Hypolipoproteinemias: Tangier Disease
A decrease in blood lipoprotein levels is a rare phenomenon. A prominent example is Tangier disease. It is caused by a genetic defect in the ABC1 protein, which normally transports cholesterol from cell membranes to high-density lipoproteins (HDLs).
Due to this defect, HDL levels drop to 1–5% of normal, low-density lipoprotein (LDL) levels also decrease, and generalized hypocholesterolemia develops. Cholesterol cannot leave cells and begins to accumulate in tissues. This leads to enlargement of the liver and spleen (hepatosplenomegaly) and damage to nerve sheaths (neuropathy) due to lipid accumulation in Schwann cells.
Classification of Hyperlipoproteinemias
Elevated blood lipoprotein levels are classified into several types depending on the genetic defect and lipid profile changes:
- Type I (Familial hyperchylomicronemia): Caused by a deficiency in lipoprotein lipase or apolipoprotein CII. Chylomicrons and VLDLs accumulate in the blood, and triacylglycerol levels rise. There is no risk of atherosclerosis.
- Type II (Familial hypercholesterolemia): Associated with an APOB gene mutation or LDL receptor defect. Characterized by high LDL concentrations and hypercholesterolemia, leading to early atherosclerosis and xanthomatosis.
- Type III (Familial dysbetalipoproteinemia): A structural defect in apoE (synthesis of the apoE₂ isoform, which fails to bind receptors). Blood levels of remnant chylomicrons, VLDLs, IDLs, and LDLs rise. Early atherosclerosis is also characteristic.
- Types IV and V (Familial hypertriglyceridemia): A heterogeneous group often associated with overproduction of VLDLs in the setting of hyperinsulinemia. Accompanied by elevated VLDLs, LDLs, triacylglycerols, and an increased risk of atherosclerosis.
Risk Assessment and Atherosclerosis Pathogenesis
An excess of atherogenic lipoproteins (especially with LDL receptor mutations, lipid peroxidation, and a high-calorie diet) leads to the formation of an atherosclerotic plaque. It damages the internal lining of arteries, disrupts blood flow, and serves as a substrate for thrombus formation, ultimately resulting in myocardial infarction or stroke.
To assess risk, the atherogenic index is calculated from a fasting blood test:
(Total Cholesterol - HDL Cholesterol) / HDL Cholesterol
Normally, this value should be less than 3.5. The higher the value, the greater the likelihood of developing atherosclerosis.
Free Cholesterol and Cholesterol Esters
Cholesterol in the body exists in free form and as esters. Free cholesterol is amphiphilic, allowing it to integrate into cell membranes. It serves as a substrate for bile acids in the liver and regulates its own synthesis by acting as a corepressor of the HMG-CoA reductase gene.
Cholesterol esters are the storage and transport form. They are formed in the intestine (by ACAT for packaging into chylomicrons) and in the blood (by LCAT within HDLs). Esters form the core of particles such as LDLs and VLDLs and are stored in cells as lipid droplets.
Pharmacotherapy
Several drug classes are used to correct dyslipidemias, each with a specific mechanism of action:
- Statins (HMG-CoA reductase inhibitors): Suppress endogenous cholesterol synthesis, forcing cells to actively take up more cholesterol from the blood.
- Bile acid sequestrants: Bind bile acids in the intestine, interrupting their enterohepatic circulation. The liver is forced to consume more blood cholesterol to synthesize new bile acids.
- Niacin (Nicotinic acid): Inhibits lipolysis in adipose tissue, which reduces VLDL production.
- Fibrates: Stimulate receptors that increase the synthesis of lipoprotein lipase and apolipoproteins A-I/A-II, lowering triacylglycerol levels and raising protective HDLs.