Classification of Hyperlipidemia

Question 1

Frederickson Classification

Answer 1

I: seen in young children; chylomicrons are involved
V: seen in adults; IDL (chylomicrons and VLDL remnants)

2b and 4 are most common
2a = familial hyperlipidemia

Question 2

Type I Hyperlipidemia

Answer 2

Chylomicronemia - very rare
Most of these children do not live/live long

Causes: Lipoprotein Lipase Deficiency

Present in early childhood with chronic abdominal pain, recurrent pancreatitis, and hepato-splenomegaly

Eruptive xanthomas on extremities and trunk
Can develop diabetes later due to the chronic pancreatitis and the inflammatory destruction of the beta cells

Question 3

Functions of LPL

Answer 3

LPL is a water soluble enzyme attached to the luminal surface of small capillaries in muscle and adipose tissue

LPL hydrolyzes the TG’s in chylomicrons and VLDL and converts them into free fatty acids (FFA’s) and glycerol

LPL also promotes hepatic uptake (post-meal clearance) of chylomicron remnants, cholesterol-rich lipoproteins, and FFA

LPL requiresApoC-IIas a cofactor

No enzyme, then serum looks milky and fatty
Serum chylomicrons are present & triglycerides (TG’s) are extremely elevated; 2,000-12,000 mg/dl
Foam cells laden with lipids can be seen in liver, spleen, and bone marrow on biopsy

Question 4

Treatment of LPL Deficiency

Answer 4

In Type I Hyperlipidemia
No effective medications
Severe fat restriction:

Question 5

Familial Hypercholesterolemia (FH)

Answer 5

Type IIa Hyperlipidemia
Abnormalities in LDL Receptor Function

FH1—LDL receptor defects (5 forms)

FH2—Apo B-100 abnormalities causing decreased LDL uptake, and HMG-CoA reductase is turn on all the time to induce production of endogenous cholesterol (aka loss of negative feedback inhibition)

ApoB = LDL association aka BAD
ApoA = HDL association aka good

Question 6

Phenotypes of FH (Type IIa)

Answer 6

Homozygote:

• 55 % reduction in LDL clearance
• serum LDL’s of 400-800 mg/d
• Premature CAD in teens-20’s

Heterozygote:

• 27 % reduction in LDL clearance
• serum LDL’s of 260-400 mg/dl
• Premature CAD in late 20’s-30”s

Question 7

Clinical Features of FH

Answer 7

Tendenous Xanthomas: achilles and patellar tendons
Arcus Cornea
Premature CAD

Question 8

Treatment of FH

Answer 8

LDL lowering with HMG-CoA reductase inhibitors (statins) has improved outcomes in heterozygote form but minor effect in homozygotes

PKCS9 antagonists were just FDA approved this year and are the most potent LDL reducing medications ever developed

Aphoresis of LDL particles q 2 weeks can be performed if patients do not respond to lipid-lowering medications and most homozygote patients require it

Liver Transplant: works, but need donor

Question 9

Combined Hyperlipidemia(Type IIb)

Answer 9

1. Familial Form (FCH): Polygenetic decreases in LDL receptor or Apo B function
2. Acquired Form (McDonald’s form): Visceral obesity and insulin resistance

Question 10

Acquired Form Type IIb

Answer 10

“ The Metabolic Syndrome”
Visceral obesity
Glucose intolerance
“Dyslipidemia”
Insulin resistance
Hypertension

Question 11

Familial Combined Hyperlipidemia Phenotypes

Answer 11

1. Elevated LDL and VLDL and ApoB
2. Elevated TG and VLDL from hepatic over-production
3. Impaired uptake of exogenous lipids from the diet

Xanthomas of Eye Lid and Heels of Familial Combined Hyperlipidemia

Question 12

Treatment of Familial Combined Hyperlipidemia

Answer 12

Aggressive lipid-lowering with combinations of HMG-Co-A Reductase Inhibitors, Fibrates, and Nicotinic Acid

Question 13

Familial Dysbeta-Lipoproteinemia(Type III Hyperlipidemia)

Answer 13

Abnormal Apo E2 isoforms
ApoE is present to effect hepatocyte uptake of TG

Palmar xanthomas
Orange colored skin from deposition of carotenoids

Dx: Using lipoprotein electrophoresis the remnant lipoproteins accumulate as a “broad β” band

Question 14

Familial Hypertriglyceridemia(Type IV)

Answer 14

Polymorphisms of the apo A-I/C-III and the insulin gene (insulin resistance)
Second most common

Clinical picture may be similar to Type IIb…. but LDL is not as high; cannot really tell between IIb and IV

Very high VLDL and low HDL with elevated LDL and TG’s
Small dense LDL particles

Question 15

Type V Hyperlipidemia

Answer 15

Mixed Hyperlipidemia
Mutations of the APOA5 gene

Between bouts of acute decompensation: look like type II diabetic with Type IV hyperlipidemia
“Acquired LPL Deficiency”

Question 16

Treatment of Type V Hyperlipidemia

Answer 16

IV insulin “reactivates” endothelial lipoprotein lipase activity and results in rapid improvement in glucose & lipid levels

Question 17

Tangiers Disease

Answer 17

Hypolipidemia
Autosomal recessive mutation of the ABCA-1 Transporter

Very low HDL, Apo-AI and Apo-AII
Orange tonsils and cells in the reticuloendothelial system

Question 18

Familial Hypo-α-Lipoproteinemia

Answer 18

Most common form of low HDL

Increased risk for premature CAD due to decreased reverse cholesterol transport of LDL out of endothelium

Question 19

LCAT Deficiency

Answer 19

Enzyme that esterifies free cholesterol on HDL to cholesterol ester and allows the maturation of HDL

Because of rapid catabolism of ApoA, get high turnover of HDL that cannot do reverse cholesterol transport and get high cholesterol in the tissues

In partial deficiency (fish eye disease) corneal opacities

Question 20

Atherosclerosis

Answer 20

Atherosclerosis is most commonly associated with abnormally high levels of LDL, apo B, and TG with low levels of HDL

However, rare abnormalities in lipoprotein synthesis or clearance result in low lipid concentrations…… (hypolipidemias)

Question 21

Hyperlipidemia Types I - V and Hypolipidemia

Answer 21

I: high TG, pancreatitis
IIa is rare with high cholesterol
IIb is America’s disease and common
III is young girls on BC and rare or post menopausal, high TG
IV: type II diabetes
V: decompensated diabetic

Low HDL associated with premature CAD and think Tangier’s and LCAT deficiency

Question 22

LDL Particles and Foam Cell Formation

Answer 22

Small LDL particles penetrate arterial intima more readily, are retained preferentially, and are more susceptible to oxidation, leading to enhanced macrophage uptake and foam cell formation

More and more evidence is accumulating that supports the concept that small LDL particles are inherently more atherogenic than large LDL

Question 23

Inflammatory Response to Endothelial Injury

Answer 23

Circulating monocytes are triggered to migrate across the endothelial cell lining and infiltrate the intima of the vessel wall

Monocytes are converted into macrophages, which acting as scavenger cells engulfing oxLDL

The oxLDL uptake by macrophages is toxic to these cells resulting in foam cell formation

Question 24

Chemotactic Molecules and Monocyte Recruitment

Answer 24

IL-6 and TNF-α are important mediators of intimal injury and recruitment of additional monocytes

Activated macrophages produce Macrophage Chemotactic Peptides (MCP-1) which attract more monocytes, which amplify the inflammatory process

Activated macrophages also release adhesion molecules such as: (ICAM, VCAM, and P-Selectin) which also amplify the recruitment of additional monocytes, T-lymphocytes, and platelets to the injured vessel

Question 25

Natural Progression of Plaque Formation

Answer 25

Small plaque that eventually expands
Smaller plaque is more threatening for acute thrombosis than large stable plaque
No prior angina with small plaque = thrombosis/ acute coronary event is first symptom

Question 26

Clinical Stages of Atherosclerosis

Answer 26

1. Initial endothelial injury and induction of the inflammatory response causing endothelial dysfunction
2. Fatty streak and early arterial plaque formation
3. Accumulation of lipid particles within plaque core
4. Initiation of smooth muscle cell migration to endothelial surface, proliferation, and formation of vulnerable plaque cap
5. Plaque rupture, thrombosis, and vessel occlusion

Question 27

Cardioprotective Effects of HDL

Answer 27

Reduces foam cell formation and the release of inflammatory cytokines
Inhibits oxidation of LDL in endothelial cells
Inhibits adhesion molecule activation
Promotes cholesterol efflux out of foam cells (“Reverse Cholesterol Transport”)

Question 28

Adiponectin

Answer 28

A “good adipokine”
Protein hormone secreted by adipocytes
Protects endothelium from inflammatory compounds
Increases insulin sensitivity and improves carbohydrate metabolism
Serum concentrations are inversely related to BMI

Question 29

Treatment Strategies of Hyperlipidemia Stages

Answer 29

Primary Strategies

• Lower LDL cholesterol
• Increase HDL cholesterol

Secondary Strategies

• Lower triglycerides
• Change lipoprotein particle composition to a “less atherogenic” phenotype

Question 30

Medications that Primarily Lower LDLs

Answer 30

Statins
Bile Acid Resins
Cholesterol Absorption Inhibitors
Combinations of these drugs

Question 31

Medications that Primarily Increase HDLs

Answer 31

Niacin
Fibrates
Certain Statins (atorvastatin and rosuvastatin)
CETP Inhibitors (in clinical trials)
Combinations

Question 32

Homocysteine

Answer 32

Homocystinuriais linked to an increased incidence ofthrombosisandASCVD
Elevated levels of homocysteine has been linked to cardiovascular disease
However, the lowering homocysteine levels has not been demonstrated to improve cardiac outcomes