Download Assessment 10 Endocrine

PaPH Assessment 10 Professor Hints
Mechanism of H axn: distinguish between the 2 classes of hormones, their
characteristics, and sites of action, including receptors
Polypeptides
Steroids
Large MW
Small MW
Fast Acting
Slow acting
Free in serum
Bound in serum
Short half life in blood
Long half life in blood
Targets surface receptors
Targets transcription
Vesicle mediated transport
Non vesicle mediated transport
Specific receptor classes: 7-TR domain (FSH,LH,ACTH,TSH,PTH,GRH,Glucagon, Dopa, TRH)
Growth factor receptors:
Group I Tyrosine kinase: Insulin, IGF,EGF
Group II (no intrinsic tyrosine kinase): GH, Prl, EPO, IL-2
Recall: Thyroid hormones bind within the nucleus
Ant pituitary: overview of nl function, know how diseases and/or pathological lesions
produce abnormalities in Hormone secretion - both hypo- and hyperpituitarism, know
clinical tests used to dx these abnormalities.
Releasing factors from Hypothalamus cause release of pituitary hormones, I will not recap the
entire endocrine physiology here. Remember that TRH also causes release of Prl, dopa inhibits
Prl and TSH, VIP also causes release of Prl, Somatostatin inhibits GH and TSH (the only ones
that are not obvious).
Hypopituitarism: Tumor (pituitary or hypothalamic), vascular ds. (Sheehan’s & pituitary
apoplexy), anything causing damage to hypothalamus
Test for pituitary
function
Insulin induced
hypoglycemia
TRH
GnRH
CRF
Hormones secreted
GH,ACTH,cortisol, Prl,
glucagon, catecholamines,
vasopressin
TSH, Prl
FSH,LH
GHRH
ACTH, endorphins,
cortisol
GH
Arginine
Sleep Study
L-Dopa
GH
GH,PRl, ACTH, cortisol
GH
Pituitary Lesion Hypothalmic Lesion
Blunted response Normal response
Blunted response Blunted or flat LH/FSH
to single dose,
increased in multiple
doses
Blunted response Prompt ACTH increase
Blunted response Normal GH increase
but may be blunted
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PaPH Assessment 10 Professor Hints
Hyperpituitarism: Hypothalmic lesions (dopa), pituitary adenomas (Prl #1, GH #2), Pituitary
hyperplasia, Ectopic tumor secreting releasing factors
Posterior pituitary: know causes, pathophys, and how to dx SIADH and DI;
know actions of oxytocin and factors responsible for its release.
Causes
Pathophysiology
Symptoms
SIADH
Malignant tumors (SCC
of lung), nonmalignant
pulmonary ds (TB),
CNS disorders
(meningitis), drugs
(narcotics)
Too much ADH
secretion
Weight gain, weakness,
lethargy, coma, etc.
Decreased serum Osm,
increased urine Osm
Dx.
Tx.
Suspect this in any
patient with low
serum osmolarity and
increased urine
osmolarity
Osmolarity
measurements, AVP
levels can be (not done
often)
Water with-holding,
vaptans
CDI
Tumor, head trauma,
CNS infections, etc.
NDI
Mutation in AQ2,
failure of V2
receptors to respond
to ADH stimulus
Not enough ADH
secretion from post.
Pit.
Polyuria, Polydypsia,
Thirst, increased
serum Osm, decreased
urine Osm
Response to ADH is
inadequate
Fail water deprivation
test, improves when
administering AVP
though
Give ADH
Fail water
deprivation test, does
not improve with
AVP
Polyuria, Polydypsia,
Thirst, increased
serum Osm,
decreased urine Osm
Oxytocin: Stimuli for release are mechanical distention of reproductive tract, suckling of nipples.
Actions: to increase uterine contraction and increase intramammary pressure during lactation. A
behavioral correlation has been made (learning, anxiety, feeding, pain perception.)
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PaPH Assessment 10 Professor Hints
Endocrine HTN: know the leading endocrine causes of htn, and the pathophys
thereof
Pheochromocytoma
Tumor within chromaffin cells
of adrenal medulla (or other
neural crest
tissue)palpitations, tremors,
headaches, high blood
pressureurinary
catecholamines /VMA
Hyperaldosteronism
(Conn’s)
Adrenal adenoma secreting
aldosterone
can result in hypernatremia
(theoretically, usually the
body compensates resulting in
normal sodium levels),
hypokalemia, metabolic
alkalosis (tetany via albumin),
swelling of feet and ankles.
Cushing’s
MOA currently debated,
probably due to direct effects
of cortisol on
mineralocorticoid receptors.
Glucocorticoids also stimulate
Angiotensin II
(vasoconstriction), and result
in increased vascular
reactivity to pressors.
Note: Can also be caused by
other problems (Chronic
Renal Failure, for example)
Remember: these are HIGH
renin problems whereas
primary is a low renin
scenario
Think: HTN and Hypokalemia
USE Aldo to PRA ratio to
determine etiology (if >50
usually primary, <30 then not
primary)
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PaPH Assessment 10 Professor Hints
Obesity: know effects of GLP, leptin, ghrelin, CCK, peptide Y, pancreatic
polypeptide
GLP
Leptin
Ghrelin
CCK
Peptide Y
Serves as a
Secreted by
Increases
Stimulates
Feeding
satiety signal fat, leads to
food intake
pancreatic
stimulates
(secreted by
satiety.
(synthesized
enzyme
works to
L intestinal
Decreases
in stomach)
secretion and cause satiety
cells), also
NPY activates stimulates
gallbladder
(inhibits
boost insulin MSH,CRH
GH.
contraction,
orixgenic
secretion and pathways
Stimulates
reduces food stuff like
suppress
(anorixegenic food intake
intake
NPY)
glucagon
pathways)
directly.
PP
Causes satiety
and reduces
food intake
after a meal
(follows
cholinergic
activation in
insulin induced
hypoglycemia)
Think: Grrr
Adrenal disorders: know the anatomy of the cortex and medulla, and where
hormones are made; distinguish among the various causes of steroid XS and clinical
manifestations thereof; distinguish between primary and secondary adrenal insuff, and
know the clinical manifestations of adrenal insuff in general; know pathophys of
mineralocorticoid excess and understand the reasons for the saline infusion test in the
workup; distinguish between different types of congenital adrenal hyperplasia
Glomerulosa: mineralocorticoids
Fasiculata: corticosteroids
Reticularis: androgens
Primary adrenal insufficiency (addison’s): most often due to autoimmune destruction of adrenal,
causes hypotension and hyperpigmentation (via ACTH and MSH feedback relation)
Secondary adrenal insufficiency: due to loss of ACTH (same signs, minus the pigmentation)
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PaPH Assessment 10 Professor Hints
Steroid excess (Cushing’s): Usually due to intake of steroids, can be due to ACTH secreting
tumors, adenoma’s, etc. (anything that causes an increase in cortisol). See below figure for
symptoms:
Mineralocorticoid excess: Hypernatremia (theoretically), Hypertension, Hypokalemia, alkalosis
(thus can have tetany). Usually hypernatremia is compensated (does not mean it will be
compensated on our assessment) and there is hypertension with hypokalemia.
Block 17α-hydroxylase leads to ↑aldo, ↓everything else
Block 21 hydroxylase leads to ↓aldo, cortisol and ↑androgens
Block 11-β hydroxylase then still have mineralocorticoids (doc), no cortisol, and increased
androgens
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PaPH Assessment 10 Professor Hints
Ovary: know normal physiology; know causes of primary and secondary
amenorrhea; know pathophys of polycystic ovary ds;
Primary amenorrhea: absence of menses by age 16
Secondary amenorrhea: absence of menses for at least 3 previous cycles
Premature ovarian failure can cause either primary or secondary amenorrhea. Also has
vasomotor problems, osteoporosis, etc.
Premature ovarian failure :
o Accelerated depletion of oocytes
o Many woman have only dysfunction of ovarian unit not allowing ovulation (not
just depletion of oocytes)
o Defined as either a failure to ovulate, failure of ovarian follicle unit, failure of
estradiol production
o FSH will be elevated in ovarian failure with estradiol decreased
o Women usually present with amenorrhea, hot flashes, night sweats, etc. due
to lack of estradiol production
 Can have consequences such as osteoporosis, etc.
o Progestin challenge test
 Has endometrium been subjected to any estradiol at all?
 Artificially give them progesterone to see if they respond
 If they do then they have a uterus and a endometrium that can function
 It also tells us that they have been exposed to estradiol
 Women with premature ovarian failure rarely respond to a progestin
challenge test, KNOW THIS
Polycystic ovarian ds.: mild hyperandrogenism, anovulation. Most common cause of female
infertility. Triad of anovulation, polycystic ovaries, and androgenism (need two of three for dx.).
Metabolic syndrome contributes to POCS.
Testis: know normal physiology; know causes of hypogonadism, especially
Kallmann's, Kleinfelter's, Prader-Willi, Noonan's syndrome; know
consequences of both androgen and estrogen excess in males
GnRH stimulates LH/FSH which stimulate Leydig and Sertoli cells to produce testosterone &
nutrients, respectively.
Klienfelter’s: XXY, small firm testes, gynecomastia, ↑gonadotropins. Absence of normal
seminiferous tubules leading to high FSH levels, leydig cells may appear hyperplastic, tall
eunuchoid appearane
Kallman’s: Hypogonadoropic hypogonadism associated with anosmia. Failure of GnRH
secetion by hypothalamus is responsible for gonadotropin deficiency leading to secondary
testicular failure. Does not respond well to clomiphene, after several pulses of GnRH the
pituitary may have a small increase in FSH/LH.
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PaPH Assessment 10 Professor Hints
Prader-Willi: obesity, hypotonia, micropenis, small hands and feet (hypothalamic ds.)
Noonan’s: Similar to Turner’s (XO), short stature, hypertelorism, webbed neck, low set ears,
cubitus valgus, ptosis, cardiovascular abnormalities.
Androgen excess: hypogonadal state, short stature, premature enlargement of penis, precocious
puberty, testis remain underdeveloped due to lack of gonadotropin stimulation
Estrogen excess: gonadoropins suppressed by estrogen resulting in secondary testicular failure
(sertoli cell tumors can do this), impotence, gynecomastia, testicular atrophy can ensue. LH/FSH
and testosterone levels will be low.
Remember: Low or inappropriately normal LH and FSH in face of low testosterone is
hypothalamic ds, whereas elevated LH and FSH is seen in testicular failure.
Thyroid: normal physiology; know pathogenesis of Graves' and Hashimoto's;
know symptoms of hyper- and hypothyroidism as well as goiter; know important
physical findings in pts with thyroid ds; know how to confirm the dx of
hyper- or hypothyroidism and goiter by lab, radiological tests; distinguish
among the 4 types of thyroid cancer; know general tx of thyroid ds - Iodine,
levothyroxine, etc.
Hashimoto’s thyroiditis: Anti peroxidase Ab leads to destruction of follicles with a lymphocytic
infiltrate (germinal centers). There can be some transient hyperthyroidism before frank
hypothyroidism. TSH will be high and T4/T3 will be low.
Graves ds.: TSI Ab constantly activate TSH-R leading to constitutive action of thyroid gland.
Know that there will be a diffuse radioiodine uptake leading to high levels of T4/T3 and low
levels of TSH (negative feedback).
Hypothyroidism: Weight gain, cold intolerance, muscle weakness, cramps, puffiness, dry skin,
somnolence, sweating, insomnia, irregular menses, poor concentration, constipation.
Hyperthyroidism: Anxiety, wt. loss, heat intolerance, muscle weakness, palpitations , irritability,
increased appetite, tremulousness, sweating, insomnia, irregular mense, poor concentration,
hyperdefecation.
Goiter: enlargement of thyroid gland, can be due to congential defects of iodine uptake, etc.
environmental factors such as low iodine intake, smoking, drugs, etc. EGF, IGF, VEGF have all
been implicated in the pathogenesis.
PE: Check eyes for exophthalmos, hair for dryness, mouth for macoglossia, neck for goiter, HR
(increase in hyperthyroidism), proximal muscle wasting (use a comb), shins for myxedema,
tremor, etc.
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PaPH Assessment 10 Professor Hints
Lab: Primary hypothyroidism (increased TSH, decreased T4/T3), Hypothyroidism ( high TSH,
low T4/T3 total thyroxine). Note: TBG is increased in pregnancy which would increase total T4
but leave the rest alone (including TSH since free T4/T3 is the same—euthyroid state).
Raioinvestigaions: Diffuse uptake= graves, adenoma=hot nodule with dampened surroundings
(neg. feedback), hypothyroidism=no image w/ no uptake. Multiple spots=toxic multinodular
goiter
Note from me: I think it would be a great way for them to ask the following question on Thyroid
disorders.
Patient presets with amenorrhea, infertility, decreased libido, increased galactorrhea. Upon
palpation a soft mass is felt near the midline of the neck slightly below the hyoid bone. What is
your first step in management?
1) Prl levels
2) Dopamine levels
3) Serum TSH
4) GnRH levels
Answer: 3, the slight mass in the midline of neck indicates probable thyroid pathology, patient is
presenting with signs of prolactinemia—prolactin levels will only confirm it is a state of
hyperprolactinemia, dopamine levels will tell you that hyperprolactin is not caused by dopamine
(which it is not), TSH would be elevated due to hypothyroidism (recall TSH releases Prl).
Remember also that Estrogen/ Contraceptives increase TBG which increases Total thyroid
hormone but has no effect on free hormone, feedback, etc. resulting in a euthyroid state with an
abnormal thyroid test.
Thyroid cancer: Recall signs of malignancy (microcalcification, irregular shape, thick wall,
absence of halo, absence of cystic elements and hypervascularity).
Papillary: 70% of malignancies, hyperplasia of cells within follicles, metastasizes to regional
lymph nodes, lungs, bone, etc.
Follicular: Less common, “Hurthle Cells”, more likely to metastasize to distal sites than papillary
carcinoma.
Medullary: “Amyloid=calcitonin”, associated with C cells, associated with MEN-2A/B. RET
oncogene.
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PaPH Assessment 10 Professor Hints
Anaplastic: Poor prognosis, rare, spreads fast.
Lymphoma: Lots of lymphocytes, presents as painless goiter.
Treatment: Levothyroxine (T4) for chronic management, T3 could be used only for short term
due to short half life. PTU or MMI block thyroperoxidase an can be used in hyperthyroidism
(graves, etc.). Li or iodine can block release of thyroid hormone (control of hyperthyroidism), βblockers used to treat symptoms, radioactive iodine used to destroy thyroid tissue, radiation can
be used in malignancy.
Mineral metabolism: know nl physiology; know causes of excess and insuff
calcium, phosphate, and magnesium; understand the mechanisms of osteoporosis,
osteomalacia, and Paget's ds
PTH increases calcium in blood (low plasma Ca stimulates). PTH activates osteoblasts and
osteocytes which bind to osteoclasts thereby activating them (RANK-RANKL). Net result is
increased bone resorption, upregulates 1-alpha hydroxylase in the kidney. PTH increases renal
absorption of calcium and decreases phosphate reabsorption.
Calcitonin does basically opposite of PTH (inhibits osteoclasts)
Vitamin D increases calcium and phosphate levels.
Excess calcium: lethargy, coma, dehydration (via inhibition of ADH), shortens QT interval.
Causes: primary hyperparathyroidism (parathyroid adenoma). Secondary hyperparathyroidism
(renal failure, diarrhea, pancreatic insufficiency), malignancy (accounts for most cases)
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PaPH Assessment 10 Professor Hints
Low calcium: Hypoparathyroidism (decrease Ca, increase phosphate),
Pseudohyoparathyroidism (receptors unable to make cAMP in response to PTH), Low Mg
(decreases PTH action and secretion) results in neuromuscular hyerexcitability, convulsions, etc.
Hyperphosphatemia: renal insufficiency can cause this, it reduces ionized alcium resulting in
elevated PTH secretion.
Hypophophatemia: Can be due to familial hypophasphatemia or hyperparathyroidoism.
Hypermagnesia: Occurs in renal insufficiency, reduces neuromuscular excitability and can result
in coma.
We really didn’t talk about osteoporosis/osteomalacia/Paget’s in class or in the notes but…
Osteoporosis: Loss of bone density (T score <-2.5)
Osteomalacia: Vit. D deficiency in adults, “brittle bone”
Paget’s: Increase bone formation and absorption leading to lytic lesions , person who has to
change their hat due to increased skull size with increased ALP.
MEN: know definition, genetics, need for screening and what to screen for,
and manifestations of the 3 syndromes
Definition: A group of disorders characterized by functioning tumors in more than one
endocrine gland, an autosomal dominant inheritance pattern and, for some, the ability of affected
cells to exhibit amine uptake and decarboxylation (APUD cells)
Genetics
Manifestation
Screening
MEN-1
MEN-1
MEN-2A
RET
MEN-2B
RET
Chromosome 11
Chromosome 10
Chromsome 10
(Codons 609,611,918)
Pituitary, Pancreatic
tumors (Zollinger
Ellison, Insulinoma),
hyperparathyroidism
Medullary carcinoma
of thyroid
Pheochromocytoma
Hyperparathyroidism
Screen for
catecholamines,
calcium
She said to know
these in class.
Medullary carcinoma
of thyroid
Pheohromocytoma
Marfanoid
Neurinomas
Screen for
catecholamines and
calcium
Fun fact: What famous person in history had MEN-2B?? Abraham Lincoln.
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PaPH Assessment 10 Professor Hints
Lipoproteins: know nl physiology and a general overview of various lipid disorders,
including what apolipoproteins are where, effects of hepatic lipase, what the atp binding
cassette transporter receptor does as well as chol ester transfer protein, features of familial
combined hyperlipidemia and familial hypercholesterolemia
Normal physiology:
Hypobetalipoproteinemia: Lower LDL (most are asymptomatic due to heterozygosity),
decreased ApoB due to truncation, etc. Some patents have fatty liver. Fat soluble vitamin def.
Acanthocytosis, neuromuscular degeneration, etc.
Abetalipoproteinemia: Absolute deficiency of MTP, can’t transport triglycerides and cholesterol
between phospholipid surfaces, can’t form lipid droplet.
Excess ApoB:
Familial combined hyperlipidemia: elevated TG, cholesterol, or both. Increased number of
VLDL but VLDL are normal. (Could be due to a def. of LPL)
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PaPH Assessment 10 Professor Hints
Hyperapolipoproteinema: Increased apoB in LDL density range, LDL particles are “heavier”
more dense than normal LDL.
Familial hypertriglyceridemia (FHT): Increased production of TG, very large VLDL, Type IV
profile.
Familial hypercholesteronemia: Defects in LDL-R, results in cholesterol levels of 250-600
mg/dl, Affected begin having MI’s by their twenties, xanthoma’s can appear (heterozgotes),
homozygotes have MI’s before the age of 10, high cholesterol diet and hypothyroidism can give
a similar profile.
ATP Binding Cassette Protein is upregulated when there is excess cholesterol in a cell, in order
to secrete more cholesterol and phospholipids (Tangier’s ds. Is a deficiency of this).
Lecithin cholesterol acyltransferase, LCAT transfers FA from phospholipid to form a cholesterol
ester. Occurs only on HDL since ApoA1 is required for LCAT activity (and HDL has ApoA1)
Hepatic lipase takes HDL into liver to be destroyed.
Cholesterol ester transfer protein (CETP): Transfers cholesterol esters and TG between various
lipoproteins.(ie. VLDL gives TG to HDL, HDL gives CE to VLDL via CETP). Therefore, high
TG cause decreased levels of HDL (down the gradient), heptic lipase also takes TG and
phospholipids out of HDL allowing ApoA1 to be degraded and thus lowering levels of HDL by
stopping ApoA1/HDL recycling.
Some CETP mut cause atherosclerosis with high HDL, others protect from atherosclerosis.
Increases in hepatic lipase decrease HDL. KNOW THIS. (Estradiol and adiponectin ihibit
hepatic lipase)
Apolipoproteins: ApoA1: HDL, ApoB48 –CM, ApoB100 VLDL, ApoCII cofactor for LPL,
ApoCIII inhibits LPL, ApoC1 inhibits CETP, ApoE binds LDLR and functions in reverse
cholesterol transport
Diabetes: know nl physiology of the endocrine pancreas; define diabetes, impaired glc
tolerance, impaired fasting glc, and gestational diabetes (current dx criteria); distinguish
between type 1 and type 2 dm; know causes of insulin resistance, and distinguish this from
metabolic syndrome; know risk factors for diabetes; know significance of glycated Hb
(HbA1c); know inheritance
Beta cells secrete insulin (more in head of pancreas), alpha cells secrete glucagon (more in tail),
delta cells secrete somatostatin which decreases both of the aforementioned hormones.
Diabetes is defined as >126mg/dl random fasting glucose, >200mg/dl random glucose (or 2h
PG), >6.5% Hba1c. Impaired glucose tolerance is >100-125 mg/dl fasting glucose, >140-199
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PaPH Assessment 10 Professor Hints
mg/dl after a meal, 5.7-6.4% HbA1c. GDM is diabetes in pregnancy, can cause increased birth
weight and other issues.
Insulin resistance can be exacerbated by obesity, sedentary lifestyle, aging, etc.
Metabolic syndrome: High BP, dyslipidemia, central obesity, etc.
Hba1c is a measure of blood glucose over the past 120 days (RBC life cycle—RBC’s
glycosylated via hyperglycemic conditions)
Risk factors for diabetes: weight, lifestyle (sedentary), central obesity, age, genetics, ethnicity
Hyperglycemic crises: know dx criteria for DKA and HHS; know precipitating
factors; distinguish between the pathogenesis of DKA and HHS
Severe DKA:
Glucose >250m/dl, pH<7.00, Bicarbonate <10 mEq/L, ketones +, osmolarity variable, Anion
gap>12
HHS (Hyperosmolar Hyperglycemic State): Glucose >600mg/dl, pH>7.30, Bicarb>15 mEq/L,
ketones small amounts, >320mOsm/kg, variable anion gap
Remember that HHS has higher glucose levels, higher osmolarity, higher pH and less ketones
than DKA.
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PaPH Assessment 10 Professor Hints
Pathogenesis of DKA:
Some initiating insult occurs, causing an acute decrease in insulin and increased counterregulatory hormones (glucagon, cortisol, catecholamines, growth hormone, prolactin, etc.). This
occurs since throughout millennia of evolution humans have evolved their metabolism to
preserve glucose levels at all cost in order to support the brain. Therefore, if there is an acute
injurious state the body tends to favor things that increase glucose levels.
InsultAcute insulin insufficiencydecrease glucose useincrease blood glucose glucosuria
(once Tm has been exceeded)polyphagia due to giving out so many calories in
urinepolydypsia since losing liquids via osmotic action of glucose in
urinedehydrationcirculatory failure
At the same time since there is a decrease in insulin there is an increase in FFA mobilization
increase FFAincrease FFA oxidationincrease ketone bodiesincrease ketonesdecrease
alkali reserveacidosis
FFA is the most important culprit as it shuts down glycolysis (PFK, HK, etc. all inhibited)
Protein break down ensues via the same token since there is less insulinincrease plasma
AAincreased BUN (urea cycle)increase GNGincrease glucosedehydration and
circulatory failure
Note: The pathogenesis of HHS is more of the same except for that in HHS there is less of an
absolute insulin def. (more of a relative) leading to more of the dehydration, impaired renal fxn,
etc. leading to hyperosmolarity. In DKA the absolute insulin def. requires that there is increased
ketosis due to the breakdown of fatty acids. In HHS there is usually decreased fluid intake
leading to a hyperosmotic state (think nursing home pt.).
Tx. Normal saline first to get ECF back up, then hypotonic in order to get ICF up.
Chronic Complications of DM: know the micro- and macrovascular
complications in general terms; know the pathophys of the complications non-enzymatic glycosylation, changes in the extracellular matrix, sorbitol
pathway, oxidation and ROS
Basic Characteristics:
Visceral fatty tissue secretes excessive FFA’s, leptin, TNF, AT II, PAI-1 while reducing
adiponectin.
Excessive glucose and FFA’s stimulate ROS production (via mitochondria) which activate
serine/threonine kinases and PKC. Superoxide can be generated via CoQ10 in the electron
transport chain. Under conditions of high FFA’s more electrons (NADH—beta ox) are dropped
off through the ETC leading to an overwhelming of CoQ10’s ability to move them & thus free
radical generation (H+ inhibits electron unloading from CoQ10).
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PaPH Assessment 10 Professor Hints
Nitrous oxide is the primary endogenous inhibitor of NF-kB, its deficiency allows inflammation
to go unchecked, in addition NO is a very potent vasodilator and it’s deficiency leads to
vasoconstriction and ischemia.
Excess glucose also leads to activation of PKC via sorbitol and AGE products, a deficiency of
myo-inositol leads to activation of PKC as well. Ceramide induces NO, NO is a pro-apoptotic
molecule (good in plaque’s, bad in islet cells)
Oxidation and ROS
Sorbitol Pathway
Increase in FFABeta
oxIncrease
NADHdecrease FA
oxidation and glucose
oxidationpartially
degraded FA’s bound to
carinitine and inhibits
more FA into the
mitochondirathese
FA’s accumulate
elsewhere G3P also
builds up (redox state,
via
glycolysis)metabolized
into GAP/DAGPKC
activation
Too much glc enters cells
that have aldose
reductaseglc to
sorbitolthen to fructose
which is a more potent
glycosylator (usually
fructose is blocked due to
redox state of cells and
sorbitol accumulates
though). Accumulation of
sorbitol osmotically
activeswellingblurring
of vision, etc.
NADPH oxidase on
vascular cells stimulated
by glucose, TNF,
neutrophils,
macrophages, etc. all
lead to Superoxide
which is potent
activator of PKC!
Hyperosmotic state
stimulates AMPKinase
which activates DAG
PKC activated
Also stimulates
JNK/MAPK which
stimulate apoptosis
Non-enzymatic
Glycosylation
Glucose covalently
interacts with
proteinsschiff
base
formedaramdori
product formed
slowly
Advanced
glycosylation end
products are formed
(irreversible)
ECM
Collagen
synthesis is
stimulated by
TGF beta and
inhibited by
NO,
proteoglycans
are inhibited by
PKC (ie.
Heparin sulfate
in the
glomerulus)
Macrophages and
endothelial cells
have a RAGE
receptor which binds
to AGE and takes
them upactivates
PKC
Sorbitol also blocks
inositol transport into a
cell, inositol is key for
many second messenger
pathways in cells, cells
require an abundance of
phosphatidylinositol to
function (recall IP3/DAG
second messenger system)
also shuts down Na/K
ATPase of cell
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PaPH Assessment 10 Professor Hints
Three organs mostly affected by diabetes (triopathy): Eyes (retinopathy), nerves (neuropathy),
and kidneys (nephropathy). Most often, the cause of death in diabetics is atherosclerotic
vascular disease.
Kidney:
Perfusion pressure increases soon in diabetic ds., causes both of the arterioles (Afferent and
efferent) to become dysfunctional and dilated. The kidneys enlarge by up to 50% in these case,
GFR is therefore also increased. As nephropathy progresses proteinuria develops
(micoabluminuria). Severity of proteinuria correlates with increase in basement membrane
collagen and reduction in heparin sulfate (charge/size filter disruption). Eventually GFR falls
due to encroachment of mesangial sclerosis (loss of nephorns—patient now becomes
hypertensive)
Eye:
Retinopathy due to diabetes is leading cause of blindness in USA. Can lead to both macular
edema and neovascularization. Early on there is a loss of pigmental epithelial cells resulting in
increased levels of fluorescin. Pericytes inhibit endothelial migration, they also contain aldose
reductase pericytes die and microaneurysms ensue. Exudates and hemorrhages form from
eaking capillaries, if the occurs between retina and choroid the retina will lose its nourishment
and die. If it occurs near the maculamacular edema (leading cause of vision loss in
diabetics). Ischemia results due to all of thee processes, VEGF is released and new blood
vessels formhemorrhage is very likelyblood is released and patient can’t seeglaucoma can
occur as a sequela to this. Laser photocoagulation therapy can be used to tx.
Neurons:
Happens within days of developing diabetes. Long nerves are most susceptible (peripheral
neuropathy in feet). Pressureischemiainflammation (process of injury to diabetic foot).
Pressure to capillaries in foot cause ischemia (After several hours of these there is inflammation,
etc. but they cannot feel the pain that should be associated with this). Get the patient off their
feet! Autonomic neuropathy can also complicate things (Gastroparesis, silent MI, etc.).
Mononeuropathies also can occurentrapment syndromes, etc.
Macrovascular ds.
Atherosclerosis. Three factors contribute to increased risk:
Leaky endothelium, glycosylation of lipoproteins, hyperglycemia.
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