Classification of Hyperlipidemia Flashcards
Frederickson Classification
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
Type I Hyperlipidemia
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
Functions of LPL
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
Treatment of LPL Deficiency
In Type I Hyperlipidemia
No effective medications
Severe fat restriction:
Familial Hypercholesterolemia (FH)
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
Phenotypes of FH (Type IIa)
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
Clinical Features of FH
Tendenous Xanthomas: achilles and patellar tendons
Arcus Cornea
Premature CAD
Treatment of FH
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
Combined Hyperlipidemia(Type IIb)
- Familial Form (FCH): Polygenetic decreases in LDL receptor or Apo B function
- Acquired Form (McDonald’s form): Visceral obesity and insulin resistance
Acquired Form Type IIb
“ The Metabolic Syndrome” Visceral obesity Glucose intolerance “Dyslipidemia” Insulin resistance Hypertension
Familial Combined Hyperlipidemia Phenotypes
- Elevated LDL and VLDL and ApoB
- Elevated TG and VLDL from hepatic over-production
- Impaired uptake of exogenous lipids from the diet
Xanthomas of Eye Lid and Heels of Familial Combined Hyperlipidemia
Treatment of Familial Combined Hyperlipidemia
Aggressive lipid-lowering with combinations of HMG-Co-A Reductase Inhibitors, Fibrates, and Nicotinic Acid
Familial Dysbeta-Lipoproteinemia(Type III Hyperlipidemia)
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
Familial Hypertriglyceridemia(Type IV)
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
Type V Hyperlipidemia
Mixed Hyperlipidemia
Mutations of the APOA5 gene
Between bouts of acute decompensation: look like type II diabetic with Type IV hyperlipidemia
“Acquired LPL Deficiency”
Treatment of Type V Hyperlipidemia
IV insulin “reactivates” endothelial lipoprotein lipase activity and results in rapid improvement in glucose & lipid levels
Tangiers Disease
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
Familial Hypo-α-Lipoproteinemia
Most common form of low HDL
Increased risk for premature CAD due to decreased reverse cholesterol transport of LDL out of endothelium
LCAT Deficiency
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
Atherosclerosis
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)
Hyperlipidemia Types I - V and Hypolipidemia
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
LDL Particles and Foam Cell Formation
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
Inflammatory Response to Endothelial Injury
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
Chemotactic Molecules and Monocyte Recruitment
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
Natural Progression of Plaque Formation
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
Clinical Stages of Atherosclerosis
- Initial endothelial injury and induction of the inflammatory response causing endothelial dysfunction
- Fatty streak and early arterial plaque formation
- Accumulation of lipid particles within plaque core
- Initiation of smooth muscle cell migration to endothelial surface, proliferation, and formation of vulnerable plaque cap
- Plaque rupture, thrombosis, and vessel occlusion
Cardioprotective Effects of HDL
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”)
Adiponectin
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
Treatment Strategies of Hyperlipidemia Stages
Primary Strategies
- Lower LDL cholesterol
- Increase HDL cholesterol
Secondary Strategies
- Lower triglycerides
- Change lipoprotein particle composition to a “less atherogenic” phenotype
Medications that Primarily Lower LDLs
Statins
Bile Acid Resins
Cholesterol Absorption Inhibitors
Combinations of these drugs
Medications that Primarily Increase HDLs
Niacin Fibrates Certain Statins (atorvastatin and rosuvastatin) CETP Inhibitors (in clinical trials) Combinations
Homocysteine
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
