Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is caused most commonly by mutations in the gene encoding the
receptor for LDL, resulting in inadequate removal of plasma LDL by the liver. Mutations in the LDL
receptor gene (LDLR) account for 80% to 85% of cases of FH. Much less commonly, FH is caused by mutations
in two other genes involved in clearance of plasma LDL. They encode (1) apolipoprotein B-100 (ApoB), the
ligand for LDL receptor on the LDL particle (5% to 10% cases), and (2) proprotein convertase subtilisin/kexin
type 9 (1% to 2% cases). This enzyme, better known by its abbreviation PCSK9, reduces expression of LDL
receptors by downregulating their recycling and consequent degradation in lysosomes. Each of these three
types of mutations impairs hepatic clearance of LDL and increases serum levels of cholesterol, giving rise to
premature atherosclerosis and a greatly increased risk of myocardial infarction. The functions of these genes in
cholesterol metabolism are discussed below.

FH caused by LDL receptor mutations is one of the most frequently occurring Mendelian disorders.
Heterozygotes with one mutant gene, representing about 1 in 200 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. Skin xanthomas and coronary,
cerebral, and peripheral vascular atherosclerosis may develop in these individuals at an early age. Myocardial
infarction may occur before age 20 years. Large-scale studies have found that FH is present in 3% to 6% of
survivors of myocardial infarction.

Normal Cholesterol Metabolism and Transport

Cholesterol may be derived from the diet or from endogenous

synthesis. Dietary triglycerides and cholesterol are incorporated
into chylomicrons in the intestinal mucosa and travel by way of
the gut lymphatics to the blood. These chylomicrons are
hydrolyzed by an endothelial lipoprotein lipase in the capillaries
of muscle and fat. The chylomicron remnants, rich in cholesterol,
are then delivered to the liver. Some of the cholesterol enters the
metabolic pool (to be described), and some is excreted as free
cholesterol or as bile acids into the biliary tract. The endogenous
synthesis of cholesterol and LDL begins in the liver (Fig. 5.6).
The first step in this process is the secretion of very-low-density
lipoprotein (VLDL) from the liver into the blood. VLDL particles
are rich in triglycerides, but they contain lesser amounts of
cholesteryl esters. In addition, they carry apolipoproteins ApoB,
ApoC, and ApoE on their surface. In the capillaries of adipose
tissue and muscle, the VLDL particle undergoes lipolysis and is
converted to VLDL remnant, also called intermediate-density
lipoprotein (IDL). Compared with VLDL, IDL particles have
reduced contente of triglycerides and an increase in cholesteryl
esters. ApoC is lost, but ApoB and ApoE are retained. 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 by receptor-mediated transport. The
receptor responsible for the binding of IDL to the liver cell
membrane recognizes both ApoB and ApoE. It is called ApoB/E,
or more commonly the LDL receptor, because it is also involved
in the hepatic clearance of LDL (described later). In the liver
cells, IDL is recycled to generate VLDL. The IDL particles not
taken up by the liver are subjected to further metabolic processing that removes most of the remaining
triglycerides and ApoE, yielding ApoB carrying cholesterol-rich LDL particles.

Although many cell types, including fibroblasts, lymphocytes, smooth muscle cells, hepatocytes, and
adrenocortical cells, possess high-affinity LDL receptors, approximately 70% of the plasma LDL is cleared by
the liver, using a quite sophisticated transport process (Fig. 5.7). The first step involves binding of LDL to cell-
surface receptors, which are clustered in specialized regions of the plasma membrane called coated pits
(Chapter 1). After binding, the coated pits containing the receptor-bound LDL are internalized by invagination
to form coated vesicles, after which they migrate within the cell to fuse with the lysosomes. Here the LDL
dissociates from the receptor, which is recycled to the surface. The recycling of LDL receptors is regulated by
PCSK9, which binds to LDL receptors on the surface of hepatocytes and causes their degradation after
endocytosis. In the lysosomes the LDL molecule is enzymatically degraded; the apoprotein part is hydrolyzed to
amino acids, whereas the cholesteryl esters are broken down to free cholesterol. This free cholesterol, in turn,
crosses the lysosomal membrane to enter the cytoplasm, where it is used for membrane synthesis and as a
regulator of cholesterol homeostasis. The exit of cholesterol from the lysosomes requires the action of two
proteins, called NPC1 and NPC2 (see “Niemann-Pick Disease Type C”). Four separate processes are affected by
the released intracellular cholesterol, as follows (see Fig. 5.7):
• Cholesterol suppresses cholesterol synthesis within the cell by inhibiting the activity of the enzyme 3-hydroxy-
3-methylglutaryl coenzyme A (HMG CoA) reductase, which is the rate-limiting enzyme in the synthetic pathway.

• Cholesterol activates the enzyme acyl-coenzyme A:cholesterol acyltransferase, favoring esterification and
storage of excess cholesterol.

• Cholesterol suppresses the synthesis of LDL receptors, thus protecting the cells from excessive accumulation
of cholesterol.

• Cholesterol upregulates the expression of PCSK9, which reduces recycling of LDL receptors and causes
degradation of endocytosed LDL receptors. This provides an additional mechanism of protecting the cells from
excessive accumulation of cholesterol.

As mentioned earlier, FH results from mutations in the gene encoding the receptor for LDL or the two genes
that compromise its function. The impact of mutations in these genes is as follows:

• Mutations in LDLR gene. Heterozygotes with FH due to mutation in the LDLR gene possess only 50% of the
normal number of high-affinity LDL receptors because they have only one normal gene. As a result of this
defect in transport, the catabolism of LDL by the receptor-dependent pathways is impaired, and the plasma
level of LDL increases two- to three-fold. Homozygotes have virtually no normal LDL receptors in their cells and
have much higher levels of circulating LDL. In addition to defective LDL clearance, both the homozygotes and
the heterozygotes have increased synthesis of LDL. The increased synthesis that contributes to
hypercholesterolemia alsoresults from a lack of LDL receptors (see Fig. 5.6). As mentioned above, IDL, the
immediate precursor of plasma LDL, also uses hepatic LDL receptors (apoB/E receptors) for its transport into
the liver. In FH, impaired IDL transport into the liver secondarily diverts a greater proportion of plasma IDL into
the precursor pool for plasma LDL.

• Mutations in gene encoding ApoB. Since ApoB on the surface of LDL particles is the ligand for LDL receptors,
mutante ApoB reduces the binding of LDL molecules with LDL receptors. This compromise in the binding of LDL
particles to its receptors increases serum LDL cholesterol.

• Activating mutation in the PCSK9 gene. This mutation greatly reduces the number of LDL receptors on the
cellsurface because of their increased degradation during the recycling process.

The transport of LDL via the scavenger receptor seems to occur at least in part into the cells of the
mononuclear phagocyte system. Monocytes and macrophages have receptors for chemically altered (e.g.,
acetylated or oxidized) LDL. Normally the amount of LDL transported along this scavenger receptor pathway is
less than that mediated by the LDL receptor–dependent mechanisms. In the face of hypercholesterolemia,
however, there is a marked increase in the scavenger receptor–mediated traffic of LDL cholesterol into the cells
of the mononuclear phagocyte system and possibly the vascular walls (Chapter 11). This increase is responsible
for the appearance of xanthomas and contributes to the pathogenesis of premature atherosclerosis.

The molecular genetics of FH is extremely complex.

More than 2000 mutations involving the LDL
receptor gene, including DNA copy number
variations, insertions, deletions, and missense and
nonsense mutations, have been identified.

These can be classified into six groups (Fig. 5.8).

Class I mutations are relatively uncommon and lead
to a complete failure of synthesis of the LDL
receptor protein (null allele). Class II mutations are
fairly common; they encode LDL receptor proteins
that accumulate in the endoplasmic reticulum
because their folding defects make it impossible for
them to be transported to the Golgi complex. Class
III mutations affect the ApoB binding site of the
receptor; the mutant LDL receptors reach the cell
surface but fail to bind LDL or do so poorly. Class
IV mutations encode LDL receptors that are
synthesized and transported to the cell surface
efficiently. They bind LDL normally, but they fail to
localize in coated pits, and hence the bound LDL is
not internalized. Class V mutations encode LDL
receptors that are expressed on the cell surface,
can bind LDL, and can be internalized; however, the
pH-dependent dissociation of the receptor and the
bound LDL fails to occur. Such receptors are
trapped in the endosome, where they are
degraded, and hence they fail to recycle to the cell
surface. Class VI mutations result in the failure of
initial targeting of the LDL receptor to the
basolateral membrane.

The discovery of the critical role of LDL

receptors in cholesterol homeostasis has led
to the rational design of drugs that lower
plasma cholesterol by increasing the number
of LDL receptors (see Fig. 5.8). One strategy is
based on the ability of certain drugs (statins) to
suppress intracellular cholesterol synthesis by inhibiting the enzyme HMG CoA reductase. The reduction in
intracellular cholesterol allows greater synthesis of LDL receptors by removing the braking action of cholesterol
on LDL receptor synthesis. In another strategy, antibodies that inhibit PCSK9 function reduce the degradation
of LDL receptors, thereby increasing their abundance on the cell membrane and consequent increased
clearance of LDL cholesterol from the blood. These agents have profound cholesterol-lowering effects, and large
clinical trials have shown the benefits of using this class of drugs in the treatment of patients who do not
respond adequately to statins alone. Interestingly, PCSK9 was discovered accidentally in individuals with
exceedingly low serum cholesterol who were found to have loss-of-function variants of the PCSK9 gene.

KEY CONCEPTS
FAMILIAL HYPERCHOLESTEROLEMIA

• FH is an autosomal dominant disorder caused by mutations in the genes encoding the (1) LDL receptor (85%
cases), (2) ApoB protein (5% to 10% cases), or (3) activating mutations of PCSK9 (1% to 2% cases).
• Patients develop hypercholesterolemia as a consequence of impaired transport of LDL into the cells.
• In heterozygotes for mutations in the LDLR gene, elevated sérum cholesterol greatly increases the risk of
atherosclerosis and resultant coronary artery disease; homozygotes have an even greater increase in serum
cholesterol and a higher frequency of ischemic heart disease. Cholesterol also deposits along tendo sheaths to
produce xanthomas.

Robbins & Cotran Pathologic Basis of Disease 10th Ed_compressed