Familial Hypercholesterolemia

Familial hypercholesterolemia is a "receptor disease" that is the consequence of a mutation in the gene encoding the receptor for low density lipoprotein (LDL), which is involved in the

transport and metabolism of cholesterol. As a consequence of receptor abnormalities, there is a loss of feedback control and elevated levels of cholesterol that induce premature

atherosclerosis, leading to a greatly increased risk of myocardial infarction.[19] [20]

Familial hypercholesterolemia is possibly the most frequent mendelian disorder. Heterozygotes with one mutant gene, representing about 1 in 500 individuals, have from birth a twofold to

threefold elevation of plasma cholesterol level, leading to tendinous xanthomas and premature atherosclerosis in adult life ( Chapter 11 ). Homozygotes, having a double dose of the mutant

gene, are much more severely affected and may have fivefold to sixfold elevations in plasma cholesterol levels. These individuals develop skin xanthomas and coronary, cerebral, and

peripheral vascular atherosclerosis at an early age. Myocardial infarction may develop before age 20. Large-scale studies have found that familial hypercholesterolemia is present in 3% to 6%

of survivors of myocardial infarction.

An understanding of this disorder requires that we briefly review the normal process of cholesterol metabolism and transport. Approximately 7% of the body's cholesterol circulates in the

plasma, predominantly in the form of LDL. As might be expected, the level of plasma cholesterol is influenced by its synthesis and catabolism and the liver plays a crucial role in both these

processes ( Fig. 5-8 ). The first step in this complex sequence is the secretion of very-low-density lipoproteins (VLDL) by the liver into the bloodstream. VLDL particles are rich in

triglycerides, although they do contain lesser amounts of cholesteryl esters. When a VLDL particle reaches the capillaries of adipose tissue or muscle, it is cleaved by lipoprotein lipase, a

process that extracts most of the triglycerides. The resulting molecule, called intermediate-density lipoprotein (IDL), is reduced in triglyceride content and enriched in cholesteryl esters, but it

retains two of the three apoproteins (B-100 and E) present in the parent VLDL particle (see Fig. 5-8 ). After release from the capillary endothelium, the IDL particles have one of two fates.

Approximately 50% of newly formed IDL is rapidly taken up by the liver through a receptor-mediated transport. The receptor responsible for the binding of IDL to liver cell membrane

recognizes both apoprotein B-100 and apoprotein E. It is called the LDL receptor, however, because it is also involved in the hepatic clearance of LDL, as described later. In the liver cells,

Figure 5-8Schematic illustration of low-density lipoprotein (LDL) metabolism and the role of the liver in its synthesis and clearance. Lipolysis of very-low-density lipoprotein (VLDL) by

lipoprotein lipase in the capillaries releases triglycerides, which are then stored in fat cells and used as a source of energy in skeletal muscles.

Figure 5-9The LDL receptor pathway and regulation of cholesterol metabolism.

Figure 5-10Classification of LDL receptor mutations based on abnormal function of the mutant protein. These mutations disrupt the receptor's synthesis in the endoplasmic reticulum,

transport to the Golgi complex, binding of apoprotein ligands, clustering in coated pits, and recycling in endosomes. Each class is heterogeneous at the DNA level. (Modified with permission

from Hobbs HH, et al: The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133–170, 1990. © 1990 by Annual Reviews.)

Figure 5-11Synthesis and intracellular transport of lysosomal enzymes.

Figure 5-12Schematic diagram illustrating the pathogenesis of lysosomal storage diseases. In the example shown, a complex substrate is normally degraded by a series of lysosomal

enzymes (A, B, and C) into soluble end products. If there is a deficiency or malfunction of one of the enzymes (e.g., B), catabolism is incomplete and insoluble intermediates accumulate in

the lysosomes.

TABLE 5-6-- Lysosomal Storage Diseases

Date: 2016-04-22; view: 650