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Lipoprotein Particles
Density (g/ml)
0.95
VLDL
Chylomicron
VLDL
Remnants
1.006
IDL
1.019
Chylomicron
Remnants
LDL-R
1.050
1.063
HDL2
Lp(a)
1.100
HDL3DL3
1.20
10
20
40
60
80
1000
Blood
Monocytes bind to
adhesion molecules
Smooth muscle
Inflammatory
response
Modification
Macrophage
Foam cell
Intestinal Cholesterol
Biliary
Intestinal
Absorption
cholesterol
epithelial cell
Through
lymphatic
system to
the liver
MTP
CM
Cholesteryl esters
ACAT
(esterification)
Free
cholesterol
excretion
ABCG5
ABCG8
Dietary
cholesterol
Luminal
cholesterol
Bile
acid
Micellar
cholesterol
uptake
Cholest
AA
FA
P,
glycerol
Vessel
wall
HDL Metabolism
exchange for TG
LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol
to cholesterol esters
Apolipoprotein A-major protein of HDL activating many reactions
Apo-B-major protein of VLDL, IDL, and LDL
Apo-CII and Apo E obtained from HDL by CMC and VLDL for
activation of LPL and receptor recognition respectively
Mechanism of Atherogenic
Dyslipidemia
Insulin resistance
increased NEFA
and glucose flux to
liver
Increased
VLDL
IR impairs
LDLR
Insulin
resistance and
decreased apoB degradation
Insulin
resistance
and
decreased
LPL
FCHL
DM II
Metabolic
syndrome
Increased Atherogenicity of
Small Dense LDL
Direct Association
Longer residence time in
plasma than normal sized LDL
due to decreased recognition
by receptors in liver
Enhanced interaction with
scavenger receptor promoting
foam cell formation
More susceptible to oxidation
due to decreased antioxidants
in the core
Enter and attach more easily
to arterial wall
Endothelial cell dysfunction
Indirect Association
Inverse relationship with
HDL
Marker for atherogenic TG
remnant accumulation
Insulin resistance
Lipoprotein (a)
Specialized form of LDL
Treatment guidelines
CHOLESTEROL
A soft waxy substance found among
DYSLIPIDEMIA
(A consequence of abnormal lipoprotein
metabolism)
PRIMARY DYSLIPIDEMIA
ETIOLOGY
SINGLE OR MULTIPLE GENE MUTATION
SECONDARY DYSLIPIDEMIA
Sedentary lifestyle
Excessive consumption of cholesterol
Secondary Dyslipidemia
(Medical Conditions Associated
with dyslipidemia)
Diabetes
Hypothyroidism
Cholestatic liver disease.
Nephrotic syndrome
cigarette smoking
SECONDARY DYSLIPIDEMIA
Beta-blockers
Thiazide diuretics
Antiretroviral drugs
Hormonal agents
Types of Cholesterol
LDL- (bad cholesterol) The major cholesterol carrier in the
HDL-
Triglycerides-
Why Do We Care?
According to the Third Report
of the National Cholesterol
Education Program Expert
Panel on Detection,
Evaluation and Treatment of
High Cholesterol in Adults
(NCEP ATP-III):
High LDL levels are a
leading cause of coronary
heart disease (CHD) and
should be the main target of
any cholesterol lowering
regimen
HDL Cholesterol
LDL Goal
(mg/dl)
LDL level
to initiate
TLC
CHD or
Equivalents
<100
> 100
<70 Ideal
> 130
2+ Risk
Factors
<130
> 130
LDL level
to
consider
Rx
therapy
(100-129 Rx
optional)
Begin TLC
Emphasize
reduction in
saturated fat
& chol.
Encourage
moderate
Physical
activity
Consider
referral to
dietician
Visit 2 (6 wks)
Visit 3 (6 wks)
Intensify Tx if not to
goal
Consider adding Rx
if not to goal
Reinforce dietary
recommendations
Consider adding
plant stanols/sterols
Evaluate for
Metabolic syndrome
Increase fiber
intake
Consider dietician
Consider dietician
Visit N
Monitor
adherence to
TLC Q4-6
mos
Recommended
Saturated fat
< 7% of total calories
Polyunsaturated fat
Up to 10% of total calories
Monounsaturated fat
Up to 20% of total calories
Total fat
25-30% of total calories
Carbohydrates
50-60% of total calories
Fiber
20-30 grams/day
Protein
Approx. 15% of total calories
Cholesterol <200 mg/day
Total calories
Balance energy intake and
expenditure to maintain
desirable body weight/ prevent weight gain
Specific Dyslipidemias:
Very High LDL (> 190mg/dl)
Causes and Diagnosis
Genetic disorders
Monogenic familial hypercholesterolemia
Familial defective apolipoprotein B-100
(Apo B)
Polygenic hypercholesterolemia
Family testing to detect affected relatives
Elevated triglycerides
Overweight and obesity
Physical Inactivity
Type 2 diabetes
Cigarette smoking
Very high carb. intakes (>60% energy)
Medications (some beta blockers, anabolic
steroids, progestational agents)
<150 mg/dl
150-199 mg/dl
200-499mg/dl
>500 mg/dl
the blood
Most LDL around 260
Angstroms
5% smaller diameter LDL
particle leads to a 50%
increase in rate of uptake
by the arterial wall
LDL particle <258
Angstroms more
atherogenic
Large LDL: Pattern A
Small LDL: Pattern B (bad)
Not measured in traditional
lipid profiles
Who Needs
Advanced lipid
analysis?
cholesterol
Speed removal of LDL from blood
18%-60% reduction in LDL
Most effective at lowering LDL; esp. HS dosing
Liver enzymes MUST be monitored. Check baseline,
3mos., then semi-annually (D/C if > 3x normal limits)
Side effects: Myalgias (D/C if total CK >10x normal),
rhabdomyolysis
Metabolized by CP450 (watch for drug interactions)
41
Dual Inhibition
LDL
apoB100
Liver
Statin
Duodenum
X
VLDL
apoB100
Ezetimibe
Jejunum
Ileum
CM
Remnant
apoB48
Dr.Sarma@works
CM
apoB48
Colon
Statins Mechanism of
Action
Cholesterol
synthesis
HMGCoA
Intracellular
Cholesterol
VLDL
Apo B
LDL receptor VLDL
VLDLRR
Apo E
(BE receptor)
synthesis
Apo B
LDL
LDL receptormediated
hepatic uptake of LDL
and VLDL remnants
Serum LDL-C
Serum VLDL remnants
Serum IDL
Hepatocyte
Systemic Circulation
42
43
reduced
Endothelial
function
restored
Days
stabilized
Ischemic
episodes
reduced
Cardiac events
reduced*
Years
in the gut
May increase triglyceride levels
Most common side effects: GI-constipation
Alternative for statins
Gall Bladder
Bile Acid
Conversion of cholesterol to BA
BA Secretion
Enterohepatic Recirculation
Terminal Ileum
BA Excretion
Liver
Reabsorption of
bile acids
Net
Net Effect
Effect -- LDL-C
LDL-C
LDL Receptors
VLDL and LDL removal
(<400mg/dl)
Increases HDL
Very effective in increasing LDL particle size
Monitor liver enzymes and glucose
Most common side effect: FLUSHING (take
ASA/ibuprofen 30 min. prior and take with
light snack). Decreased with time released
formulas (Niaspan)
VLDL
TG
synthesis
VLDL
VLDL
secretion
Serum VLDL
results in reduced
lipolysis to LDL
Serum LDL
LDL
HDL
Liver
Circulation
Hepatocyte
Systemic Circulation
48
Comparison of Lipid
Lowering Drugs
beneficial)
Avocado: monounsaturated fat
Beans: High in fiber, low fat; contain lecithin
Phytosterols: sesame, safflower, spinach, okra,
strawberries, squash, tomatoes, celery, ginger.
Shiitake mushrooms: contain lentinan (25% reduction in
animal studies)
Garlic, onion oil: lowers chol. 10-33%
Omega 3 fish oils
Red Yeast Rice: a natural substance that inhibits HMGCoA reductase. Same ingredient in Lovastatin.
of LDL
Study of genetic alterations : cholesterol medications
tailored to specific genetic profiles
Microsomal triglyceride transfer protein (MTP): the
gene for MTP provides blueprint for production of the
protein that helps assemble LDL. Those who carry 2 copies
of a variant form of the gene had LDL levels 22% lower
than those who had one or no copy of the variant. Some
drug companies have already begun looking at MTP
inhibitors to help lower LDL
Lecithin-cholesterol acetyltransferase (LCAT): an
enzyme bound to HDL acts as a powerful antioxidant
(reduce oxidation of chol.)
Thyroid hormones: Molecules similar to thyroid
hormones could assist with weight loss and cholesterol
reduction. 2 kinds of receptors that receive the hormone
and pass its signal to the body.
ENHANCE trial
New England Journal of Medicine
720 FH patients over one year
Endpoint: Carotid artery intima-media thickness (CIMT)
per ultrasound
Findings: Vytorin did not reduce CIMT compared to
Zocor alone
TAKE HOME: Its NOT just about the numbers
JUPITER trial
Does Crestor reduce major CV events in pts
Other Interesting
Studies
Atherosclerosis: Maternal smoking disturbs
lipid profiles in adult offspring
placebo
After 4 weeks, all groups but placebo had lower LDL levels
Most significant reductions in those with baseline LDL > 125
LDL decreased from 160 to 152
HDL increased from 57 to 62
Decrease in (apo) B and oxidized LDL cholesterol
Polyphenols in cocoa, tea, wine, fruit and vegetables may
lead to decrease in atherosclerotic disease
Case Study 1
35 YO male, a police officer. 511,
weight=258 (BMI=35, obese)
Hx: hypertension, anxiety. Has taken
testosterone supplements in past, now
uses body building shakes.
Family Hx: Father, paternal grandfatherDM
Labs: FBS=79, TSH normal
Case Study 1
Visit 1
3
TC= 167
TG=539
HDL= 18
LDL= ?
Tricor started
Visit 2
164
288
260
24
95
Niaspan
(intolerant)
Visit
158
28
88
Levaza
Case Study 2
39 YO male (hasnt been in for 2 years)
c/o frequent urination, excessive
thirst, blurred vision.
Hx: Mod. Obesity, BMI= 33
Family Hx: Mother DM
Meds: None
Non-fasting Accucheck= 297 (3 hrs PP)
Case Study 2
TC
705
252
212
195
144
Trig
6710
149
146
128
123
HDL
170
33
36
39
42
LDL
190
140
131
82
A1C
11.9
5.6
Meds
5.6
Case Study 3
62 YO Female with CHD s/p CABG wanted me to
manage lipids. Also has Hypertension.
Meds: Plavix, Atenolol, lisinopril, Atorvastatin
(stopped by pt.-myalgias)
Current labs:
TC= 248
Trig= 144
HDL= 41
LDL= 156
Case Study 3
Changed atenolol to Coreg
Started Pravachol 20mg
Disease management/diet counseling
Resume walking 3-4 days/week
Repeat labs:
TC=190
Increase Pravachol 178
Trig= 130 to 40mg
128
HDL= 39
41
LDL= 112
98
Framingham Risk
Prediction Score
47 YO Female
Labs: TC= 178 Trig= 133 LDL= 110 HDL=
35
BP: 162/98
Hx: Smoker, non-diabetic
Framingham Risk
Prediction Score
47 YO Female
Labs: TC= 178 Trig= 133 LDL= 110 HDL= 35
BP: 162/98
Hx: Smoker, non-diabetic
Treatment of Dyslipidemias
(Medication Comparison Chart)
Treatment of Dyslipidemias
(Medication Comparison Chart)
Final Question!!!!!
58 Year old Male (smoker)
Fam. Hx: Mother with NIDDM, sister died age 70 from MI
BP= 156/86 Pulse 78
Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88
Final Question!!!!!
58 Year old Male (smoker)
Fam. Hx: Mother with NIDDM, sister died age 70 from MI
BP= 156/86 Pulse 78
Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88
Thank You
Questions?
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