Block 9 Week 6

Firek Lipids Lecture Notes

Risk Assessment
Rules of risk assessment
o Count major risk factors
o For patients with 2 or more risk factors, perform a 10-year risk assessment
o For patients with less than 2 risk factors, a 10-year risk assessment is not required
Major Risk Factors
o Cigarette smoking
o HTN (BP > 140/90)
o HDL < 40 mg/dL
o Family history of premature CHD
o Age (men 45 y.o., women 55 y.o.)
o HDL > 60 mg/dL counts as a negative risk factor
Cardiovascular Risk Equivalents
Any of the following can be considered the equivalent of a heart attack, requiring appropriate treatment
o Peripheral vascular disease
o Abdominal aortic aneurysm
o Symptomatic CAD
o > 20% 10-year CHD risk by Framingham
o Type II DM and Metabolic Syndrome
Specific Dyslipidemia
Very high LDL cholesterol (>190
mg/dL)
Elevated triglycerides (>150 mg/dL)

Causes of Dyslipidemia
Monogenic familial hypercholesterolemia, defective
apolipoprotein B-100, polygenic hypercholesterolemia
Obesity and overweight, physical inactivity, cigarette
smoking, excess alcohol intake, high carbohydrate diets,
Type II DM, chronic renal failure, nephrotic syndrome
Corticosteroids, estrogens, retinoids, high doses of betablockers
Same as those that cause elevated triglycerides

Low HDL cholesterol (<40 mg/dL)

Goals of LDL cholesterol modification

Risk category
Goal LDL (mg/dL)
CHD and CHD risk equivalents < 100
2 or more risk factors
< 130
Less than 2 risk factors
< 160
How Lipids Are Processed Normally
Exogenous Route
1. Dietary lipids are absorbed by
small intestine and placed into
chylomicrons
2. Chylomicrons are converted to
chylomicron remnants in the
periphery by lipoprotein lipase
(LPL), which transfers free fatty
acids to muscle and adipose cells.
3. The chylomicron remnants are
taken up by the liver via LDL
receptors
Lipoprotein
Chylomicrons
VLDL
LDL
HDL

Action
LDL-lowering therapy, weight reduction, fibrates or nicotinic acid
Therapeutic lifestyle changes; if unsuccessful, try drug therapy
Therapeutic lifestyle changes; if unsuccessful, try drug therapy

Endogenous Route
1. VLDL is made by the liver,
which is converted to IDL in
the periphery by LPL (which
transfers free fatty acid to
muscle and adipose cells)
2. IDL is either taken up by the
liver or further broken down
into LDL
3. LDL is also taken up by the
liver via LDL receptors

Major apolipoproteins
A-I, A-II, B-48, C-II, E
B-100, C-II, E
B-100
A-1, A-II

Page 1 of 3

Block 9 Week 6
Firek Lipids Lecture Notes

LCAT esterifies cholesterol

CETP helps transfer fats between the CLDL, LDL and chylomicrons
CETP blockers will inhibit this process and increase HDL levels
LPL hydrolyzes triglycerides in chylomicrons and VLDL

Type of
Lipoproteinemia
Type I familial
chylomicronemia
syndrome

Molecular
defect
LPL and
Apo C-II

Elevated
Lipoprotein
Chylomicrons

Type IIa familial

hypercholesterolemia

LDL
receptor
and Apo
B-100

LDL

Type IIb familial

combined
hyperlipidemia

Unknown

LDL and
VLDL

Type III familial

dysbetalipoproteinemia

Apo E

Chylomicron
and VLDL
remnants

Type IV familial
hypertriglyceridemia

Unknown

VLDL

Details
Apo C-II is a cofactor LPL
The plasma looks lactescent (because the TG levels are ~
1000 mg/dL)
Autosomal recessive in inheritance
Lipemia retinalis retinal blood vessels are opalescent
Eruptive xathomas yellowish-white papules on back,
buttocks and extensor surfaces; typically painless
Hepatosplenomegaly can result from uptake of circulating
chylomicrons
LDL receptor mutations
Elevated plasma LDL with normal triglycerides
Autosomal co-dominant disorder
Total cholesterol levels of 500 1000 mg/dL
Tendon xanthomas and xanthelasmas (cholesterol deposits
around the eyelids)
Heterozygous familial hypercholesterolemia is one of the
most common single-gene disorders
HMG-CoA reductase inhibitors are useful in treatment
Familial Defective Apo B-100
Autosominal dominant disorder
Physical findings are identical to those found in LDL
receptor mutations
Tend to have lower plasma LDL than patients with LDL
receptor mutations
HMG-CoA reductase inhibitors are useful in treatment
Moderate elevation of plasma TG and cholesterol and
reduced plasma HDL
Disease is autosomal dominant
Almost always have elevated plasma Apo B
Family members typically have mixed hyperlipidemias
These patients do not develop xanthomas
Plasma appears clear
Apo E is on chylomicron and VLDL remnants
Apo E gene has three common isoforms: E2, E3, and E4
o E2 patients have a lower affinity for the LDL
receptor
o E4 patients have an increased incidence of lateonset Alzheimer disease
Tuberoeruptive xanthoma clusters of small papules on the
elbows, knees, buttocks
Palmar xanthomas orange-yellow discoloration of creases
in the palms
Plasma appears turbid (but not lactescent)
Moderately elevated plasma TG
Caused by increased VLDL production, impaired VLDL
catabolism or a combination
Autosomal dominant disorder

Page 2 of 3

Block 9 Week 6
Firek Lipids Lecture Notes
Polygenic Hypercholesterolemia
A normal plasma TG in the absence of secondary causes of hypercholesterolemia
Treatment is identical to that of other forms of hypercholesterolemia
Sitosterolemia
Autosomal recessive disease in ABCG5 or ABCG8 (ABC = ATP-binding cassettes)
Intestinal absorption of plant sitosterol is increased and biliary excretion of sitosterol is reduced
Patients will develop cutaneous and tendon xanthomas and premature atherosclerosis
LDL will also be low
Plasma sitosterol levels will be elevated
Does not respond to HMG-CoA reductase inhibitors, but bile acid sequestrants and cholesterol-absorption inhibitors
work
Apo A-I deficiency/mutation
Virtual absence of HDL from plasma
Apo A-I is required for LCAT function
Because of decreased LCAT function, plasma and tissue levels of free cholesterol are increased corneal opacities
and planar xanthomas
Tangier Disease
Autosomal ABCA1 gene mutation
ABCA1 is a cellular transporter that facilitates efflux of unesterified cholesterol and phospholipids from cells to Apo
A-I (which is important in forming HDL)
Without ABCA1, HDL is rapidly cleared patients have HDL levels of 5 mg/dL and low levels of Apo A-I
Hepatosplenomegaly from cholesterol accumulation
Pathognomonic enlarged, grayish yellow or orange tonsils
LCAT Deficiency
Proportion of free cholesterol in lipoproteins increases because they cannot be esterified by LCAT
HDL cant be made and Apo A-I is rapidly catabolized
Two forms
o Complete deficiency classic LCAT deficiency
o Partial deficiency fish-eye disease
Deposition of free cholesterol in lens corneal opacification (seen in complete and partial)
Hemolytic anemia and end-stage renal disease are seen in complete deficiency)
CETP Deficiency
High HDL levels in homozygotes, moderately elevated HDL levels in heterozygotes

Page 3 of 3