism by using a combination of TSH receptorantibodies, radioactive iodine uptake, and/or measurement of thyroid blood flow on ultrasound.
ADVERSE EFFECTS
Tachycardia, heat intolerance, tremors, arrhythmias.
Hypothalamic/pituitary drugs
DRUG
CLINICAL USE
Conivaptan, tolvaptan
ADH antagonistsSIADH (block action of ADH at V
2 -receptor)
Demeclocycline
ADH antagonist, a tetracyclineSIADH (interferes with ADH signaling)
Desmopressin
ADH analogCentral DI, von Willebrand disease, sleep enuresis, hemophilia A
GH
GH deficiency, Turner syndrome
Oxytocin
Induction of labor (stimulates uterine contractions), control uterine hemorrhage
Octreotide
Somatostatin analogAcromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices
Fludrocortisone
MECHANISM
Synthetic analog of aldosterone with glucocorticoid effects.
Fluid
rocortisone retains
fluid
CLINICAL USE
Mineralocorticoid replacement in 1° adrenal insufficiency.
ADVERSE EFFECTS
Similar to glucocorticoids; also edema, exacerbation of heart failure, hyperpigmentation.
ENDOCRINE
`
ENDOCRINEPHARMACOLOGY
`
SEC TION III
Cinacalcet
MECHANISM
Sen
sitizes
calc
ium-sensing receptor (CaSR) in parathyroid gland to circulating Ca
2+
p
r
PTH.
Pronounce “
Sen
a
calc
et.”
CLINICAL USE
2° hyperparathyroidism in patients with CKD receiving hemodialysis, hypercalcemia in 1°
hyperparathyroidism (if parathyroidectomy fails), or in parathyroid carcinoma.
ADVERSE EFFECTS
Hypocalcemia.
Sevelamer
MECHANISM
Nonabsorbable phosphate binder that prevents phosphate absorption from the GI tract.
CLINICAL USE
Hyperphosphatemia in CKD.
ADVERSE EFFECTS
Hypophosphatemia, GI upset.
Cation exchange resins
Patiromer, sodium polystyrene sulfonate, zirconium cyclosilicate.
MECHANISM
Bind K
in colon in exchange for other cations (eg, Na
, Ca
2+
p
K
excreted in feces.
CLINICAL USE
Hyperkalemia.
ADVERSE EFFECTS
Hypokalemia, GI upset.
