HDL particles contain apo A-I, A-II, and C. Apo A-I is an activator of LCAT,
which catalyzes the esterification of free cholesterol in HDL particles. Levels of apo
A-I have a stronger inverse correlation with CHD risk than apo A-II levels. HDL
particles that contain only A-I apolipoproteins are associated with a lower CHD risk
than are HDL particles containing both A-I and A-II.
Low-Density Lipoprotein Receptor
Cholesterol is taken up by peripheral and hepatic cells via binding of the ligands, apo
B-100 and E, on circulating lipoproteins to cell-surface LDL receptors. The
concentration of LDL receptors is mediated by intracellular cholesterol
concentration. Synthesis of LDL receptors is stimulated by a low intracellular
cholesterol concentration. Conversely, the concentration of cell-surface LDL
receptors may be downregulated by the action of proprotein convertase
subtilisin/kexin type 9 (PCSK9), which targets the LDL receptor for degradation
within intracellular lysozymes.
21 Within the cell, the receptor protein is synthesized
in the mitochondria and migrates to clathrin-coated pits on the cell surface. The LDL
receptor may then bind to lipoproteins that contain apo E or B-100, including VLDL,
remnant VLDL, IDL, and LDL. Because remnant VLDL and IDL particles contain
both B-100 and E proteins, they may have a higher affinity for LDL receptors than do
LDL particles, which contain only the B protein. Drugs that upregulate the synthesis
of LDL receptors (e.g., statins), therefore, may increase the clearance of both VLDL
remnant particles and LDL particles from the circulation. Thus, statins may reduce
serum TG levels as well as cholesterol levels. Following binding of lipoproteins to
the LDL receptor, the lipoproteins undergo endocytosis and are taken up by
lysosomes, where they are metabolized into elemental substances for use by the cell.
The cholesterol is transferred into the intracellular cholesterol pool. The LDL
receptor may be returned to the cell surface, where it can bind with another
circulating apo E- or apo B-containing lipoprotein.
ABNORMALITIES IN LIPID METABOLISM
Lipid synthesis and transport is complex with hundreds of possible steps that can
malfunction resulting in a lipid disorder. However, there are only a few relatively
common and important lipid disorders seen in clinical practice. The first two
described subsequently, polygenic hypercholesterolemia and atherogenic
dyslipidemia, are largely the result of an interaction between genes and lifestyle
choices. Several prominent, but rarer, familial lipid disorders are subsequently
described. Table 8-2 summarizes the characteristics of the most common lipid
POLYGENIC HYPERCHOLESTEROLEMIA
Polygenic hypercholesterolemia is the most prevalent primary disorder causing an
increase in cholesterol. It is caused by a combination of environmental (e.g., poor
nutrition, sedentary lifestyle) and multiple genetic factors. In patients with this
disorder a diet high in saturated fatty acids can reduce LDL receptor activity, thus
reducing the clearance of LDL particles from the systemic circulation. Patients with
polygenic hypercholesterolemia have mild to moderate LDL-C elevations (usually in
the range of 130–250 mg/dL), but no unique physical findings are usually present. A
family history of premature CHD is present in approximately 20% of cases. These
patients may often be effectively managed with dietary restriction of saturated fats
and cholesterol and by drugs that lower LDL-C levels (statins, bile acid sequestrants
Atherogenic dyslipidemia is characterized by moderate elevations of TG (150–500
mg/dL, indicative of the elevated VLDL remnant particles), low HDL-C levels (<40
mg/dL), and mild to moderate elevations of LDL-C level.
increased concentrations of small, dense, cholesterol-poor LDL particles, non–HDL-
C, and apo B-100. Most commonly, patients have increased visceral adiposity and
are hypertensive and insulin resistant.
In the presence of increased visceral adiposity there is impaired glucose
metabolism and/or diabetes with increased mobilization of fatty acids from adipose
cells to the systemic circulation. The excess of free fatty acids leads to increased TG
synthesis and secretion of TG-rich VLDL particles by the liver. These TG-rich
particles contain apo C-III, which inhibits the action of LPL, thus retarding lipolysis
of TGs from VLDL particles. This results in an excess of TG-rich VLDL remnant
23 CETP mediates the exchange of TGs from these particles with cholesteryl
esters from HDL, resulting in VLDL remnant particles that are enriched with
cholesterol (Fig. 8-6). TGs are also exchanged from VLDL remnant particles with
cholesteryl esters from LDL particles. Thus, VLDL remnants become even more
of TG-rich HDL results in low HDL due to excretion of lipid-poor apo A-I by the
Characteristics of Common Lipid Disorders
↓LDL clearance ↑LDL-C LDL-C: 130–250
Atherogenic dyslipidemia ↑VLDL secretion
apo B, gain-offunction mutations
apo B, gain-offunction mutations
Familial defective apoB-100 Defective apoB on
↑ApoB production ↑ApoB ApoB: >125 mg/dL None distinctive
Hypoalphalipoproteinemia ↑HDL catabolism ↓HDL-C HDL-C: <40 mg/dL None distinctive
VLDL, very-low-density lipoprotein.
Figure 8-6 The role of CETP in creation of atherogenic dyslipidemia.
13 Role of cholesterol ester transfer protein
therapies and future agents. Expert Opin Pharmacother. 2003;4:1901–1938.
Patients with atherogenic dyslipidemia may be effectively managed with weight
reduction and increased physical activity. Pharmacologic agents that enhance the
removal of remnant VLDL and small dense LDL particles (i.e., statins) and that
lower TG levels (i.e., Omega 3 fatty acids or fibrates) may be effective in the
FH is a disorder of defective LDL-C clearance. This autosomal dominant disorder is
strongly associated with premature CHD.
24,25 Most recent estimates indicate that the
prevalence of heterozygous FH (HeFH) ranges from 1 of 250 to 1 of 500 people in
26 Homozygous FH (HoFH) may occur in 1 of 1 million to 1 of
250,000 people in the United States. The most common cause of this disorder is a
genetic mutation resulting in a defective or absent LDL receptor. Consequently,
heterozygotes possess approximately half the number of functioning LDL receptors
and double the LDL-C level of unaffected patients (LDL-C levels ranging between
250 and 450 mg/dL). Clinically, FH patients may exhibit excess cholesterol
deposition in the iris, clinically manifested as arcus senilis. Cholesterol may also
deposit in tendons, particularly the Achilles’ tendon and extensor tendons of the
hands, resulting in tendon xanthomas. The clinical diagnosis of FH is established by
documenting a very high LDL-C level, a strong family history
of hypercholesterolemia and premature CHD events, and the presence of tendon
xanthomas. Untreated HeFH patients have approximately a 5% chance of a
myocardial infarction (MI) by age 30, a 50% chance by age 50, and an 85% chance
by age 60. The mean age of death in untreated male heterozygotes is in the mid-50s;
for untreated female heterozygotes, it is in the mid-60s.
Homozygotes generally have LDL-C levels greater than 500 mg/dL. This rare
disorder results in CHD by age 10 to 20 years. Because these individuals have lost
the ability to clear cholesterol-carrying lipoproteins from the circulation,
combination pharmacotherapy and/or LDL-apheresis may be required to help remove
Familial defective apo B-100 (FDB) is a genetic disorder clinically
indistinguishable from HeFH. These patients have normally functioning LDL
receptors, but defective apolipoprotein B-100, resulting in reduced binding of LDL
particles to the LDL receptor and reduced clearance of LDL particles from the
27–29 As with FH, LDL-C levels are usually 250 to 450 mg/dL.
Presumably, the apo E and half of the apo B in heterozygous FDB patients function
normally, providing mechanisms for removal of some lipoproteins from the systemic
circulation. Clinical diagnosis of FDB is based on a very high LDL-C level, a family
history of premature CHD, and tendon xanthomas. The definitive diagnosis requires
molecular screening techniques.
Proprotein Convertase Subtilisin/Kexin Type 9 Gain-ofFunction Gene Mutation
FH may also be caused by “gain-of-function” mutations in the gene encoding for
proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays an
important role in cholesterol homeostasis.
30 The frequency of these mutations in
patients with FH is uncertain. When PCSK9 is secreted into the plasma, it binds to
the epidermal growth factor-like repeat A (EGF-A) domain of the cell-surface LDL
receptors. PCSK9 binding leads to endocytosis of the LDL–LDL receptor–PCSK9
complex into intracellular lysozymes for degradation, resulting in a reduced number
of LDL receptors and increased LDL-C (to approximately 300 mg/dL). Drugs that
inhibit PCSK9 have demonstrated significant reductions in LDL-C in patients with
HeFH, HoFH, and polygenic hypercholesterolemia.
Familial Combined Hyperlipidemia
Familial combined hyperlipidemia (FCHL) is caused by increased production of apo
B-containing particles, VLDL, and LDL.
32 Patients with FCHL have an elevated apo
B-100 level, hypercholesterolemia with LDL-C usually in the range of 250 to 350
mg/dL, elevated TGs (usually between 200 and 800 mg/dL), and reduced levels of
HDL-C. First-degree relatives of these individuals frequently have a lipid disorder
and often there is a family history of ASCVD. Patients with FCHL commonly are
overweight, are hypertensive, and may have metabolic disturbances such as insulin
resistance, diabetes, or hyperuricemia. The diagnosis of FCHL is presumed in
patients who have increased cholesterol or TG levels, a strong family history of
premature CHD, and a family history of dyslipidemia.
Familial Dysbetalipoproteinemia
Familial dysbetalipoproteinemia, also called type III hyperlipidemia or remnant
disease, is caused by poor clearance of VLDL and chylomicron particles from the
systemic circulation as a result of a defect in apo E.
33,34 Apo E is necessary for the
normal clearance of chylomicrons and VLDL. It is inherited as an E2, E3, or E4
isoform from each parent. The E2 isoform has a low binding affinity for the LDL
receptor. Thus, individuals with an apo E2/E2 phenotype have delayed clearance of
VLDL remnant (and possibly chylomicron) particles from the circulation and a
reduced conversion of IDL to LDL particles. However, a clinically significant lipid
disorder usually does not result unless triggered by other metabolic problems such as
diabetes, hypothyroidism, or obesity. Patients with this disorder have high
cholesterol due to enrichment of cholesterol esters in VLDL remnant particles, high
TGs in the range of 400 to 800 mg/dL, and a VLDL-C to TG ratio greater than 0.3.
Patients may have palmar xanthomas (yellow-orange discoloration in the creases of
the palms and fingers) and tuberoeruptive xanthomas (small, raised lesions in areas
of pressure, particularly the elbows and knees). A personal and family history of
premature atherosclerotic vascular disease often is present. As noted above, these
patients often have diabetes mellitus, hypertension, obesity, and hyperuricemia.
Familial Disorders of Triglyceride Metabolism
(<130 mg/dL) and HDL-C is decreased (<40 mg/dL). FHTG is usually relatively
mild and asymptomatic unless secondary causes of hypertriglyceridemia are present
(poorly controlled diabetes, obesity, medications, etc.). TG levels are in the range of
200 to 500 mg/dL, but may be greater than 1,000 mg/dL. Patients with more marked
TG elevations (>500 mg/dL) may present with eruptive xanthomas and/or acute
Rare mutations in the LPL or cofactor apo CII genes may also be associated with
35 Familial LPL deficiency usually presents in childhood
with TG levels from 2,000 to 25,000 mg/dL and lipemic plasma, pancreatitis,
eruptive xanthomas, and lipemia retinalis (creamy-white appearance of retinal blood
vessels). The clinical presentation of familial deficiency in apo CII is similar to
familial LPL deficiency in homozygotes, but heterozygous individuals may have
normal plasma lipid concentrations. Patients with familial hepatic lipase deficiency
may also present with severe hypertriglyceridemia (>500–1,000 mg/dL) associated
with modest elevations in LDL-C and normal to increased HDL-C. This disorder is
most common in individuals of Indian ancestry.
Isolated low HDL-C (<40 mg/dL) without an increase in TG level is fairly
uncommon, but is associated with increased ASCVD risk. The precise molecular
defects causing this problem are uncertain, although genetic influences are likely
36 Tangier disease, which is characterized by low HDL-C, orange tonsils,
and hepatosplenomegaly, has been linked to a defect in the ABCA-1 transporter
responsible for the efflux of cholesterol from peripheral cells (i.e., inflammatory
cells in the arterial wall). The inherited tendency to have low HDL-C is accentuated
by lifestyle factors such as obesity, smoking, and lack of exercise. Despite strong
epidemiologic evidence showing an inverse relationship between HDL-C and CHD,
clinical trials demonstrating a benefit of raising isolated low HDL-C with drugs are
lacking. Therapy in patients with low HDL-C is, therefore, directed at lowering
LDL-C to reduce ASCVD risk. Therapies to raise HDL-C by novel mechanisms are
under investigation to determine if HDL-directed strategies can reduce CHD risk.
Epidemiologic studies have conclusively established a direct relationship between
blood cholesterol concentrations in a population and the incidence of ASCVD
38–40 For every 1% increase in blood cholesterol levels, there is a 1% to 2%
increase in the risk of CHD. In addition, using gene variants that exclusively affect a
biomarker of interest (i.e., that do not have pleiotropic effects on other factors),
investigators have confirmed LDL-C as a causal risk factor for CAD. HDL-C is
inversely associated with CHD risk. For every 1% decrease in HDL-C levels, there
is a 1% to 2% increase in the risk of CHD events.
41 However, gene variants that
affect HDL-C have cast doubt on whether HDL-C directly influences risk for CAD.
The role of TGs in the pathogenesis of ASCVD continues to be a subject of
23 Most epidemiologic studies have found that a high TG level
is an independent risk factor for CHD when evaluated with univariate analysis. When
other lipid abnormalities such as increased LDL-C or low HDL-C are included in a
multivariate analysis, TGs may lose independent predictive power. This is, in part,
because it is difficult to establish a causal relationship in observational
epidemiology, especially given the correlations among TGs, LDL-C, and HDL-C.
Patients with hypertriglyceridemia usually have low HDL-C (due to the action of
CETP and increased renal clearance of apo AI) which is an important predictor of
ASCVD risk. In addition, elevated TG levels are associated with increased levels of
TG-rich lipoprotein remnants (remnant VLDL and chylomicron particles and IDL),
increased LDL particle concentration, and small, dense LDL particles. These
particles are all potentially atherogenic and mediate a higher CHD risk than that
associated with an elevated LDL-C alone.
epidemiologic studies found that TGs independently predicted CHD risk, even after
adjustment for other lipid-risk factors.
23 High TG levels are also found in certain
familial disorders, including dysbetalipoproteinemia and FCHL, which carry
33,34 Additionally, hypertriglyceridemia is associated with a
procoagulant state, which promotes coronary thrombosis.
A recent analysis of 185 common genetic variants mapped for plasma lipids
levels was correlated with the magnitude of its effect on CAD risk.
suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Paradoxically, very high TG levels (>500 mg/dL) are not commonly associated
with an increased CHD risk, but do cause an increased risk of pancreatitis,
especially when levels exceed 1,000 mg/dL. Often, a genetic defect in LPLis present
in these cases that impairs the removal of TGs from TG-rich particles (VLDL and
chylomicrons). These particles do not become enriched with cholesterol and,
therefore, are not often atherogenic.
If the blood sample is stored in the refrigerator
overnight, a thick creamy layer often appears on the surface, indicating the presence
of chylomicrons. Although most patients with very high TGs remain free of CHD
throughout their lives, some do experience ASCVD events.
Pathogenesis of Atherosclerosis
Circulating cholesterol plays a central etiologic role in the pathogenesis of
1 Atherosclerotic vascular lesions begin in the first decade of life and
may progress in the presence of elevated levels of cholesterol and other uncontrolled
48 Atherosclerosis is considered to be a chronic inflammatory
process in response to injury of the vascular endothelium by factors such as
glycoxidation products in diabetes, shear stress, excess free fatty acids released by
adipocytes, bacterial products, and neurohormonal abnormalities, among other
factors. The damaged endothelium becomes prothrombotic, has reduced release of
nitric oxide and impaired vasodilatory capacity, and releases chemoattractants for
inflammatory cells and platelets. Regulation of blood cholesterol levels and
management of other risk factors can restore endothelial function, nitric oxide
release, and the vasodilatory response.
In patients with excess apo-B-containing lipoproteins [VLDL remnants, IDL, LDL,
and Lp(a)], atherogenic particles migrate through the endothelial junction into the
subendothelial space or intima. The subsequent accumulation and retention of
lipoproteins in the subendothelium (Fig. 8-7)
subendothelial matrix molecules such as chondroitin sulfate proteoglycans.
Soon after taking up residence in the subendothelial space, lipoproteins are
structurally modified primarily by oxidation. Modified lipoproteins stimulate
dysfunctional endothelial cells to release cell adhesion molecules (intracellular
adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin) and
chemoattractants (monocyte chemotactic factor 1 and macrophage colony-stimulating
factor) which promote adhesion and stimulate transmigration of monocytes and
lymphocytes into the intimal space.
49–51 Thus, atherosclerosis is an inflammatory
process in response to retained and modified lipoproteins. Once recruited,
monocytes are converted to macrophages, which ingest oxidized lipoprotein particles
via special scavenger or acetyl-LDL receptors on the surface of macrophage cells.
Further engorgement with oxidized lipoproteins inhibits mobility of resident
macrophages and the cells become cytotoxic causing further damage to the vascular
endothelium. As the uptake of modified lipoproteins into macrophage cells continues,
the cells become laden with lipid and eventually become foam cells (Fig. 8-8).
Monocytes and foam cells continue to secrete growth factors and cytokines
establishing a chronic inflammatory process and progression to a more complex
During plaque growth, smooth muscle cells from the media migrate upward and
proliferate near the luminal surface.
53 Collagen synthesis is also increased. This
leads to conversion of early atherosclerotic lesions that are lipid rich with a thin
fibrous cap to a potentially more stable lesion that has a small inner lipid core and
more collagen and matrix proteins. At any given time, atherosclerotic lesions at
various stages of development can be found all along the vascular arterial tree in
high-risk patients (Fig. 8-7).
As atherosclerotic lesions grow, the coronary artery remodels to accommodate the
lipid-rich core. Lesions initially enlarge away from the lumen toward the
media/adventitia, thus preserving the vascular lumen and ensuring normal blood flow
(positive remodeling). Late in the growth of the lesion, however, the luminal space is
invaded and becomes progressively narrowed as the atherosclerotic lesion
progresses (negative remodeling). Inflammatory cells secrete matrix
metalloproteinases that degrade collagen and fibrin produced by arterial smooth
muscle cells, causing a weakened fibrous cap and a lesion more vulnerable to plaque
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