high dose dex test-when does it suppress?
- Suppresses ACTH/cortisol in a pituitary adenoma
- Does NOT suppress is ACTH caused by ectopic ACTH (small cell carcinoma)
- If adrenal secreting neoplasm, will have high cortisol, low ACTH and NO CHANGE with dexmethasone (ACTH already low and adrenal gland not responsive to it)
PTHrP
Squamous cell lung cancer
Breast cancer
branching papillae with a stalk and cuboidal epithelium. Ground glass appearance.
Psamomma bodies
papillary thyroid cancer
Sheets of Hurthle cells(eosinophilic cytoplasm) OR follicular cells
follicular thyroid cancer
large pleomorphic cells and multinucleated osteoclasts in thyroid histology. Also spindle cells
Anaplastic thyroid cancer
Uniform polygonal/spindle cells positive for calcitonin and amyloid
MTC
Carpal tunnel associated with:
hypothyroidism, diabetes
What is the single best test for hypothyroidism? Why?
TSH. Will be high. Because T4 levels can be within normal limits early on. TsH more sensitive. Serum t3 is the last thing to decline, a late indicator.
BUT if a hypothalamic problem, (central) then will not detect….
RANK-L is generated by
osteoblasts
Differentiation of osteoclasts is done by
RANK-ligand and monocyte CSF
OPG
secreted by osteoblasts, acts as a decoy receptor.
Bone turnover increased when:
Ratio of RANK-L:OPG is high.
How does PTH work on bone cells?
Stimulates secretion of Monocyte CSF and RANK-L BY osteoblasts to stimulate osteoclasts. Does not directly stimulate osteoclasts
How does low estrogen cause breakdown of bone?
Overexpression of RANK receptors causes more osteoclastic activity
Side effects of TZDs
Liver function–check LFTs.
Also, fluid retention
Signs of hypercalcemia
Stones
Groans (GI)
Bones
and psychiatric overtones (mental status)
rT3 made from
T4. Converted by hypothalamus and pituitary and also by peripheral tissues. If T4 is low, will have decreased rT3 too.
How does glucocorticoid affect the HPA axis?
Suppresses all levels, hypothalamus, pituitary, and adrenal. Can have adrenal crisis.
thyroid diverticulum arises from
floor of primitive pharynx
connects thyroid to tongue
thyroglossal duct
pyramidal lobe of thyroid=
persistence of thyroglossal duct
normal remnant of thyroglossal duct
formaen cecum
anterior midline neck mass that MOVES with swallowing
thyroglossal duct cyst
lateral neck mass that does not move with swallowing
branchial left cyst –from PERSISTENT CERVICAL SINUS
when does fetal adrenal become active
secretes cortisol late in gestation
fetal cortisol secretion controlled by
ACTH and CRH from fetal pituitary and placenta
Neuroblastoma
tumor of adrenal medulla in children
cells in adrenal medulla
chromaffin cells
left adrenal drains to
left renal vein–>IVC
right adrenal vein drains to
IVC
posterior pituitary derived from
neuroectoderm
anterior pituitary derived from
oral ectoderm (Rathke’s pouch)
Melanotropin secreted by
anterior pituitary
acidophils
GH and prolactin
Basophils
B-FLAT
-FSH, LH, ACTH, TSH
alpha subunit of pituitary hormone
TSH, LH, FSH, hCG
B subunit of pituitary hormone determines
specificity
alpha cells of pancreas found where?
periphery
beta cells of pancreas found where?
inside
pathophys of insulin release
- glucose enters
- ATP increase
- ATP gated K+ channels open
- depolarization of beta cell
- VG-Ca channel opens
- insulin secretion
Does insulin cross the placenta?
No. Ok in pregnancy
which organs uptake glucose independently of insulin?
brain RBC intestine Cornea Kidney Liver
GLUT 1 found in
RBC and brain (insulin independent)
GLUT 2 found in
beta cells, liver, kidney, small intestine
GLUT 4
adipose tissue, skeletal muscle
effect on insulin on kidneys
increased NA retention
Things that increase insulin
hyperglycemia
GH
B2 adrenergic ANTAGONIST
Things that decrease insulin
hypoglycemia
somatostatin
a-2 agonist
What type of receptor is insulin receptor?
tyrosine kinase
pathophys after insulin binds cell
Tyrosine kinase phosphorylates
- -IP3 causes GLUT-4 vesicles to fuse and glycogen, lipid, and protein synthesis
- -RAS/MAP kinase causes cell growth
Can RBCs use ketones for energy/
NO! they have no mitochondria
effects of glucagon
Glycogenolysis
gluconeogenesis
lipolysis
ketone
Glucagon inhibited by
somatostatin
and obvi insulin and hyperglycemia
TRH stimulates
TSH and prolactin
Dopamine inhibits
prolactin
CRH stimulates
ACTH
MSH (melanocyte stimulating hormone)
beta endorphin
Somatostatin inhibits
GH
TSH
which drugs would stimulate prolactin secretion?
Antipsychotics (dopamine antagonist)
Also OCPs
prolactin negative feedback at
hypothalamus–increasees dopamine
what stimulates prolactin secretion
TRH
Describe how growth hormone works
GH stimulates liver to release IGF-1/somatomedin. Causese growth
when is secretion of GH high?
exercise and sleep (when glucose is low). Pulsatile secretion.
Gh inhibited by
glucose and somatostatin
bilateral adrenal hyperplasia
congential adrenal hyperplasia
Boy with ambiguous genitalia
–>hypertension, hypokalemia
17a-OH deficiency (“boys are 17 when they hit puberty”)
high aldo
low testosterone
Girl with normal sex organs
–hypertension, hypokalemia
17alpha-OH deficiency
Girl with ambigulous genitalia
- -hypotension, hyperkalemia
- -High renin
21 OH deficiency
Boy with hypotension, hyperkalemia, and increased renin
21 OH deficiency
Girl with ambiguous genitalia
–Hypertension
11B OH deficiency (“girls are 11 when they hit puberty”)
–will have high 11 deoxycorticosterone
Boy with normal genitalia
–hypertension
11B OH deficiency
Cortisol effects
BBIIG
blood pressure decreased bone formation Inflammatory (anti) Insulin resistance Gluconeogenesis
how does cortisol maintain blood pressure?
upregulates alpha 1 receptors on arterioles
how does cortisol effect anti-inflammatory response?
- inhibit leukotriene and prostaglandin synthesis
- inhibit leukocyte adhesion
- block histamine release
- reduce eosinophil count
- block IL-2 production
PTH secreted by what cells
chief cells
effects of PTH
- increased bone resorption Ca and Po4
- Increased calcium resabsorption
- Decreased phosphate in PCT
- Stimulates kidney 1alpha-OH
Overall effect of PTH on serum levels
Ca increase
PO4 decrease
urine phosphate increase
PTH=Phosphate trashing hormone
What increases PTH secretion
decreased calcium
slight decrease Mg2+
What decreases PTH secretion
HUGE decrease in Mg2+
Cause of MG2+ deficiency
diarrhea
Aminoglycosides
diuretics
alcohol
Effect of vitamin D?
Increases calcium reabsorption in GUT
Increases phosphate release from matrix
Increases intestinal phosphate reabsorption
–>Thus, INCREASES CALCIUM AND PO4
Vitamin D3 from
sun exposure
Vitamin D2 from
plants
what increases 1, 25 OH2 production
Increased PTh
decreased PO4
decreased ca
what cells make calcitonin
parafollicular cells
effect of calcitoning
decreases bone resorption
t3/T4 receptor
steroid
IGF-1, PDGF, EGF (growth factor) receptor
Intrinsic tyrosine kinase–>MAP kinase
acidophile and cytokine recptor
receptor tyrosine kinase
Nitric oxide, ANP receptor
cGMP
vitamin D receptor
steroid
GnRH, GHRH signaling pathway
IP3
Oxytonin and ADH signaling pathway
IP3
TRH signaling pathway
IP3
FSH, LH, ACTH, TSH, pathway
cAMP
hitamine and gastrin pathway
IP3
PTH and calcitonin signaling pathway
cAMP
glucagon signaling pathway
cAMP
SHBG and testosterone
Increase SHBG lowers testosterone.
SHBG levels during pregnancy
Increase.
Excess iodide temporarily inhibits thyroid peroxidase
Wolff Chaikoff effect
what converts t4 to t3
5’ deiodinase
thyroid binding globulin effect
binds hormone, preventing it from having any effects
When are TBG levels low? high?
low: hepatic failure
high: pregnancy
how does thyroid hormone increase basal metabolic rate?
Upregulates Na/K ATPase
peroxidase
coupling of MIT and DIT
–oxidation of iodide
Methimazole effect
Inhibits peroxidase only
‘A MONO EFFECT)
propylthiouracil effect
Inhibits peroxidase AND peripheral 5’deiodinase
A POLY effect
Cushing’s disease
INCREASED ACTH causing cushing’s syndrome
Other causes of cushing’s syndrome
ectopic ACTH
Adrenal hyperplasia/adenoma
striae
hypercortisolism
low dose dex: cortisol elevated
high dose dex: cortisol suppressed
cushing’s disease
-ACTH producing tumor
low dose dex: coritsol elevated
high dose dex: cortisol elevated
Ectopic ACTH OR adrenal hyperplasia/adenoma/carcinoma
Conn’s syndrome
aldosterone secreting adenoma
Treatment for Conn’s or adrenal hyperplasia
surgery or spironolactone
Cause of secondary hyperaldosteronism
renal artery stenosis
CHF
nephrotic syndrome (perception of low intravascular volume)
Cause of addison’s
Adrenal Atrophy
Absence of hormone
hypotension
hyperkalemia
acidosis
signs of adrenal insufficiency
how to disginguish primary from secondary adrenal insufficiency
Primary
- -High ACTH: skin pigmentation
- -hyperkalemia (ALSO aldosterone is low!)
Secondary:
- -No hyperkalemia
- -ONLY cortisol is low
- -LOW ACTH
how to distinguish primary from secondary hyperaldosteronism?
renin levels
Pheos associated with:
NF-1
MEN2A
MEN2B
Treatment for pheo
- alpha blockade
- beta blockade
- surgery
Rule of 10’s
Pheos are 10%:
- malignant
- bilateral
- extra-adrenal
- calcify
- kids
describe pathway of phenylalanine breakdown
phenylalanine tyrosine L-dopa Dopamine norepinephrine epinephrine
Breakdown product of dopamine
HVA, increased in pheos along with VMAs
Waterhouse friederichsen
acute primary adrenal insufficiency from adrenal hemorrhage
Waterhouse friederichsen is associated with
neisseria meningitidis
DIC/Shock
dx: neuroblastoma
elevated homovanillic acid in the urine.
What’s different about neuroblastoma vs a pheo?
Less likely to develop hypertension
oncogene associated with neuroblastoma
n-myc
how does a neuroblastoma classically present?
- abdominal fullness
- compression of sympathetic chain (horner’s)
- small blue round cells
facial/perorbital myxedema
sign of hypothyroidism
pretibial myxedema
exopthalmos
Specific to graves. Not found in other causes of hyperthyroidism
dx: hypothyroidism
increased TSH (if primary) Decreased T4
dx: hyperthyroidism
decreased TSH (if primary) increased free or total T4/T3
What is the most sensitive test for primary hypothyroidism?
increased TSH
hashimotos association
HLA-DR5
Histology of hashimoto’s
Hurthle cells
lymphocytic infiltrate with germinal centers
enlarged nontender thyroid
hashimoto’s
pathophys of hashimotos’
anti-thyroglobulin antibodies
cretinism caused by
severe fetal hypothyroidism
Cause of endemic cretinism
lack of dietary iodine
cause of sporadic cretinism
Defect in T4 formation
Pot bellied, pale, puffy faced kid with
Protruding umbilicus and Protuberant tongue
5P’s of hypocretinism
self-limited hypothyroidism after a flu like illness
subacute thyroiditis
Histology of subacute thyroiditis
granulomatous inflammation
hypothyroidism with increased ESR, jaw pain, early inflammation, and a tender thyroid
subacute thyroiditis
hypothyroidism where thyroid is replaced by fibrous tissue
riedel’s thyroiditis
fixed, hard rock like and painless goiter
riedel’s
Cause of Riedel’s thyroiditis
IgG4 systemic disease
–overproduction of IgG4, causing fibrosis
Jod basedow phenomenon
thyrotoxicosis if a patient with iodine deficiency goiter is made iodine replete
Toxic multinodular goiter etiology
mutation in TSH receptor
pathophys thyroid storm
stress causes a huge catecholamine surge and arrhythmia
serious complication of hyperthyroidism
thyroid storm.
ALP during thyroid storm
Increased
Hashimoto’s thyroiditis cancer
lymphoma
orphan annie’s eyes, psamomma bodies, nuclear grooves. Excellent prognosis
papillary carcinoma
Calcitonin producing tumor with sheet of cells
medullary carcinoma
who gets anaplastic thyroid cnacer
older pts, poor prognosis
cystic bone spaces filled with brown fibrous tissue
osteitis fibrosa cystica
Cause of osteitis fibrosa cystica
High PTH
cause of primary hyper PTH
adenoma
lab findings in primary hyperPTH
hypercalcemia
hypercalciuria
hypophosphatemia
increased alkaline phosphatase
cause of secondary hyperparathyroidism
chronic renal disease
Labs in secondary hyperparathyroidism
hypOcalcemia
hypophosphatemia
increased alkaline phosphatase
renal osteodystrophy
bone lesions from 2ndary or tertiary hyperparathyroidism
Tertiary hyperparathyroidism
Autonomous hyperparathyroidism secretion from chronic renal disease.
- VERY high PTH
- hyPERcalcemia
Causes of hypoPTH
- DiGeorge
- Surgical excision accidnetal
- autoimmune destruction
Findings of Hypoparathyroidism
hypocalcemia
tetany
Chvostek’s sign
Trousseau’s sign
Chvostek’s sign
tapping of facial nerve=contraction of facial muscles
Trousseau’s sign
Occlusion of brachial artery with BP cuff
Pseudohypoparathyroidism
Kidney unresponsive to PTH.
- -inherited.
- -hypocalcemia with shortened 4th/5th digits and short stature
Inheritance of pseudohypoparathyroidism
autosomal dominant
Dx of acromegaly
Increased serum IGF-1 OR Glucose tolerance test-->failure to suppress serum GH OR MRI for pituitary mass
Treatment for prolactinoma
bromocriptine
cabergoline
–dopamine agonists
treatment of acromegaly
Pituitary adenoma resection
somatostatin analog
causes of central DI
tumor
trauma/surgery
histiocytosis X
causes of nephrogenic DI
lithium
hypercalcemia
demeclocycline
lab findings of diabetes insipidus
Urine specific gravity < 1
serum osmolality > 290
dx of diabetes insipidus
water deprivation test
how to distinguish central vs nephrogenic DI
Central: Will respond to Desmopressin
Nephrogenic: No response
Treatment for nephrogenic diabetes insipidus
hydrochlorothiazide
indomethacin
amiloride
Main problem in SIADH
hyponatremia from:
- High ADH
- Low aldosterone
treatment of SIADH
- fluid restriction
conivaptan
demeclocycline
drugs that can cause SIADH
cyclophosphamide
pulmonary dz too
Causes of hypopituitarism
- Pituitary adenoma/craniopharyngioma
- Sheehan
- empty sella
radiation and brain injury
Cause of coma in type 2 diabetes
hyperosmolarity of blood
cause of dehydration in insulin deficiency
osmotic diuresis with glucose and ketones in the urine
Main BUZZWORD FOR DIABETES
nonenzymatic glycosylation
nonenzymatic glycosylation is responsible for
small vessel disease and large vessel disease
- -retinopathy, glaucoma, renal failure, nephropathy
- CAD
Ostmotic damage in diabetes causes
neuropathy and cataracts
Histology of T1D
islet leukocytic infiltrate
Histology of T2D
islet amyloid deposit
Serum labs in diabetic ketoacidosis
Hyperkalemia (but depleted intracellular K) Acidosis Decreased bicarb (anion gap metabolic acidosis)
signs of carcinoid syndrome (labs)
Increased 5-HIAA
Niacin deficiency
treatment of carcinoid syndrome
octreotide (somatostatin analog)
Rule of 1/3rds
applies to carcinoid syndrome
- -1/3 metastasize
- -1/3 present with a second malignancy
- -1/3 have multiple tumors
zollinger ellison associated with
MEN type I
Men 1 tumor
Pituitary, Pancreas, parathyroid (3P’s)
Men 2A
Parathyroids and pheo(2P)
Men 2B
Pheo (1P)
MEN inheritance
autosomal dominant
gene mutation in MEN 2A and 2B
ret
pt with kidney stones and stomach ulcers
Men1
- -Hyperparathyroidism
- -Zollinger ellison (pancreas)
Medullary thyroid cancer seen in
MEN2
Oral ganglioneuromatosis
Men2B
–Associated with marfanoid habitus
intermediate insulin
NPH
Effects of metformin
decreased gluconeogenesis
Increased glycolysis
Increased peripheral glucose uptake
Most serious adverse effect of metformin
- lactic acidosis
Who is metformin contraindicated in?
renal failure
can you use metformin in type 1?
YES–does not require islet function to work! It enhances glucose uptake without insulin
Mechanism of sulfonylureas
Increases insulin release
tox: sulfonylureas
first generation: disulfiram
2nd generation: hypoglycemia
Tobultamide
chlorpropamide
first generation sulfonylurea
glyburide
glimepiride
glipizide
second generation sulfonylureas
pioglitazone
rosiglitazone
TZDs
mechanism of TZDs
increase insulin sensitivity in peripheral tissue
–Binds PPAR-y nuclear transcription factor
Indication of TZDs
Type 2 diabetes
Side effect of TZD
weight gain, edema
hepatotoxicity
heart failure
acarbose
miglitol
alpha glucosidase inhibitors
mech: alpha glucosidase inhibitor acarbose miglitol
Inhibit intestinal brush border a-glucosidases
- -decreased sugar absorption
- -reuces postprandial hyperglycemia
tox: a-glucosidase inhibitors
GI disturbances
pramlintide
amylin analog
mechanism pramlintide
decreases glucagon
Mechanism: exenatide/liraglutide
increase insulin
decrease glucagon
linagliptin
saxagliptin
sitagliptin
DPP-4 inhibitors
-gliptin mechanism
Increase insulin
decrease glucagon
Which oral anti-diabetic agents can be used in type 1?
metformin
pramlintide
side effect of acarbose/miglitol
GI disturbance
Side effect of GLP-1
GLP-1
Side effect of DPP4 gliptins
urinary/respiratory infections
Side effects of propylthiouracil/methimazole
agranulocytosis
aplastic anemia
skin rash
side effect of propylthiouracil
hepatotoxicity
side effect of methimazole
teratogen
demecoglycline use
SIADH
octreotide use
Somatostatin analog
acromegaly carcinoid (somatostatin inhibits gastric neuroendocrine cells, gastrin, CCK, gastrinoma glucaonoma esophageal varices
oxytocin use
stimulates labor milk let down uterine hemorrhage (contracts spiral arteries?)
tox of demeclocycline
nephrogenic DI (if too much)
photosensitivity
bone/teeth abnormalities
Mechanism glucocorticoids
Inhibits phospholipase A2 and Cox2
–decreases leukotrienes and prostaglandins
How do you treat addison’s disease
Give glucocorticoids
What happens if you stop giving glucocorticoids suddenly?
Can have adrenal insufficiency (takes time for adrenal to take over, HPA has been suppressed for such a long time)
Side effect of glucocorticoids
peptic ulcers
diabetes
origin of thyroid parafollicular cells
neural crest cells
classic addison’s presentation
Hyperpigmentation! Less insulin requirement if diabetic Orthostatic hypotension GI symptoms Fatigue, weight loss --TYPICALLY LOSS OF CORTISOL AND ALDOSTERONE
Leuprolide mechanism
GnRH agonist: --Increase testo/DHT --then DECREASE a form of androgen deprivation therapy --abolishes pulsatile secretion
Finasteride
5a-reductase
- -increase in testosterone
- -decrease in DHT
flushing
diarrhea
bronchospasm
carcinoid syndrome
Sarcoidosis results in hypercalcemia from
Excess vitamin D (calcitriol)