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V. Dyslipidemia Pathophysiology
a. Lipids
i. Cholesterol
1. Cell membrane formation
2. Bile Acid precursor
3. Steroid, hormone, Vit D synthesis
4. Sources
a. In vivo synthesis – 80% in liver and intestines
i. Mevalonate production is rate limiting step
1. Catalyzed by HMG-CoA reductase –
statin target
b. Extraction from lipoproteins
c. Diet has modest impact
ii. Triglycerides
1. Glycerol + fatty acids
2. Derived from food
3. Stored energy in adipose
iii. Phospholipids
1. Lipid transport
2. Oxidation of arterial wall lipoproteins
b. Lipoproteins
Lipoprotein Content Metabolism Function
chylomicron 98-99% TG LPL into FFA Transfers TG
Bile Acids and remnants and cholesterol
gut -> liver
VLDL & IDL Mostly TG VLDL + LPL -> LDL Precursor
15-20% of IDL -> LDL
serum
cholesterol
apo B
LDL 60-70% of Liver removes VLDL transport
serum 70% TG and
cholesterol cholesterol
PCSK9 inhibition IDL transports
-> increase LDL cholesterol
metabolism Atherosclerosis
by attaching to
arterial walls by
oxidation
Small, dense
LDL is worse
HDL 20-30% of Removes
serum excess
cholesterol cholesterol
CETP allows
exchange of TG
and cholesterol
LCAT allows
cholesterol
collection
c. Risk Factors
i. Non-modifiable
1. Male ≥45 YO, Female ≥ 55 YO
2. Family history
3. Gender
4. Socioeconomic status
ii. Modifiable
1. Tobacco
2. Stress
3. Diet
4. Physical Activity
5. Obesity
6. HTN
7. Lipid disorders
8. diabetes
d. Pathogenesis
i. Injury to endothelium -> inflammation -> fibrous cap -> plaque
rupture
ii. LDL oxidation triggers inflammation and macrophage
activation
1. Foam Cells – lipid filled macrophages
2. Foam cells accumulate to form fatty streak
iii. Fibrous cap – Protects core of lipids, macrophages, collagen
1. Can rupture to release material
2. Forms clot to block vessel
e. Secondary Causes
i. TC > 200 mg/dL
1. Hypothyroid
2. Liver disease
3. Corticosteroids
4. Protease inhibitors
5. Thiazide diuretics
6. Beta blockers
ii. LDL ≥ 190 mg/dL
1. Usually primary cause (FH, apo B-100 defect)
iii. TG ≥ 150 mg/dL
1. TG >500 mg/dL -> pancreatitis
2. T2DM
3. Obesity
4. Tobacco
5. Alcohol
6. Physical inactivity
7. High carbohydrate intake
8. Corticosteroids
9. Beta blockers
10.Thiazide diuretics
11. Bile acid sequestrant
12. Atypical antipsychotics
iv. HDL < 40 mg/dL
1. Obesity
2. Physical inactivity
3. Tobacco
4. T2DM
5. Beta blockers
6. Anabolic steroids
7. Progestational agents
f. Lab Values
i. TC <200 mg/dL
ii. Non-HDL <130 mg/dL
iii. LDL <100 mg/dL
iv. HDL >40 in men, >50 in women
v. TG <150 mg/dL