Fortunately, few individuals carry the inherited defects in lipoprotein metabolism that lead to hyper- or hypolipoproteinemias (see Tables below for brief descriptions). Persons suffering from diabetes mellitus, hypothyroidism and kidney disease often exhibit abnormal lipoprotein metabolism as a result of secondary effects of their disorders. For example, because lipoprotein lipase (LPL) synthesis is regulated by insulin, LPL deficiencies leading to Type I hyperlipoproteinemia may occur as a secondary outcome of diabetes mellitus. Additionally, insulin and thyroid hormones positively affect hepatic LDL-receptor interactions; therefore, the hypercholesterolemia and increased risk of athersclerosis associated with uncontrolled diabetes or hypothyroidism is likely due to decreased hepatic LDL uptake and metabolism.
Of the many disorders of lipoprotein metabolism, familial hypercholesterolemia (FH) may be the most prevalent in the general population. Heterozygosity at the FH locus occurs in 1:500 individuals, whereas, homozygosity is observed in 1:1,000,000 individuals. FH is an inherited disorder comprising four different classes of mutation in the LDL receptor gene. The class 1 defect (the most common) results in a complete loss of receptor synthesis. The class 2 defect results in the synthesis of a receptor protein that is not properly processed in the Golgi apparatus and therefore is not transported to the plasma membrane. The class 3 defect results in an LDL receptor that is incapable of binding LDLs. The class 4 defect results in receptors that bind LDLs but do not cluster in coated pits and are, therefore, not internalized.
FH sufferers may be either heterozygous or homologous for a particular mutation in the receptor gene. Homozygotes exhibit grossly elevated serum cholesterol (primarily in LDLs). The elevated levels of LDLs result in their phagocytosis by macrophages. These lipid-laden phagocytic cells tend to deposit within the skin and tendons, leading to xanthomas. A greater complication results from cholesterol deposition within the arteries, leading to atherosclerosis, the major contributing factor of nearly all cardiovascular diseases.
