1
Q
what drugs increase the risk of gout
A
thiazide diuretics
cyclosporines +tacrolimus
allopurinol + probenecid *initial increase in risk of acute gout attacks)
2
Q
describe the HPA axis for prolactin
A
3
Q
what effect do mental/emotional and physical stress have on blood glucose levels
A
physical stress (i.e. excercise) –> hypo-glycemia
mental/emotional stress –> hyper-glycemia
4
Q
general symptoms seen in glycogen storage disorders vs lysosomal storage disorders
(list the big examples of each)
A
GLYCOGEN STORAGE DS
- hypoglycemia, change in blood lactate levels, change in skeletal M tone, myoglobinurea
- secondary effects on cardiac myscle
- GLYCOGEN ACCUMULATIONS WILL STAIN PAS+
- 1= von gierke : 2=pompe : 3= cori : 4=mcardle
LYSOSOMAL STORAGE DS
- neurodegeneration/demyelination, angiomatosis-like processes, changes in marrow EPO
- secondary effects on liver+spleen (extramedullary hematopoeisis)
- SPHINGLIPIDOSES (tay-sachs, niemann pick, gaucher, fabry, kravve, metachromatic leukodystrophy) + MUCOPOLYSACCHARIDOSES (Hurler+Hunter)
5
Q
who are the three regulators of glycogen levels in the body and how do they exert their effect
A
glycogen is stored in the liver and in skeletal M
- glucagon + epinephrine –> stimulate glycogen phosphorylase kinase –> phosphorylate glycogen phosphorylase –> breakdown of glycogen into glucose
- glucagon: liver glucagon receptors = Gs-linked –> cAMP–> PKA–> inc GPK
- epinephrine: liver+M (beta)R = Gs-linked –> cAMP–> PKA–> inc GPK
- epinephrine: liver alpha-R = inc Ca release from ER –> inc GPK
- insulin –> stimulate glycogen synthase –> build glucose into glycogen
- TRK dimerization on liver –> inc protein phosphotase –> inc GS
6
Q
where in the body do these occur?
- glycogenesis
- glycogenolysis
who are the big enzymes in these processes
which diseases are associated with each?
A
liver and sk. M >> adipose - CYTOPLASM
GLYCOGENESIS: glucose –> glycogen
- glucose –> G6P –> G1P…
- G1P –> UDP glucose = UDP-glucose pyrophosphorylase
- UDP-glucose –> glycogen = glycogen synthase
- add a branch to glycogen = branching enzymes
GLYCOGENOLYSIS: glycogen –> glucose
- first step= RATE LIMITING STEP = glycogen phoshphorylase will take G1Ps off the end of a branch until there are just 4 G1Ps left on the branch
- x (in M cells only) = McArdle Ds
- OR lysosomal alpha-1,4 glucosidase can break down branched glycogen into glucose directly
- x= Pompe Ds
- debranching enzymes : x= Cori Ds
- will relocate the 3 G1Ps at the end of the branch to the end of the main stem =4-alpha-D glucanotransferase
- debranch the last G1P = alpha 1,6 glucosidase
- once debranched, removed each G1P at a time –>
- G1P –> G6P –> glucose
- G6P –> glucose = glucose 6 phosphatase x = Von Gierke Ds
- G1P –> G6P –> glucose
7
Q
McArdle Ds, Cori Ds, Pompe Ds, Von Gierke Ds
- x enzyme –> what builds up, what cannot be made
- clin features
- blood glucose levels
- other key lab findings
A
McArdle Ds <em>McArdle McMuscle Man</em>
- x enzyme
- x glycogen phosphorylase IN THE SKELETAL M, enzyme intact in the liver
- build up of muscle glycogen, but defiency of glucose in the skeletal M
- clin features
- only have M sx = M cramps and myoglobinuria after intense excercise / high glucose demand on Muscles that can’t be met
- pain with excercise
- blood glucose levels
- normal
- other key lab findings
- inc CK, urine is red but MYOglobin= no RBCs in urine, inc M BF in an attempt to provide more nutrients and glucose
- electrolyte abnormalities –> arrythmias
- no lactic acid production during excercise, normal ammonium production
CORI DS *Cori Coral Branches on Mild Beaches*
- x enzyme
- = debranching enzymes: α-1,6-glucosidase and 4-α-d-glucanotransferase
- clin features
- mild hypoglycemia, mild inc TG
- gout, liver and renal inc size
- cardiomyopathy
- blood glucose levels
- mild hypoglycemia
- other key lab findings
- normal blood lactate
- NORMAL gluconeogenesis (pyruvate–>glucose), impaired glycogenolysis (glycogen–>glucose)
POMPE DSAbn Cell-Volcano (lysosome) –> systemic destruction, death
- x enzyme
- x lysosomal acid α-1,4- glucosidase (acid maltase) (cannot break linked G1Ps)
- n lysosomal acid α-1,6- glucosidase
- clin features
- hypotonia, proximal M wknss+dystrophy, resp M wknss
- excercise intolerance
- cardiomegaly+hypertrophic cardiomyopathy
- early systemic findings + death
- blood glucose levels
- normal
- other key lab findings
- x heart, liver, and muscle activity
VON GIERKE DS
- x enzyme
- x glucose-6-phosphatase
- build up of G6P, glucose deficiency
- clin features
- SEVERE FASTING hypoglycemia,
- inc uric acid –> inc GOUT
- hepatomegaly, renomegaly
- blood glucose levels
- severely low
- other key lab findings
- inc TGs
- INC BLOOD LACTATE (vs Cori)
- inc glycogen build up in liver and kidneys
- x glycogenlysis AND gluconeogenesis –> require frequent oral glucose intake
- AVOID FRUCTOSE AND GALACTOSE (bc cannot make glucose)
8
Q
ketoacidosis develops from the lack of insulin due to what function of insulin failiing to be carried out
A
inhibition of lipolysis and ketogenesis
9
Q
tingling and M cramps results from ____calcemia
A
HYPOcalcemia i..e chvostek’s sign
10
Q
at what step does insulin affect glycolysis
A
insulin –> inc phosphofructokinase-2 (PFK2)
fructose 6-phosphate –> fructose1,6 bisphosphate
=inc glycolysis
11
Q
what pathways induce releases insulin from the pancreatic beta cells
A
GLUCOSE-GLUT2
- glucose enters the beta cells through GLUT-2
- glucose–glucokinase–> glucose-6-phosphate
- G6P enters glycolysis, produces ATP
- inc ATP –> closure of ATP-sensitive K channels on the beta cell membrane –> stop outflow of K+ –>depolarize beta cells
- depolarization of beta cells triggers opening of voltage-dependent Ca channels on membrane –> inc Ca influx into beta cells
- inc Ca levels –> insulin release
GLP-1
- glucagon-like peptide 1 binds to GLP-1 receptor on beta cells
- inc intracellular cAMP
- insulin release
12
Q
embryologic malfunction in digeorge syndrome that leads to hypocalcemia?
A
failure of neural crest migration into the third and fourth pharyngeal pouches
- x third pouch –> x inferior parathyroid+ thymus
- x fourth pouch –> x superior parathyroid
13
Q
how do defects in fructose metabolism present
- etiology +pathophys
- clin
- trx
A
essential fructosuria =
- x fructokinase = x fructose–>fructose-1P
- benign, fructosuria because of compensatory hexokinase activity (converts fructose–>F6P so it can enter glycolysis)
hereditary fructose intolerance =
- AR x adolase B = x fructose1P–> DHAP –>GAP-3P (enter gluconeogenesis
- build-up of toxic fructose 1P–> depletion of intracellular phosphate + inhibition of gluconeogenesis
- present with severe, lifethreatening hypoglycemia when baby starts to consume formula or real food
- not only are they not breaking down fructose, but they are not producing glucose from gluconeogenesis
- hypoglycemia –> pale, diaphoretic, lethargy, V/D
- trx = stop intake of fructose, sucrose (fructose+sucrose), and sorbitol (metabolized into fructose)
14
Q
what four functions will pyruvate go on to play in the body and what cofactors are needed for each function
A
15
Q
what essential substances are derived from the following amino acids
- phenylalanine
- tyrosine
- tryptophan
- histidine
- glycine
- glutamate
- arginine
A
16
Q
how deficiencies in the enzymes needed for glycolysis typically present?
what are the important enzymes in this pathway?
A
hemolytic anemia –> without glycolysis, RBCs will die
17
Q
in what 3 ways can a 21-alpha hydroxylase deficiency present
what changes will be seen in the adrenal gland
A
=adrenal cortex hyperplasia
18
Q
what is the clinical indication for thiazolidinediones and what is their mechanism of action
A
thiazolidinediones
=class of drugs use to treat insulin resistance
- bind to PPAR-y (peroxisome-proliferator-activated receptor gamma) in the nucleus
- PPAR-y is a nuclear receptor and transcription factor that will bring RXR when activated by the TZD
- PPARy-TZD binding to DNA will result in
- inc FA uptake and adiponectin production, dec leptin production
- inc insulin sensitvity in liver and M
- dec TNF-alpha production
19
Q
what is the pathway that leads to creation of ketone bodies
A
hormone sensitive lipase is activated by: stress hormones (ACTH, catecholamines, glucaon)
20
Q
which endocrine hormones are NOT lipophilic and must bind surface
- G protein coupled receptors
- tyrosine kinase receptors
A
- G protein coupled receptors
- ACTH, ADH, epinephrine, glucagon
- tyrosine kinase receptors
- insulin, growth hormone
21
Q
what is the clinicial indication for and MOA of dipeptidyl peptidase-4 inhibitors
A
improves glycemic control and decreases hgbA1C
22
Q
how does congenital hypothyroidism present
A
as maternal T4 wanes (a couple months): baby becomes difficult to rouse from naps + lethargic
–>puffy face and irreversible intellectual disability
-trx with levothyroxine starting at 2 weeks can prevent the development of sx
23
Q
phenylalanine metabolism requires what cofactors
A
dihydrobiopterin reductase
24
Q
list the 6 big lysosomal storage diseases
- x enzyme, inheritance
- accumulation of what
- clinical features
- special lab/test/histo findings
A
Tay Sachs Ds
- x AR hexosaminidase A heXosaminidase x in taysaX(1)
- accumulate GM2 ganglioside
- neurodegeneration+developmental delay, hyperreflexia,
- cherry red spot on macula, onion skinning of lysosomes
Niemman-Pick Ds
- x AR sphingomyelinase (6)
- accumulation of sphingomyelin,
- progressive neurodegeneration, hepatomegaly (in contrast to taysachs)
- cherry red spot on macula, foam cells (lipid laden macrophages)
gaucher ds
- x AR glucocerebrosidase (5)
- inc glucocerebroside
- MC OF ALL DSs: hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of the femur
- Gaucher cells= lipid laden macrophages that looked like crumpled up tissue paper
Fabry ds
- XR x alpha galactosidase A (2)
- inc ceramide trihexodase
- early= TRIAD : episodic peripheral neuropathy + angiokeratomas (small dark spots on the skin) + hypohidrosis (dec sweating)
- late= progressive renal failure + CV ds
Krabbe ds
- AR x galactocerebrosidase (4)
- inc galactocereroside
- peripheral neuropathy, destroyed oligodendrocytes, developmental delay
- optic atrophy, globoid cells (giant multinucleated cells)
metachromatic leukodystrophy
- AR xarylsulfatase
- cerebroside sulfate
- central and peripheral demyelination w ataxia+dementia
25
what is the mechanism of action of glyburide
what other medication is in the same class as this drug
glyburide = a sulfonylnurea second generation
* close ATP-sensitive K-channels on pancreatic beta cell membrane --\> inc intracellular Ca --\> release insulin INDEPENDENT OF GLUCOSE LEVELS
glipizide + glyburide = 2nd gen sulfonylurea
26
what are the 4 big MOAs of DM drugs
what are the drug classes
1. inc insulin sensitivity
1. **metformin** : inhibit mGPD--\> x hepatic gluconeogenesis , inc glycolysis and peripheral glucose uptake
2. **glitazones** (aka thiazolidinediones) : activate PPAR-y = regulate glucose metabolism and fatty acid storage
2. inc insulin secretion (glucose independent)
1. **sulfonylurea (1st gen= chlorpropamide, tolbutamide) (2nd gen= glipizide, glyburide), meglinitides ("-glinide")** = close K+ channels--\> release insulin via inc Ca
3. inc glucose induced insulin secretion
1. **GLP-1 analogs**= **exenatide, liraglutide** --\> dec glucagon release and gastric emptyinh, inc insulin release w glucose
2. **DPP-4 inhibitors** (-glips) --\> inhibit the GLP-1 inhibitors, so increase the actions of GLP-1
4. decrease glucose absorption
1. **Na-glucose cotransporter 2 (SGLT2) inhibitors "-gliflozin"** --\> block reabsorp of glucose in PCT
2. **alpha-glucosidase inhibitors (acarbose, miglitol)** --\> inhibit intestinal brush border alpha glucosidase --\> dec prostprandial hyperglycemia
27
what type of insulin is prescribed for
* once daily use
* twice daily use
* post-prandial use
* IV use for DKA
* once daily use
* basal long acting: **glargine, detemir, degludec**
* twice daily use
* basal intermdiate acting: **NPH (isophane)**
* post-prandial use
* short acting (peak 0.5-3 hrs): **lispro, aspart, glulisine**
* IV use for DKA
* short acting, **regular** insulin: peak 2-5 hours
28
what process is disrupted by anti-TPO enzymes
thyroglobulin iodinization
29
how do the following affect the pathway that leads to Vit D synthesis
* sunlinght
* PTH
* Ca
7-dehydrocholesterol **--UV LIGHT--\>** cholecalciferol --\> 25 hydroxy-VitD
PTH and Ca work on 25VitD --1-alpha-hydroxylase--\> 1,25 VitD in the liver
PTH= inc, Ca= dec
30
in general, patient's with DM are most likely to die from what
coronary heart ds (MI)
31
what are the endocrine effects of a prolactinoma
32
describe the mechanism by which CKD can lead to changes in serum Ca and bone density
CKD --\> dec 1,25VitD production
* --\> dec Ca reabsorption from small intestine
* --\> secondary inc in PTH = secondary hyperparathyroidism
* --\> inc osteoclast activity = renal osteodystrophy
33
which class of anti-hyperlipidemics is most effective at
* dec LDLs
* dec TGs
* inc HDLs
* dec LDLs
* statins
* dec TGs
* fibrates
* inc HDLs
* niacin
34
does oral glucose or IV glucose have a greater effect on insulin release into the body
why
oral glucose : bc will stimulate incretins which will further inc insulin release
* GLP-1
* gastric inhibitory protein (GIP)
35
which substance will provide feedback to determine whether pyruvate will enter the TCA cycle or gluconeogenesis
what enzymes are involved?
36
what changes are seen in the pancreas in DM type 1 vs type 2
Type 1 DM = islet infiltration with leukocytes (associated with HLA and anti-islet Abs)
Type 2 DM= amyloid deposition
37
what are the clinical manifestations of a urea cycle disorder
what is the most common urea cycle disorder
characterized by high blood ammonia levels (hyperammonemia)
* metabolic emergency : episodes of vomiting and confusion/coma
* tachypnea with central hyperventilation and respiratory alkalosis
* presents in young age: the acute decompensation is triggered by a preceding illness (viral URI, otitis media), prolonged fasting time, or inc protein intake
MC cause = ornithine transcarbamylase deficiency
--\> excess carbamoyl phosphate --\>inc urinary orotic acid
38
what is pituitary apoplexy
in whom does it occur
how does it present
39
the effectiveness of SGLT-2 inhibitors is dependent on \_\_\_\_, which means patient's should have their ____ measured before starting therapy
1. glomerular filtration rate of glucose
2. serum creatinine (estimate of GFR)
40
3 major precautions/ contraindications to metformin therapy
41
what are the two major side effects of "-glitazone" therapy for DM?
inc fluid retention (edema, decompensation of congestive heart failure)
weight (fat) gain
42
clinical presentation of hypercalcemia
what can cause this
hypercalcemia:
-lethargy, loss of appetite, constipation, weakness, inc thirst and urination, stupor, dry mucus membranes, nephrolithiasis, bone pains (long term)
occur in: Vit D toxicity, sarcoidosis/TB (granulomatous ds), hypercalcemia of malignancy, hyperparathyroidism, Hogkin lymphoma, some NHLs
43
what is the function of the smooth ER
producle lipophilic compounds = lipids, phospholipids, cholesterol and their derivatives (STEROID HORMONES)
44
how will defects in fatty acid metabolism / beta oxidation present clinically
they'll present after a long period of fasting (~ a day for kids, longer for adults)
* normally, the body will start to break down ketones after a certain period of fasting
* in patients with abn beta oxidation, they can't break make ketones so their body will be unable to cope to long periods of fasting (ie. no glucose intake)
* --\> **HYPOKETOTIC HYPOGLYCEMIA =labs will show undetectable acetoacetate levels**
* they'll also have liver disfunction, and a metabolic crisis (seizure, coma, death)
45
which diabetic treatment medications can result in AE of weight change
which can have the AE of diarrhea
weight gain= sulfonylureas, meglinitides, pioglitazone
weight loss= exinatide, liraglutide
diarrhea= metformin, acarbose, miglitol
46
what is heriditary orotic aciduria and how does it present clinically
what drugs can disrupt the same pathway that is disrupted in HOA
xUMP synthase = disrupt pyrimidine synthase pathway --\> inc orotic acid crystal build up
* babies with physical and mental retardation, megaloblastic anemia, and elevated orotic acid crystal build-up
hydroxyurea, 5FU, MTX, TMX, pyrimethamine
47
what is the pathogenesis and trx of exophthalmos
pathogenesis--\> inflammatory infiltrate and T-cell activation in response to TSH activation of orbital fibroblasts
trx= steroid immunosuppression
48
when and how are triglycerides broken down for E
which enzymes are involved
broken down when in a state of fasting / low insulin
lipase, glycerol kinase,
49
how does somatostatin affect the gallbladder
inhibit CCK--\> dec biliary motility = biliary stasis --\> inc risk gallstones
50
what are the 4 big enzymes in the pentose phosphate pathway
what cells/organs is the PPP really important for
G6PD, 6PGD, transketolase, transaldolase
PPP needed in:
* cells with high oxidative stress (erythrocytes) bc they need the PPP to make glutathione = an antioxidant
* liver and adrenal cortex: fatty acid+cholesterol+steroids synthesis,
* phagoyctic cells: NADPH needed for the respiratory burst
51
MOA of drugs used to treat hyperthyroid
52
how does TNF-alpa affect insulin function
TNF-alpha (inflammation) causes **insulin resistance**
when insulin binds, it the RTK activates intracellular IRS-1--\> GLUT4 moved to the membrane
-**TNF-alpha stimulates serine phosphorylation which inactivates IRS-1**
53
how does pyruvate dehydrogenase deficiency present
what is the treatment
54
via what intracellular mechanism does insulin cause glycogen breakdown
55
what are the clinical complications of fabry ds
56
what are the three categories of drugs used for weight loss
57
AFTER 24 HOURS- glucose is maintained by GLUCONEOGENESIS not glycogenlysis anymore
58
59
what histology is seen in hashimoto's thyroiditis vs de quervain's thyroiditis
60
61
what effect does hypothyroid have on cholesterol levels
be specific
62
what physical findings are specific to graves disease
63
64
MOA of diabetic medications "-gliflozin"s
how do they treat diabetic nephropathy
reduce glomerular hyperfiltration
65
histology of follicular adenoma va follicular carcinoma in the thyroid
66
67
68
69
SIADH = (hyper/hypo/eu) volemic & (hyper/hypo/eu)natremic
70
compare the onset and duration of the diff insulins
aspart, lispro, glulisine = short onset, short acting
Gals And Lads
regular, NPH = short onset, med acting
Rest Now
detemir, glargine = long onset, long acting
Don't Go
71
will SIADH present with peripheral edema?
no:
* inc water resorption without Na resorp --\> hypervolemia
* suppress RAAS and inc ANP = atrial natriuretic peptide
* --\> natriuresis = lose the fluid but still lose NA
* =euvolemic hyponatremia
no signs of hypervolemia = no peripheral edema, elevated JVP, pulmonary edema/crackles
72
how will a high carb diet / the fed state affect the biochemistry of fatty acid metabolism
= inc fatty acid synthesis, and dec beta oxidation
-main mechanism of finding the correct balance is at the carnitine shuttle, which seperates the two systems
* synthesis in the cytosol
* beta oxidation in the mitochondria
malonyl Co-A = the product of the rate limiting step of fatty acid synthesis
* negative regulation of the carnitine shuttle between cytosol and mitochondria
* block precursors from entering mitochondria = no beta oxidation
73
clin presentaiton of
primary carnitine deficiency
mitochondrial acetyl Coa dehydrogenase deficiency
74
describe levels of **serum Na, K, bicarb, H, renin** in Conn Syndrome
Conn Syndrome = primary hyperALD
75
in T1-DM patients treated with exogenous insulin, how does risk of hypoglycemic episodes change over time
increase: because exogenous insulin is not subject to regulation by glucagon, alpha cells eventually atrophy overtime secondary to non-use
dec glucagon --\> inc risk of hypoglycemia
(they'll also have blunted autonomic response to hypoglycemia (epinephrine), but the effect is not as significant on blood glucose levels
76
differentiate the major clinical manifestations of
* familial hyperchylomicronemia
* familial hypercholesterolemia
* familial dysbetalipoproteinemia
* familal hypertriglyceridemia
77
which enzymes catalyze the production of dopamine, NE, and epinephrine respectively
PNMT= phenylethanolamine-N-methyltransferase
78
what is the biochemistry and clinical presentation of Maple Syrup Urine Ds
79
differentiate treatment of
* maple syrup urine disease
* PKU
* homocysteinuria
80
what three reaction require biotin (vitamin b\_) as a cofactor
what leads to biotin deficiency and how will a deficiency present
81
etiology and presentation of Hartnup Ds
82
what does leuprolide change levels of T and DHT in the serum
=GnRH agonist
initial rise, then fall --\> trx prostatic hyperplasia
83
what does the metyrapone stimulation test reveal?
how does it work/what changes are seen in n and abn test?
84
what is the pathogenesis of stress hyperglycemia
85
what substance is given to patients exposed to large amounts of radiation in order to protect the thyroid
potassium iodide
will competitively inhibit the uptake of RADIOACTIVE iodine
86
what formation of insulin will best mimic the natural release of insulin in the body
87
what is the clinical presentation of sufonylurea abuse?
what is the whipple triad?
88
describe pancreatic function in cystic fibrosis
89
mutations, inheritance, and tumors seen in
MEN1
MEN2A
MEN2B
ALL ARE AD
MEN1
* AD xMEN1 gene (chr 11)
* pituitary, pancreas, parathyroid
MEN2A
* AD xRET (neural crest)
* parathyroid, medullary thyroid, pheochromocytoma
MEN2B
* AD xRET
* medullary thyroid, pheochromocytomas, mucosal neuromas (ganglionomas on tongue/lips)
* +marfanoid habitus
90
how do serum levels of FFA contribute to the pathophysiology of T2DM
91
92
what is reverse T3
how does treatment with exogenous T3 affect levels of rT3
rT3 is an inactive form of T3 that is made entirely from the conversion of peripheral T4
w exogenous T3 supplementation --\> dec TSH+T4 --\> dec rT3
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