Overview:

• Hyperlipidemias are characterized by high levels of lipids in the blood (hyper = elevated, lipid, emia = blood).
• Hyperlipidemia is often asymptomatic, it significantly increases one’s risk for cardiovascular diseases, especially atherosclerosis.
• Two commonly used systems of classification:
  – The older scheme, which focuses on inherited lipidemias, is called the Fredrickson Classification system.
  – The newer system divides lipidemias according to primary (aka, genetic) or secondary (aka, acquired) causes.
  – Primary lipidemias can be exacerbated by secondary causes.

Lipoproteins

• Comprise proteins and phospholipids that transport cholesterol and triglycerides in the body.
• Outer surface of a lipoprotein:
  – Apolipoprotein = protein that binds lipids.
  There are several types of apolipoproteins, some of which are implicated in hyperlididemias, as we’ll soon see.
  – Phospholipids and free cholesterol.
• Core:
  – Triglycerides (aka, triacylglycerol)
  – Cholesterol esters

• Chylomicrons deliver dietary triglycerides and cholesterol to the liver and peripheral tissues.
• Chylomicron remnants are produced when triglycerides are removed from chylomicrons; thus, they are rich in cholesterol esters.
• Very Low Density Lipoproteins (VLDL) are made in the liver, and are rich in triglycerides.
• Intermediate Density Lipoproteins (IDL) are produced when triglycerides are removed from VLDL; thus, like the chylomicron remnants, they are rich in cholesterol.
  – Because they are formed from VLDL, Intermediate Density Lipoproteins are sometimes referred to as VLDL remnants.
• Low Density Lipoproteins are produced after even more triglycerides are removed from the Very Low Density Lipoproteins and their remnants; thus, LDL is very rich in cholesterol, which it carries to the peripheral tissues.
  – LDL is sometimes referred to as “bad” cholesterol, because it distributes cholesterol throughout the body and vessels. In the vessels, the deposited cholesterol contributes to obstructive plaque formation and atherosclerosis.
• High Density Lipoproteins (HDL), which are part of the reverse cholesterol transport pathway, carry cholesterol from the peripheral tissues to the liver.
  – In addition to removing excess cholesterol, High Density Lipoproteins have various other anti-atherogenic properties, so it they are often referred to as “Good” cholesterol.

Hypercholesterolemia is often defined as:

• Total cholesterol > 200 mg/dL
• Low-Density Lipoproteins > 130 mg/dL
• High-Density Lipoproteins < 40 mg/dL
  Hypertriglyceridemia = levels above 150 mg/dL.

Xanthomas

• Created by lipid deposits in the skin associated with foam cells(macrophages that have ingested lipids).
• Tuberous xanthomas form small to large bulges in the skin over the joints, particularly the elbows and knees.
• Eruptive xanthomas are erythematous bumps that tend to appear on the buttocks, shoulders, and extensor surfaces.
• Plane xanthomas are thin yellow plaques. Xanthelasma is characterized by plaques around the eyelids.
• Palmar xanthomas are characterized by yellow plaques that form along the creases of the palm of the hands.
• Tendinous xanthomas are bumps that form over the tendons or ligaments
  – The Achilles tendon at the posterior ankle is a common site for these xanthomas.

Primary hyperlipidemias and their associated Fredrickson Phenotypes.

Be aware that there is variation in the names of these disorders.

Hyperchylomicronemia (Fredrickson Type I)
– Occurs when there is a deficiency in lipoprotein lipase or an alteration in apolipoprotein C-II, which activates lipoprotein lipase.
– These deficiencies cause elevated chylomicrons and triglyceride levels exceeding 500 mg/dL.
– This disorder is associated with acute pancreatitis, eruptive xanthomas, and, when triglyceride levels are exceedingly high, lipemia retinalis.

Hypercholesterinemia (Type IIa)
– Occurs when LDL receptors are deficient.
– Results in elevated Low-Density Lipoproteins and cholesterol.
– There are heterozygous and homozygous forms.
– Patients are at increased risk of premature Atherosclerotic Cardiovascular Disease (ASCVD), tendinous xanthomas, and, corneal arcus, which is a whitish ring around the iris.

Hyperlipidemia (Type IIb)
– Occurs when there is a reduction in LDL receptors or increased apolipoprotein B.
– Characterized by elevated Low Density Lipoproteins and Very Low Density Lipoproteins
– Both triglycerides and cholesterol are also elevated.
– Patients are at increased risk of premature ASCVD and may have tendinous xanthomas.
– This is the most common inherited dyslipidemia.

Dysbetalipoproteinemia (also called hyperlipoproteinemia, Type III)
– Occurs when apolipoprotein E-2 is defective.
– The disorder is characterized by elevated chylomicron remnants and Intermediate Density Lipoproteins (hence, this disorder is sometimes called Remnant Removal Disease).
– Both triglyceride and cholesterol levels are elevated.
– Patients are at increased risk of ASCVD, and may have palmar xanthoma and/or tuberoeruptive xanthomas of the elbows and knees.

Hypertriglyceridemia (Type IV)
– Characterized by increased production and decreased secretion of Very Low Density Lipoproteins.
– Elevated levels of triglycerides.
– Patients are at increased risk for acute pancreatitis and ASCVD.
– Type IV is another relatively common inherited hyperlipidemia.

Mixed hypertriglyceridemia (Type V)
– Associated with increased Very Low Density Lipoprotein production and decreased Low Density Lipoprotein production.
– Characterized by elevations in chylomicron remnants and VLDL.
– Increased triglyceride and cholesterol levels.
– Patients are at risk for acute pancreatitis, eruptive xanthomas, and ASCVD.

Secondary Hyperlipidemia

Recall that these may exacerbate primary lipid disorders.

• The most significant contributors in the United States are diets high in saturated fats, cholesterol, and trans fats,coupled with sedentary lifestyles.
• High levels of alcohol consumption also elevate lipid levels.
• Several other disorders may contribute to hyperlipidemia, including: diabetes mellitus, chronic kidney disease, nephrotic syndrome, hypothyroidism, cholestatic liver diseases, and Cushing syndrome.
• Several drugs can cause hyperlipidemia, including oral contraceptives, diuretics, beta-blockers, and antiretroviral agents.