Annabelle Rodriguez-Oquendo
In the previous edition, David E. Kern, MD, and Marc R. Blackman, MD, contributed to this chapter.
Interest in plasma lipids, lipoproteins, and apoproteins stems from their strong relationship to the development of atherosclerosis (1, 2, 3). At a time when it is possible to reduce the frequency of premature death and disability from atherosclerotic disease, the clinician should be knowledgeable about and capable of diagnosing and treating the major disorders of lipid metabolism.
Lipid and Lipoprotein Nomenclature and Composition
Lipids are insoluble in the blood. They circulate in plasma as component parts of macromolecules that consist of a nonpolar hydrophobic lipid core of cholesterol esters and triglycerides and a polar hydrophilic monolayer surface coat of protein, phospholipid, and unesterified cholesterol (Fig. 82.1). These macromolecules, which are made miscible in plasma by their surface coat, are called lipoproteins.
Traditionally, lipoproteins have been classified as a family of molecules containing the same basic constituents but in different proportions (Table 82.1). The major classes of lipoproteins can be separated from each other by differences in density (ultracentrifugation), net surface charge (electrophoresis), size, and composition. Ultracentrifugation, which has been the traditional method of classification, separates lipoproteins into five principal classes: chylomicrons, very-low-density lipoproteins (VLDLs),
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intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs) (4).
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FIGURE 82.1. Structure of the lipoprotein macromolecule with the nonpolar lipids, cholesterol ester, and triglyceride in the lipoprotein core surrounded by a monolayer composed of specific apolipoproteins, proteins, and the polar lipids, unesterified cholesterol and phospholipid. (From The Johns Hopkins Physicians Lipid Education Program. 2nd ed. Baltimore: The Johns Hopkins University, 1988:11, with permission. ) |
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TABLE 82.1 Classification of Plasma Lipoproteins by Physical and Chemical Characteristics |
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Each lipoprotein contains characteristic proportions of lipids and type-specific apoproteins (apos) such that, with increasing lipoprotein density, the relative amount of lipid decreases and that of apoprotein increases (Table 82.1). For example, triglyceride is the major lipid component in chylomicrons and VLDL, whereas cholesterol is the major component of LDL. Intermediate-density or remnant lipoproteins are catabolic products of chylomicrons and VLDLs, and contain similar amounts of both lipids and apos (see Normal Physiology of Lipoprotein Transport). The HDLs are the most dense lipoproteins; they contain proportionally the most apos and ordinarily consist of 15% to 25% cholesterol with a small amount of triglyceride in the core. HDLs are further subdivided into HDL2 and HDL3. The former is more buoyant, as reflected by its higher lipid-to-protein ratio and richer apo A-I and apo C and E content, relative to the more dense HDL3, which has a lower lipid-to-protein ratio and a higher apo A-II than A-I composition. Some studies have shown an inverse relationship of coronary risk to plasma concentrations of HDL2 and apo A-I, related to the capacity of the latter molecules to transport cholesterol from cells (this process is termed reverse cholesterol transport) (5).
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FIGURE 82.2. The normal physiology of lipoprotein transport is illustrated schematically. |
Normal Physiology of LIPID Transport
Plasma lipoproteins arise from both exogenous dietary sources and endogenous hepatic sources (Fig. 82.2). They carry lipids in three distinct but interacting pathways: The exogenous pathway consists primarily of chylomicrons; the endogenous pathway consists mostly of VLDL, IDL, and LDL; and the reverse cholesterol transport pathway consists mostly of HDL activity.
After the ingestion of fat, dietary triglycerides are hydrolyzed in the gut and absorbed by intestinal enterocytes. The triglyceride-containing chylomicrons formed in these cells are secreted into lymphatic vessels, and subsequently enter the venous system via the thoracic duct.
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Chylomicrons function as a system of high-energy caloric transport, allowing the calories ingested in excess of the immediate needs of the body to be transferred to sites of storage between meals. Absorbed dietary cholesterol is also esterified and transported in chylomicrons.
Other triglyceride-rich lipoproteins are synthesized from endogenous sources by the liver and intestine. Cholesterol synthesis from acetate also occurs in the liver and is regulated by the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. Triglycerides synthesized in the liver combine with cholesterol ester and are enveloped in a lipoprotein monolayer before being secreted into the hepatic venous outflow system as endogenous triglyceride-rich VLDLs.
Chylomicrons and VLDLs are transported to adipose tissue and muscle for storage and use. The uptake and storage of triglyceride are regulated by lipoprotein lipase (LPL). LPL hydrolyzes triglyceride and surface components from chylomicrons and VLDL to transform them into remnant lipoproteins (Fig. 82.2). The fatty acids released during this reaction migrate to muscle cells for combustion or to adipose cells for resynthesis and storage as triglyceride (6). The remnant lipoproteins are smaller, denser, and relatively enriched in cholesterol, apo B, and apo E, compared with the chylomicrons and VLDL from which they are derived. They are taken up by apo B-E (LDL) receptors in the liver. The chylomicron remnants are further degraded, and the VLDL remnants are processed into IDL and cholesterol-rich LDL (Fig. 82.2). Apo C-II and apo C-III, and the phospholipids and free cholesterol released during the LPL reaction, are transferred to HDL for use. The surface material generated by LPL-mediated removal of core triglyceride from VLDL and chylomicrons is the substrate (apo A-I is the cofactor) for the enzyme lecithin-cholesterol acyl transferase (LCAT), which converts nascent HDL to mature spherical HDL and plays a major role in reverse cholesterol transport.
The LDLs are the principal carriers of cholesterol in plasma. Cholesterol is a major structural component of all cell membranes and is a precursor for steroid hormone synthesis by the adrenal glands and gonads. The LDL cholesterol-rich particles are derived mainly from VLDL and their catabolic remnants via the action of LPL and hepatic lipase. The principal removal of LDL occurs in the periphery by cells having a specific cell surface receptor (1) that recognizes all forms of apo B; this is currently referred to as the apo B-E (LDL) receptor (Fig. 82.2). After specific cell receptor binding, LDLs are internalized by receptor-mediated endocytosis and carried to lysosomes, where apo B is irreversibly degraded to amino acids and LDL cholesterol ester is hydrolyzed to free cholesterol. The free cholesterol is transported to an intracellular cholesterol pool, where it regulates, by a cellular feedback pathway, the resynthesis of cholesterol, cholesterol ester, and apo B-E (LDL) receptors (7).
The cholesterol content of the cell is also regulated by a removal system involving HDL as a vehicle for cholesterol transport from peripheral to hepatic cells for catabolism and excretion into bile directly or after conversion to bile acid (7,8). This process, termed reverse cholesterol transport, is thought to be one of the mechanisms for the antiatherogenic effect of HDL. It provides an efficient mechanism for the transfer of esterified cholesterol to LDL and VLDL, the absorption of free cholesterol from vascular endothelial cells, and the removal of cholesterol arising from cell membrane turnover and cell death. An apparent antiatherogenic alteration in both the lipoprotein and apoprotein composition of HDL, the formation of HDL2, occurs during high-cholesterol feeding and represents one pathway by which the body can enhance its capacity to clear excess cholesterol from cells (7). HDL is also thought to be cardioprotective by acting as an antioxidant and endotoxin scavenger. The identification of the HDL receptor SR-BI has shown that the receptor plays a major role in reverse cholesterol transport, with a key role in the selective uptake of cholesteryl esters in hepatocytes and gonadal cells (9,10). Research is currently underway to better define the role of SR-BI in atherosclerosis and to determine whether it might be a useful target for pharmacologic intervention.
Continued LDL catabolism in excess of that performed by hepatic and other parenchymal cells occurs in macrophages via a scavenger pathway. The observation that oxidatively modified LDLs are efficiently taken up by the scavenger pathway receptors, and subsequently influence macrophage and monocyte motility, served as the basis for proposing the current oxidative theory of atherogenesis (11). Abnormalities in oxidative metabolism of LDL are considered to account for the dyslipidemia in persons with homozygous familial hypercholesterolemia (11).
Apoproteins occupy specific domains on the three-dimensional structures of the individual lipoproteins. Alterations in lipid–protein interactions occur during the normal metabolism of lipoproteins, resulting in changes in the association of apoproteins with lipoproteins. Abnormalities in lipoprotein transport occur when the domains of apoproteins are altered by substitutions or deletions in amino acids. For example, the abnormal recognition of β-VLDL by the apo B-E receptor on cells occurs because of an abnormality in apo E in dysbetalipoproteinemia (see Pathophysiology of Lipoprotein Disorders), and abnormalities in the apo B-E receptors are responsible for the defect in familial hypercholesterolemia (1,12).
Plasma Lipoproteins as Risk Factors for Atherosclerosis
Among the risk factors for atherosclerotic vascular disease (13), the most clearly established ones are plasma total
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cholesterol levels (and plasma LDL and HDL content), hypertension, cigarette smoking, family history of premature coronary artery disease (CAD), and age. Diabetes mellitus is considered a risk equivalent to having CAD (Table 82.2).
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TABLE 82.2 CAD Risk Factors as Defined by the NCEP Adult Treatment Guidelinesa |
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Evidence from several large prospective and retrospective epidemiologic studies among diverse populations has demonstrated that variations in plasma levels of certain lipids and lipoproteins are associated with an increased likelihood of developing or having CAD.Hypercholesterolemia, for example, is strongly associated with the subsequent development of CAD. The relationship is uniformly consistent, dose related, and independent of gender. The predictive value of the plasma level of total cholesterol is somewhat limited, however, by the fact that it reflects the opposing influences of LDL and HDL cholesterol. Levels of LDL correlate positively, whereas those of HDL, in general, are inversely related to CAD risk. The negative correlation between HDL levels and CAD depends mainly on its subfraction, HDL2, which may provide, along with its major protein component apo A-I, a better index of risk than the total plasma level of HDL (5). Over the range of total and HDL cholesterol plasma levels found in an average American population, the risk of CAD varies roughly fivefold. Although the impact of cardiovascular risk factors declines after 75 years of age, they are still predictive of CAD in older people. The relative risks of CAD associated with any particular risk factor (e.g., cholesterol levels) decrease with aging because of the increased prevalence of multiple risk factors; however, the absolute risk of morbidity and mortality increases markedly (14). Most, but not all, studies indicate that plasma levels of total cholesterol retain predictive value in the “old old”—that is, in men age 75 to 95 years (15, 16, 17, 18). Moreover, HDL cholesterol levels and the ratio of LDL to HDL cholesterol remain useful predictors in this age group.
The relationships of plasma levels of total, LDL, and HDL cholesterol with CAD are independent ones, in that the associations remain significant even after statistical adjustment for other risk factors. A low concentration of HDL cholesterol is a stronger independent risk factor for CAD than is either total cholesterol or LDL cholesterol (3).
Increased fasting levels of plasma triglyceride and of its major lipoprotein transporter, VLDL, also correlate with an increased risk of atherosclerotic disease. There has been uncertainty about whether the association is independent of other risk factors (19,20). Recent analyses suggest that plasma triglyceride levels are a risk factor for CAD and are independent of HDL cholesterol levels (21,22). Treatment of hypertriglyceridemia depends on the causes and degree of elevation and on the presence or absence of other risk factors (Table 82.2; seeTreatment). Hypertriglyceridemia may be especially important prognostically in patients with diabetes mellitus (23) or end-stage renal disease (24). Not only do these lipoprotein and apoprotein abnormalities increase the risk of CAD, but there also is a parallel increased risk for cerebrovascular disease (13,25), as well as for peripheral vascular disease (25).
A number of lipid fractions are even more strongly related to CAD than are total, LDL, and HDL cholesterol or apo A-I, and measurements of these fractions may become more useful in cardiovascular and cerebrovascular risk factor assessments (3). Elevated plasma concentrations of LDL apo B appear to discriminate between patients with and without atherosclerosis of the coronary and peripheral vasculature, even in the presence of normal total and LDL plasma cholesterol levels (2,26). The determination of the plasma LDL apo B concentration may also prove useful in assessing risk in hypertriglyceridemic patients (2,22). It is known that LDL consists of several lipoprotein subclasses that differ in size and core lipid content, and that LDL subclass pattern B, characterized by small, dense LDL particles, is associated with a threefold increased risk of myocardial infarction (MI), independent of age, gender, and body weight (27).
In addition, MI, the progression of angiographically documented CAD, postangioplasty restenosis, and cerebrovascular disease are strongly associated with the lipoprotein (a) [Lp(a)] blood pattern, particularly in patients with increased levels of LDL cholesterol (28). The evidence (29) suggests that Lp(a) (distinct from apo A) consists of a circulating complex of LDL and apo(a) that is more atherogenic than LDL. Apo(a) exists in more than 30 isoforms and accounts for the substantial variability in the plasma concentrations of Lp(a). Moreover, Lp(a) is
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structurally similar to plasminogen and inhibits the conversion of plasminogen to plasmin, thus attenuating fibrinolysis. Finally, Lp(a) appears to be directly involved in the formation of atherosclerotic plaques, perhaps because of its susceptibility to oxidative alteration in the arterial wall. However, at present there is no evidence from clinical trials to support routine measurement of Lp(a).
A number of investigations have demonstrated that tissue oxidative damage to LDL, and the subsequent interactions between damaged LDL and vascular endothelium, smooth muscle, macrophages, and monocytes, elicit more atherogenic activity than occurs with native LDL (11). Research in animals indicates that use of exogenous antioxidants retards the progression of experimentally induced atherogenesis by 30% to 80%. Although there have been epidemiologic reports that antioxidants (e.g., vitamin E) protect hyperlipidemic patients from the development or worsening of atherosclerotic heart disease (30,31), several prospective randomized trials have shown no benefit in this regard (32,33).
In familial dysbetalipoproteinemia, a genetic disorder characterized by elevated plasma concentrations of IDL and an abnormally migrating β-VLDL (12), there is an increased risk of both peripheral and coronary atherosclerotic disease. In contrast, fasting chylomicronemia is associated with recurrent episodes of abdominal pain and pancreatitis, but not with the early development of atherosclerosis.
In several epidemiologic studies, plasma total cholesterol levels lower than 180 to 195 mg/dL were associated with an increased risk of cancer, especially cancer of the colon. The evidence does not, however, suggest a significant causal link because (a) in most studies the association was strongest in the first year of followup, then attenuated and disappeared in subsequent years, suggesting that preclinical cancer might have lowered levels of plasma cholesterol rather than vice versa; (b) studies comparing populations show a positive association between dietary fat intake and risk for major cancers such as breast, prostate, and colon cancer; and (c) the relationship was generally weak, was present in a minority of studies, and demonstrated no consistent relation between cholesterol level and cancer risk (34).
Rationale for Diagnosis and Treatment
Despite the fact that many risk factors linked with coronary and other atherosclerotic vascular disease have been identified and targeted for intervention, atherosclerotic disease constitutes the leading cause of death and disability in Western industrialized societies. In response, major efforts at risk factor identification and treatment, as well as prevention, primarily targeting hyperlipidemia, hypertension, and smoking, have been undertaken, and mortality from CAD has fallen steadily (35).
The “lipid (or cholesterol) hypothesis,” based on the data described, also postulates that favorable alterations of plasma lipoprotein levels by diet, drugs, or other therapy reduce the risk of atherosclerosis in humans. Indeed, randomized primary prevention trials have shown that lowering LDL cholesterol in asymptomatic hyperlipidemic middle-aged men significantly reduces their risk of death from coronary artery disease and of nonfatal MI (36, 37, 38, 39). The relative risk reduction over 5 years is approximately 30%, and the absolute risk reduction is approximately 2% (the number needed to treat to avoid an adverse event is 50).
Results from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) have lent greater support to the rationale for primary prevention treatment (39). A total of 5,608 men and 997 women with average total and LDL cholesterol levels (221 and 150 mg/dL, respectively) and below-average HDL cholesterol levels (36 and 40 mg/dL, respectively) were studied for an average followup period of 5.2 years. This study compared the effects of placebo and lovastatin on the primary end points of unstable angina, fatal and nonfatal MI, and sudden cardiac death in middle-aged patients (men age 45 to 73 years and postmenopausal women age 55 to 73 years). For study subjects receiving lovastatin treatment, the relative risks were significantly reduced for first acute coronary events, MI, unstable angina, coronary revascularization procedures, coronary events, and cardiovascular events. Lovastatin lowered LDL cholesterol levels by 25% (to 115 mg/dL) and increased HDL cholesterol levels by 6% (to 39 mg/dL).
Secondary prevention trials also have shown conclusively that cholesterol-lowering drugs can decrease CAD progression as well as the incidence of new and recurrent CAD-related events in patients with known atherosclerotic vascular disease (40, 41, 42). There is a consensus that treatment should be more aggressive in these populations (see Treatment). Relative risk reductions of 20% to 40% have been reported, with absolute risk reductions of 3% to 4% over 5 years of treatment. In these studies, all-cause mortality was also reduced by approximately 20%.
The importance of targeting HDL cholesterol levels, particularly in patients with known CAD, was highlighted in the report from the Veteran's Affairs High-Density Lipoprotein Cholesterol Intervention Study (VA-HIT) (42). In this study, 2,531 men with known CAD, low HDL cholesterol levels (mean: 32 mg/dL), and “desirable” LDL cholesterol levels (mean: 111 mg/dL) were treated with placebo or gemfibrozil 600 mg twice daily for a mean followup period of 5.1 years. Gemfibrozil was chosen as the pharmacologic agent because of its relatively neutral effects on LDL cholesterol levels. The results showed significant relative risk reductions for nonfatal MI, CAD death, transient
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ischemic attack, angioplasty, carotid endarterectomy, stroke, and hospitalization for congestive heart failure. These beneficial effects of gemfibrozil treatment were associated with significant reduction in plasma triglyceride levels (24%) and increased HDL cholesterol levels (8%).
Results from the Heart Protection Study (HPS) have contributed substantially to the newer guidelines advocating lowering the target LDL cholesterol levels in patients at high risk for CHD (42a). Approximately 20,000 adult men and women, between the ages of 40 and 80 years, with either diabetes mellitus, hypertension, occlusive disease of noncoronary artery disease, or coronary artery disease were enrolled in this double-blind, placebo-controlled, randomized study of statin therapy (simvastatin vs. placebo) of 5 years duration. Overall, the results showed that all participants on statin therapy (regardless of age, gender, baseline LDL cholesterol levels) benefited from statistically significant relative-risk reduction in major coronary events, stroke and revascularization.
Hyperlipidemia
Definition
The diagnosis of hyperlipidemia historically has been based on plasma levels of lipids or lipoproteins above the 95th percentile of those found in a reference population. The Adult Treatment Panel (ATP) of the National Cholesterol Education Program (NCEP) has established criteria for the diagnosis of hyperlipidemia based on prognostic significance (Table 82.3) (43,44).
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TABLE 82.3 Adult Treatment Panel III Criteria for the Classification of LDL, Total, and HDL Cholesterol (mg/dL) Based on Prognostic Significance |
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TABLE 82.4 Causes of Secondary Lipoprotein Disorders |
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Classification
Primary versus Secondary
For clinical purposes, hyperlipidemic states should be classified as primary (hereditary or sporadic genetic disorders of metabolism), secondary, or both. Secondary hyperlipidemia is associated with an identifiable disease or condition and is reversible with control or eradication of that disease or condition. Table 82.4 lists the major causes of secondary hyperlipoproteinemia.
Phenotypic versus Genotypic and Pathophysiologic
In the 1960s, it was popular to classify the various hyperlipidemic states phenotypically, based on specific concentrations of lipids and lipoproteins and electrophoretic patterns (Table 82.5). Although the phenotypic classification describes in abbreviated fashion the plasma lipoproteins that are present in elevated or low concentrations, it does not reflect the genetic mechanisms or pathophysiology of the lipoprotein disorders. It is desirable to classify patients
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pathophysiologically and genotypically (Table 82.5) to diagnose and treat lipoprotein disorders accurately. Because apoproteins, enzymes, and cellular receptors are the major regulators of lipoprotein metabolism, it is appropriate to categorize lipoprotein disorders whenever possible in terms of pathophysiologic defects in the structure, function, and metabolism of these molecules, rather than by using a rigidly fixed phenotypic classification. Often, the pathophysiologic and genotypic classification can be surmised from a patient's phenotypic pattern, medical history, family history, and physical examination. Sometimes family members must be studied or more sophisticated laboratory analyses performed, necessitating referral to a specialist in endocrinology and metabolism.
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TABLE 82.5 Classification of Lipoprotein Disorders by Phenotypes and Genotypes and Corresponding Clinical Manifestations |
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Pathophysiology of LIPID Disorders
The abnormal accumulation of lipoproteins in plasma results from their excessive production, defective removal, or both. Lipoprotein disorders may be primary (usually genetic); they may be secondary to certain diseases (especially diabetes mellitus, chronic renal disease, hypothyroidism, dysglobulinemia) or drugs (corticosteroids, estrogens, thiazide diuretics); or they may represent an interaction between primary and secondary factors. Abnormalities can occur in triglyceride-rich lipoprotein synthesis, LPL-mediated triglyceride catabolism, remnant lipoprotein catabolism, cholesterol-rich lipoprotein catabolism, or cholesterol-rich lipoprotein (LDL cholesterol) synthesis and absorption.
Increased Triglyceride Synthesis
Most triglyceride input is from the diet in normal individuals. However, abnormalities in the regulation of the endogenous production of triglyceride-rich VLDLs are fairly common and are the most common causes of hypertriglyceridemia. They are associated with an increase in plasma levels of VLDL (type IV) or of VLDL plus chylomicrons (type V). The underlying metabolic cause for endogenous hypertriglyceridemia is usually related to hyperinsulinemia and insulin resistance, most often as a result of obesity, diabetes mellitus, the ingestion of excessive calories or alcohol, or the use of estrogens or corticosteroids.
The primary forms of endogenous hypertriglyceridemia are familial hypertriglyceridemia and primary familial combined hyperlipidemia.Familial hypertriglyceridemia results in an increase in the endogenous synthesis of large triglyceride-rich VLDLs. Many such patients are obese and exhibit mild glucose intolerance, hyperinsulinemia, and clinical evidence of diabetes mellitus, conditions that contribute to the excessive hepatic production of VLDL triglyceride.
In contrast, patients with familial combined hyperlipidemia (multiple lipoprotein–type hyperlipidemia) exhibit an increase in the production of apo B, which can appear in VLDL, LDL, or both. Various lipoprotein types (IIA, IIB, or IV) are found in patients with familial combined hyperlipidemia, and the presenting sign can be an increase in VLDL triglyceride, LDL cholesterol, or both. The clinical expressions of this disorder vary among individual patients depending on diet, degree of obesity, level of physical activity, and concomitant use of other drugs.
Familial hypertriglyceridemia and familial combined hyperlipidemia are inherited as separate autosomal-dominant disorders, each occurring in approximately 1% of the general population. Familial hypertriglyceridemia is not associated with xanthomas unless hyperchylomicronemia supervenes. Basal concentrations (after a 12-hour fast) of total triglycerides and VLDL triglycerides are characteristically elevated, but plasma levels of total and LDL cholesterol are normal or low unless levels of VLDL cholesterol are also increased. Familial hypertriglyceridemia is not associated with an increased incidence of premature CAD; however, patients with familial combined hyperlipidemia are at high risk, primarily because of their increased plasma levels of apo B as well as abnormalities in the composition of HDL and reduced levels of apo A-I and HDL2 (2). Familial combined hyperlipidemia may be present in as many as 10% of survivors of MI who are younger than 60 years of age and thus represents a common and important risk factor for atherosclerosis.
The diagnosis of these disorders of lipoprotein metabolism and their exact definition can be established only by family studies. A strongly positive family history of atherosclerosis favors the diagnosis of familial combined hyperlipidemia in hypertriglyceridemic patients in whom secondary causes for hyperlipidemia have been excluded. Differentiating between these two disorders of lipoprotein metabolism is important in the evaluation of a patient with hyperlipidemia, particularly with regard to deciding whether therapeutic intervention is warranted for the prevention of CAD and its complications.
Occasionally, patients have marked hypertriglyceridemia and hyperchylomicronemia (triglyceride levels greater than 1,000 mg/dL), pancreatitis, eruptive xanthomas, and lipemia retinalis. Coexistence of familial hypertriglyceridemia or familial combined hyperlipidemia with obesity, uremia, untreated diabetes mellitus, chronic alcoholism, or the use of corticosteroids, thiazide diuretics, or estrogens can result in this syndrome. The chylomicronemia syndrome requires immediate treatment with elimination of dietary fat, nasogastric suction when severe, and treatment of the secondary causes. Prevention is the primary means to avoid recurrences, and patients with primary hypertriglyceridemia often receive lipid-lowering agents prophylactically (7).
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Decreased Lipoprotein Lipase-Mediated Triglyceride Catabolism
LPL is the rate-limiting enzyme for the uptake and storage of triglyceride by adipose or muscle tissue and for the processing of triglyceride-rich lipoproteins to chylomicrons and VLDL remnants. In patients with the autosomal-recessive trait of apo C-II deficiency, LPL activity is normal but marked hypertriglyceridemia is present. In contrast, in the more commonly encountered (yet also rare) autosomal-recessive syndrome of familial LPL deficiency, marked hypertriglyceridemia and chylomicronemia are both evident and LPL activity is absent. The type I phenotypic pattern is more likely to occur in patients with the familial form of LPL deficiency, rather than in those with apo C-II deficiency; yet both conditions manifest in childhood with episodes of eruptive xanthomas and with the acute abdominal pain of pancreatitis.
Most adult patients who have an acquired impairment in LPL function have moderately severe type 1 diabetes mellitus, hypothyroidism, end-stage renal disease, or dysgammaglobulinemia or are receiving corticosteroids or thiazide diuretics. The severity of the lipoprotein abnormality seems to be directly related to the decrease in LPL activity in postheparin plasma and adipose tissue.
The hypertriglyceridemia can be controlled by restriction of dietary fat and substitution of carbohydrates or medium-chain triglycerides as energy sources. Effective treatment of diabetes mellitus with diet, insulin, or an oral agent usually normalizes LPL activity and plasma triglyceride levels within several months. Similar beneficial changes are seen after treatment of hypothyroidism or of uremia.
LPL also plays a role in the formation of HDL2 (see Normal Physiology of Lipoprotein Transport). LPL appears to mediate the increase in HDL2seen in endurance-trained athletes (45) and in patients with primary hypercholesterolemia treated with colestipol. Hence, diseases associated with abnormalities in LPL often have concomitant reductions in HDL cholesterol.
Defective Remnant Lipoprotein Catabolism and Dysbetalipoproteinemia
Excessive accumulation of lipoprotein remnants in plasma is usually caused by a defect in their removal as a result of an autosomal-recessive derangement in the structure of apo E (12). Apo E3, the predominant form of apo E in the normal population, is absent in patients with the classic form of dysbetalipoproteinemia (type III hyperlipoproteinemia). The mutation causing this syndrome results in the occurrence of an abnormal form of apo E. Of the 1% of people who are homozygous for this condition, only 1% to 2% exhibit hyperlipoproteinemia clinically.
Dysbetalipoproteinemia (remnant removal disease or broad-β disease) has served as a prototype for the study of remnant lipoprotein metabolism. It appears that several defects in lipoprotein metabolism are required before excessive accumulation of IDL and of cholesterol-enriched β-VLDL can occur. The diagnosis is suggested by the initial findings of increased levels of β-VLDL (rather than pre-β-VLDL) and similarly elevated plasma concentrations of cholesterol and triglyceride. It is made more likely by the finding of an abnormally cholesterol-rich VLDL fraction (ratio of VLDL cholesterol to VLDL triglyceride greater than 0.42). The presence of tuberous and planar xanthomas (Fig. 82.3) is highly characteristic of the disorder. Definitive diagnosis, however, requires analysis of VLDL to demonstrate the absence of apo E3. A strong association between this lipoprotein disorder and atherosclerosis of the coronary arteries and peripheral vessels has been reported, and vasculopathy appears to diminish during treatment.
The accumulation of remnants in plasma is also found in certain patients with hypothyroidism, end-stage renal disease, or liver disease. The latter disorders are associated with an increase in the activity of the enzyme hepatic lipase, suggesting that a relationship may exist between this enzyme and the catabolism of remnant lipoproteins by the liver.
Increased Cholesterol Synthesis
The accumulation of cholesterol-rich LDL can occur as a result of an increased input of cholesterol into the plasma from dietary or endogenous sources. The latter occurs because of an increase in HMG-CoA reductase activity and enhanced synthesis of cholesterol, or as a consequence of a primary genetic increase in the hepatic synthesis of apo B and cholesterol. The presence of apo B-enriched VLDL suggests a genetic disorder of overproduction of apo B, compared with the overproduction of VLDL triglyceride in familial hypertriglyceridemia.
The overproduction of apo B-containing LDL and VLDL leads to an increased propensity for the development of atherosclerosis (2). Moreover, the coexistence of obesity promotes the overproduction of apo B-enriched VLDL and cholesterol in these individuals. Finally, the augmented intake of dietary cholesterol usually contributes to the hypercholesterolemia that is characteristic of these patients.
Primary (sporadic) forms of hypercholesterolemia, with a genetic defect in the steps controlling the rate of hepatic synthesis of cholesterol from acetate, lead to an overproduction of cholesterol and resultant hypercholesterolemia. Usually, dietary therapy involving an increase in polyunsaturated fat and a reduction in sucrose and simple carbohydrates is helpful in the treatment of these
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disorders; less often, drugs are required. Hypercholesterolemia in obese hyperinsulinemic patients with type 2 diabetes mellitus is decreased by hypocaloric diets and the return of body weight toward normal. In patients who are noncompliant with dietary measures, therapy with cholestyramine, nicotinic acid, or HMG-CoA reductase inhibitors (commonly known as statins) is usually effective in lowering plasma cholesterol levels.
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FIGURE 82.3. Dermatologic manifestations of lipid disorders. A: Tendinous xanthomas. B: Tuberous xanthomas. C: Tuberous xanthomas. D: Eruptive xanthomas. E: Planar xanthomas. F: Eruptive xanthomas. G: Planar xanthomas on eyelids (xanthelasma). H:Planar xanthomas confined to palm creases (xanthoma striata palmaris). |
Defective Removal of Low-Density Lipoproteins
Isolated primary elevations of plasma LDL or combined elevations of LDL and VLDL can be seen in affected members of families with familial hypercholesterolemia (1). Although the cells of some homozygous patients may be totally lacking in identifiable LDL (apo B-E) receptors, in other patients, these receptors are present but functionally defective. Individuals who are heterozygous for familial hypercholesterolemia exhibit more than a 50% reduction in LDL receptor number or a 50% defect in receptor-mediated catabolism; commonly their plasma levels of LDL cholesterol are greater than 400 mg/dL, regardless of their level of cholesterol synthesis. In homozygous patients, plasma levels of LDL cholesterol may reach 1,000 mg/dL (7). Documentation of abnormal receptor binding in cultures of skin fibroblasts is necessary for the precise diagnosis of individuals with familial hypercholesterolemia.
Although primary causes (including familial combined hyperlipoproteinemia) predominate, secondary causes of increased concentrations of LDL cholesterol occur in patients with hypothyroidism, nephrotic syndrome, multiple myeloma, obstructive liver disease, or porphyria, and in patients who have ingested excessive amounts of dietary cholesterol. The primary forms are associated with marked susceptibility to CAD and a high frequency of complications associated with early mortality, such as MI, stroke, and peripheral vascular disease. The hallmark of these disorders is the tendon xanthomas that often affect the Achilles tendon or the extensor tendons of the forearm and hand (Fig. 82.3). Patients with secondary hypercholesterolemia appear not to develop atherosclerosis at as high a rate as people with the primary disorders.
Common Secondary Disorders of LIPID Metabolism
Several disease states are commonly associated with increased plasma levels of VLDL, increased levels of both VLDL and LDL, or decreased levels of HDL cholesterol.
Diabetes Mellitus
Abnormalities in fat transport are often noted in patients with diabetes mellitus and are related to abnormalities in insulin action or insulin availability that lead to increased production or decreased removal of plasma lipoproteins. For example, patients with type 2 diabetes mellitus who are often obese, hyperinsulinemic, and insulin resistant exhibit both an enhanced production and reduced plasma clearance of triglycerides. These patients also have abnormalities in HDL cholesterol. In contrast, the hypertriglyceridemia that occurs in patients with insulin-dependent (type 1) diabetes mellitus is caused by markedly reduced levels of LPL activity, because insulin is required for normal synthesis of the enzyme (7). The diabetic lipemia syndrome is characterized by low or absent levels of LPL in the plasma and tissues of these patients. Although the underlying enzyme deficiency can be reversed after insulin repletion, normalization of the lipoprotein abnormalities can take several months.
In the treated diabetic patient, variability in plasma levels of lipoprotein lipids is primarily related to dietary factors, the amount and distribution of body fat, physical activity, and the degree of glycemic control. If glucose tolerance deteriorates because of inadequate insulin administration or increased insulin resistance, severe hypertriglyceridemia may ensue and alter the concentrations of other classes of lipoproteins. In well-treated type 1 diabetic patients, plasma levels of HDL cholesterol are increased; in contrast, even patients with well-treated type 2 diabetes usually have low HDL cholesterol levels. Regardless of the specific treatment or type of diabetes mellitus, women ordinarily exhibit higher plasma levels of VLDL triglyceride and LDL cholesterol, and lower levels of HDL cholesterol, than do diabetic men (23). This may explain the increased prevalence of atherosclerosis in diabetic women and the disappearance of the usual preponderance of atherosclerotic disease in men compared with premenopausal women (13).
Hypercholesterolemia, with increased plasma concentrations of LDL cholesterol and apo B, also can occur in patients with either type 1 or type 2 diabetes mellitus and is usually induced by diet. Intensive therapy with diet, exercise, and insulin usually normalizes lipoprotein levels, unless a genetic lipoprotein disorder coexists.
Hyperlipidemia in the patient with diabetes mellitus increases the risk for the major complications of atherosclerosis, CAD, cerebrovascular disease, and peripheral vascular disease. The severity of peripheral vascular disease is associated with the lipoprotein abnormalities in diabetic women. Whether treatment of the lipid abnormalities in diabetic patients will decrease their risk for CAD and other arteriosclerotic complications remains to be proven, but it can be recommended based on the known efficacy of treatment in other populations.
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Chronic Uremia and Treatment with Dialysis
Many patients with chronic uremia have increased plasma levels of VLDL triglycerides and decreased levels of HDL cholesterol (24). These abnormalities persist during maintenance hemodialysis or peritoneal dialysis. The accelerated atherosclerosis observed in white men undergoing long-term hemodialysis, which is not seen in their African American counterparts, appears to be related to the abnormal composition of HDL2 cholesterol in the plasma of white men. A sedentary lifestyle, obesity, high-fat diets, or treatment with corticosteroids, β-blockers, or androgens worsens the lipoprotein profiles in these patients, and effective reversal of these secondary causes improves the lipid profile (24).
Hypothyroidism
Adequate levels of thyroid hormone appear to be necessary for the homeostatic maintenance of lipoprotein physiology. Decreases in LDL receptor function, abnormalities in LPL and hepatic lipase-mediated metabolism of triglycerides and HDL, and reduced lecithin-cholesterol acyl transferase (LCAT) activity have been demonstrated in some patients with hypothyroidism. Consequently, increased plasma levels of VLDL, IDL, and LDL, and reduced levels of HDL cholesterol have all been reported in patients with this disease. Treatment with thyroid hormone improves LDL receptor function, increases the activity and function of LPL and LCAT, and normalizes lipoprotein profiles.
Other Common Secondary Causes of Hyperlipidemia
Patients with the nephrotic syndrome commonly lose apo C-II in the urine, thus decreasing LPL-mediated triglyceride clearance. The hypoalbuminemia that accompanies the nephrotic syndrome increases hepatic VLDL synthesis, thereby elevating plasma levels of VLDL triglyceride and LDL cholesterol. Treatment of the disease that has caused the nephrotic syndrome usually corrects the lipoprotein abnormalities, but drug therapy and a low-fat diet may be required. Reports suggest that statin therapy can ameliorate the nephrosis independently of its benefit in lowering LDL cholesterol levels (46).
Hypercortisolemia of endogenous or exogenous origin increases hepatic synthesis of VLDL, LDL, or both. Kidney transplant recipients treated with high dosages of corticosteroids often exhibit increased plasma levels of both VLDL and LDL as well as reduced levels of HDL cholesterol. The atherosclerosis that develops in such patients is probably related to these lipid abnormalities, which should be treated accordingly.
Obesity, alcohol ingestion, and androgen administration tend to increase hepatic lipoprotein synthesis but have different effects on levels of HDL cholesterol and LDL cholesterol. In obese people, plasma levels of VLDL triglyceride and LDL cholesterol are increased, whereas those of HDL are decreased. Mild alcohol ingestion (up to 2 oz/day) increases levels of VLDL triglyceride and HDL cholesterol but lowers levels of LDL cholesterol. Exogenous androgens raise levels of LDL cholesterol and lower HDL cholesterol levels.
Diseases affecting the liver, such as hepatitis or cholelithiasis, alter lipoprotein metabolism. Diseases causing an obstruction in the hepatobiliary system tend to elevate plasma LDL, IDL, and remnant lipoproteins and cause abnormal lipoproteins (Lp X) to accumulate in plasma.
Inflammatory processes usually lower levels of HDL and LDL cholesterol and raise VLDL, depending on the nutritional state of the patient.
Some drugs used to treat hypertension, such as thiazide diuretics and β-adrenergic blockers, may cause a modest increase in serum lipids. The benefit of these classes of antihypertensives in reducing the risk of coronary disease is generally greater than their adverse impact on lipids, and in most patients with lipid disorders their use is not contraindicated.
Hyperlipidemia occurs in patients with systemic lupus erythematosus or dysgammaglobulinemia. This may be related to interactions among amyloid protein, certain immunoglobulin fractions, and various steps in the lipoprotein cascade.
Table 82.6 lists several exogenous and endogenous factors that affect plasma levels of HDL cholesterol.
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TABLE 82.6 Factors That Affect High-Density Lipoprotein Cholesterol Levels |
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Clinical Manifestations of Lipoprotein Disorders
Adverse clinical sequelae of the lipoprotein disorders most commonly manifest as disorders of the vascular, dermatologic, and gastrointestinal systems. Table 82.5 outlines the clinical manifestations associated with each of the major disorders of lipoprotein metabolism.
Vascular
As discussed previously, increased levels of total cholesterol, LDL cholesterol, apo B-enriched lipoproteins, oxidized LDL, and Lp(a) and decreased levels of HDL cholesterol, HDL2, and apo A-I contribute to the development of atherosclerotic disease. The earlier the onset of symptomatic disease of the coronary, cerebral, or peripheral vasculature, the more likely it is that a lipoprotein abnormality or another major risk factor (cigarette smoking, hypertension, diabetes) is present (13). In the most severe form of hypercholesterolemia, homozygous familial hypercholesterolemia, plasma levels of total cholesterol vary from 600 to 1,200 mg/dL, CAD generally develops in childhood, and very few patients survive past 30 years of age. In heterozygotes, plasma levels of total cholesterol vary from about 270 to 550 mg/dL and the time of onset of CAD varies between early adulthood and late middle age, with approximately 50% of men becoming symptomatic by age 50 years and 50% of women by age 60 years. Patients with monogenic familial combined hyperlipoproteinemia exhibit increased levels of VLDL, LDL, or both, as well as abnormalities in HDL, apo A-I, and apo B; most patients manifest symptoms of CAD by age 60 years. Individuals with familial dysbetalipoproteinemia develop premature peripheral vascular disease and CAD at about equal rates, with the mean age at onset in both men and women being about 40 years. Such patients seem to be especially responsive to therapy. Individuals withmonogenic familial hypertriglyceridemia or with fasting chylomicronemia do not appear to be at increased risk for CAD unless other risk factors for atherosclerosis are also present.
Dermatologic
Xanthomas may occur in any of the hyperlipidemias; however, they are present in a minority of hyperlipidemic patients. They occur with increasing frequency as the plasma lipid levels rise. They are present predominantly in the primary forms of hyperlipoproteinemia: familial hypercholesterolemia, familial dysbetalipoproteinemia, and familial LPL deficiency. Xanthomas are cutaneous or subcutaneous papules, plaques, or nodules characterized histopathologically by localized collections of lipid-laden histiocytes (foam cells). The presence or absence of xanthomas should always be noted. If present, their appearance can provide useful information about the nature of the underlying lipid disorder (Table 82.5). Unless tendons (especially the Achilles tendon) are palpated, the tendon thickening that is characteristic of tendon xanthomas may be missed. Xanthomas are divided morphologically into several types:
Hypercholesterolemia is associated with tendinous, planar, and tuberous xanthomas. Severe hypertriglyceridemia and chylomicronemia are associated with eruptive and occasionally tuberoeruptive or tuberous xanthomas. Palmar xanthomas are characteristic of familial dysbetalipoproteinemia and florid obstructive liver disease. Planar xanthomas on the body or palms in the presence of a type II lipid profile suggest homozygous monogenic familial hypercholesterolemia. The presence of tendinous or tuberous xanthomas or premature xanthelasma with a type II lipid profile suggests either heterozygous or homozygous
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monogenic familial hypercholesterolemia, as opposed to the polygenic or nongenetic forms. Tendon xanthomas are found in one-third to one-half of heterozygotes, whereas tuberous xanthomas are seen most often in patients with familial dysbetalipoproteinemia.
Occasionally, xanthomas appear in the absence of a hyperlipidemic state. For example, xanthelasma occur commonly in normolipidemic older individuals and in nonwhites, and planar xanthomas can occur in patients with lymphoma, leukemia, or myeloma. Studies in normolipidemic individuals with xanthelasma have revealed abnormalities in apo B and E suggestive of familial dysbetalipoproteinemia and/or increased levels of LDL apo B (47), suggesting that these individuals may be at an increased risk of developing atherosclerosis.
Differences exist in the responses to treatment of the various hyperlipidemia-associated xanthomas. Tendon xanthomas are the most resistant to treatment and, in practice, seldom disappear. In contrast, eruptive and planar xanthomas can disappear within a few weeks after plasma lipid levels return to normal.
Gastrointestinal
As many as 35% to 55% of patients with fasting chylomicronemia experience episodes of recurrent abdominal pain. Symptoms are ordinarily associated with marked elevations of plasma triglyceride concentrations (>1,000 to 2,000 mg/dL). Abdominal pain may be so severe that it prompts unnecessary surgery, particularly if the lipid disorder is not suspected. The pain is often associated with pancreatitis, although the responsible pathogenetic mechanism is not well understood. Routine serum amylase determinations are often subject to technical artifacts when hyperlipidemia is present because of the presence of an amylase-inhibiting factor that may or may not be triglyceride. In such cases, a more reliable estimate of the serum amylase value can be obtained by determining amylase levels on serial dilutions, until the value obtained no longer changes with further dilution. Another cause of abdominal pain may be rapid hepatic or splenic enlargement with capsular distension from triglyceride deposition in reticuloendothelial cells. Often the cause is unclear. Gastrointestinal symptoms other than abdominal pain, such as nausea, vomiting, borborygmi, and diarrhea, also occur.
Other Clinical Associations
Other clinical concomitants of hyperlipidemia include premature arcus corneae (grayish-white corneal ring caused by lipid droplets) in hypercholesterolemia (elevated LDL); aortic stenosis in homozygous monogenic familial hypercholesterolemia; Achilles tendinitis in heterozygous monogenic familial hypercholesterolemia; obesity, glucose intolerance, hyperinsulinemia, hyperuricemia, and perhaps cholelithiasis in association with hypertriglyceridemia and elevated VLDL; recurrent polyarthralgias, arthritis, tenosynovitis, and siccalike syndromes in hypertriglyceridemia (elevated VLDL) or hypercholesterolemia (elevated LDL); and lipemia retinalis (cream-colored retinal vessels) in chylomicronemia (evident when plasma triglycerides rise above 3,000 mg/dL; obvious when they exceed 10,000 mg/dL).
Diagnosis
Indications for Screening and Evaluation
Over the years there has been disagreement about the optimal, cost-effective approach to the identification of hyperlipidemic patients at high risk for CAD (48, 49, 50). Some authorities believe that routine screening of healthy young adults who have no CAD risk factors, family history, or clinical evidence of CAD is unwarranted because the benefits of case finding may be outweighed by the long-term risks of treatment. There is, however, a general consensus that screening is important, although there is some disagreement still about which populations should be targeted. The most widely used guidelines for case findings are those issued by the ATP of the NCEP (44). The NCEP emphasizes LDL as the primary target of cholesterol-lowering therapy, the role of the clinical approach to primary prevention of CAD, and dietary therapy as the initial treatment, with hypolipidemic drug therapy reserved for patients at high risk for CAD. These guidelines, however, emphasize CAD risk status as a major determinant for the type and intensity of treatment, pay more attention to HDL as a risk factor, and underscore the importance of including physical activity and weight loss as components of dietary therapy. With regard to assigning risk factor status, the NCEP report places patients with existing CAD and those with diabetes mellitus or other atherosclerotic disease at highest risk, maintaining lower target levels of LDL cholesterol in these patients. The report uses Framingham projections to predict CAD risk over a 10-year span and targets patients with the metabolic syndrome (see Treatment, General Approach) for aggressive intervention. The panel also continues to recommend that HDL cholesterol greater than 60 mg/dL be considered a negative risk factor and that HDL cholesterol levels be used in the decision making for drug therapy.
The panel continues to recommend that levels of total cholesterol should be measured in all adults 20 years of age or older at least once every 5 years, assuming that blood cholesterol levels are lower than 200 mg/dL, and that HDL should be measured at the same time if accurate results are available (see Laboratory Evaluation). An HDL level of less than 40 mg/dL is considered to be a low value. Measurements of total cholesterol and HDL for screening
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purposes can be obtained from nonfasting people. However, final classification of abnormal lipid profiles requires lipid determinations in subjects who have fasted overnight. The NCEP classifies individuals by serum levels of total, LDL, and HDL cholesterol (Table 82.7). Serum levels of total cholesterol less than 200 mg/dL are considered desirable blood cholesterol; levels between 200 and 239 mg/dL, borderline-high blood cholesterol; and levels of 240 mg/dL or higher, high blood cholesterol. Data from numerous epidemiologic studies reveal that the relationships between serum levels of total (or LDL) cholesterol and CAD risk are continuous and that CAD risk at a cholesterol value of 240 mg/dL is almost double that at 200 mg/dL and rises rapidly at levels above 240 mg/dL. Total cholesterol levels of 240 mg/dL or more correspond to the uppermost 20% of cholesterol values in the entire population 20 years of age and older. Patients with levels of total serum cholesterol between 200 and 239 mg/dL and either an HDL cholesterol concentration lower than 40 mg/dL, known CAD or diabetes mellitus, or two or more known risk factors for CAD (Table 82.2) are considered to have high blood cholesterol values.
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TABLE 82.7 LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC)a and Drug Therapy in Different Risk Categories |
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Although there is a consensus on targets for lipid values and intervention in those with the highest CAD risk (e.g., diabetes mellitus) or known CAD, there exists a difference of opinion regarding when to begin screening for lipid disorders in the adult population. The U.S. Preventive Services Task Force (USPSTF) recommends that screening begin at age 35 years for men and at age 45 years for women, and that individuals age 20 years and older be screened only if they have associated risk factors for CAD (50,51). The USPSTF limits screening to measurement of total cholesterol and HDL, and finds no evidence supporting the routine measurement of triglycerides and, by extension, LDL for screening purposes. An older American College of Physicians (ACP) report did not support routine screening in young adult men (age 20 to 35 years), premenopausal women (age 20 to 45 years), or persons older than 65 years of age (52). It should be noted that the NCEP guidelines have been endorsed by more than 40 medical and health care organizations, including the American College of Cardiology, American Academy of Family Physicians, American Medical Association, American College of Preventive Medicine, and American Heart Association (AHA) (53,54).
The practitioner must decide, in consultation with his or her patients, which recommendations to follow. It is clear, however, that screening is indicated and that most patients with hyperlipidemia should be treated.
Evaluation of the Patient with Hypercholesterolemia
Once a patient is found to have a high blood cholesterol level or physical stigmata of hypercholesterolemia (e.g., dermatologic signs), decisions regarding possible diet, drug, or other therapy are made after a more detailed lipoprotein analysis, including measurements of triglyceride levels on a blood specimen obtained after an overnight fast, calculation of the LDL cholesterol level, and determination of other CAD risk factors. The updated NCEP guidelines adjust the classification for LDL cholesterol levels as follows: LDL cholesterol levels greater or equal to 190 mg/dL are considered very high; 160 to 189 mg/dL, high; 130 to 159 mg/dL, borderline high; 100 to 129 mg/dL, near or above optimal; and less than 100 mg/dL, optimal. In
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patients with known CAD, diabetes mellitus, or two or more major CAD risk factors (Table 82.2), and LDL cholesterol levels between 130 and 159 mg/dL are considered high risk. The NCEP considers an HDL level lower than 40 mg/dL to be an independent risk factor for CAD. Therefore, decisions regarding both the implementation and the goals of therapy are based not on ratios of LDL (or total) cholesterol to HDL cholesterol but on absolute levels of LDL and HDL cholesterol. Such decisions are also influenced by the presence or absence of other CAD risk factors.
Triglycerides
The current NCEP guidelines classify fasting triglyceride levels lower than 150 mg/dL as normal levels, those between 150 and 199 mg/dL asborderline high, those between 200 and 499 mg/dL as high, and those greater than or equal to 500 mg/dL as very high. There is a complex link between hypertriglyceridemia and CAD, which is explained in part by the association between high triglycerides and low HDL and/or unusually atherogenic forms of LDL. Moreover, elevated triglycerides often reflect increased triglyceride-rich remnant lipoproteins that have atherogenic potential. There is disagreement about the usefulness of measurement of triglyceride levels in the screening of healthy people.
Measurement of plasma levels of total cholesterol, HDL cholesterol, and fasting triglyceride concentrations and calculation of the level of LDL cholesterol are desirable when abnormalities are detected on screening or conditions coexist that could cause secondary abnormalities in lipoprotein metabolism (Table 82.4).
Laboratory Evaluation
Plasma or serum levels of total cholesterol are not appreciably influenced by acute dietary intake and therefore can be obtained from patients in the nonfasting state and at any time of the day. There is considerable biologic variability (6%) and laboratory variability (3%) in repeated measurements of total cholesterol in a given individual (51,55). Therefore, to be within 10% of the true value, two measurements are necessary. It is also important to obtain blood for cholesterol measurements from a nonstressed patient and to send the blood for analysis to a reliable laboratory.
Levels of total (and LDL) cholesterol fall during the first few days after an MI (55), so cholesterol determinations either should be made within 24 hours after a severe acute MI (when they are still valid) or should be postponed until 3 to 4 weeks after recovery. Fasting triglyceride (and VLDL) levels tend to rise slowly after an MI, peaking at 3 to 4 weeks and returning to baseline by 8 to 12 weeks. Therefore, triglyceride levels should be obtained either within 24 hours after the acute event or after 8 to 12 weeks.
The determination of HDL cholesterol is the measurement most subject to laboratory error. Again, there is considerable biologic variability (7.5%) and laboratory variability (6%) in repeated measurements of HDL in a given individual (51,55). To be within 10% to 15% of the true value, two to three measurements of HDL are necessary. Such measures to enhance validity are important because there is a relatively narrow range of HDL cholesterol values within which even small differences are prognostically important. For example, a reduction in HDL cholesterol of 5 mg/dL—from 40 to 35 mg/dL—increases the risk for CAD by approximately 25%. HDL levels are unreliable when triglyceride concentrations exceed 400 mg/dL. Under such circumstances, the plasma or serum should be ultrafiltered. If this is required, the clinician should consult the laboratory.
In the nonfasting state, HDL levels are 5% to 10% lower than in the fasting state and therefore may slightly overestimate the risk of CAD. However, for screening purposes, nonfasting levels are acceptable.
Because triglyceride levels are 25% to 30% higher in the nonfasting state, it is important that triglyceride measurements be made only in fasting patients.
Calculation of LDL Level
Measurements of HDL and triglyceride levels allow one to calculate the LDL cholesterol level (provided the triglyceride concentration is less than 400 mg/dL) by the following formula: LDL-C = TC - (TG/5 + HDL-C), where LDL-C is the LDL cholesterol level, TC is the plasma level of total cholesterol, TG is the fasting plasma triglyceride level, and HDL-C is the level of HDL cholesterol.
Observation of a fasting plasma sample that has been left undisturbed overnight in a refrigerator at 39.2°F (4°C) is indicated in the presence of a significantly elevated fasting plasma triglyceride level. Increased levels of total (or LDL) cholesterol do not affect the appearance of plasma, whereas hypertriglyceridemia associated with increased levels of VLDL imparts uniform turbidity to plasma, and hypertriglyceridemia associated with chylomicronemia is characterized by a creamy supernatant fraction that floats on the top of plasma.
A marked abnormality in plasma lipid concentrations, especially marked hypertriglyceridemia (greater than 2,000 mg/dL), can affect the validity of other laboratory tests. Marked hypertriglyceridemia has an inhibitory effect on the plasma amylase assay, interferes with the measurement of liver enzymes (aspartate aminotransferase, alanine aminotransferase) and calcium by autoanalyzer, and causes artifactual reductions in the serum concentration of molecules restricted to the aqueous phase (e.g., sodium). Ultracentrifugation of plasma, with the removal of chylomicrons, permits these measurements to be performed accurately; but sometimes serial dilutions of the
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plasma are necessary, particularly for the measurement of amylase.
Clinical Evaluation
Clinical data contribute substantially to the diagnosis of specific lipoprotein disorders and to decisions about treatment when abnormalities are found. History, physical examination, and indicated laboratory evaluation are required to rule out secondary causes of hyperlipidemia (Table 82.4). A positive family history, the presence of premature atherosclerotic disease, and the presence of specific dermatologic manifestations may permit the diagnosis of a primary form of hyperlipoproteinemia (Table 82.5). Assessment of the patient's family history and cardiovascular status is also important for risk stratification.
If the initial laboratory and clinical evaluations do not clarify an apparent disorder of lipid metabolism, or if the disorder is severe, referral to a lipid disorders clinic or to a specialist in endocrinology and metabolism is indicated. Such specialists can perform (or readily obtain) and interpret more sophisticated tests, such as ultracentrifugal quantification of lipoprotein levels, apoprotein measurement, receptor analysis, and determination of LPL activity. They may also assist in the evaluation of family members, so that the presence of a genetic disorder can be accurately diagnosed. Referral should also be considered for patients who are refractory to lifestyle and pharmacologic management strategies. The Lipid Metabolism Branch of the National Heart, Lung and Blood Institute (National Institutes of Health, Bethesda, MD 20205) can provide the names of research centers in each geographic area where sophisticated evaluation of lipoprotein abnormalities, consultation services, and experimental forms of therapy are offered.
Treatment
General Approach
The first step in the management of a lipoprotein disorder is accurate diagnosis. Causes of secondary lipoprotein disorders should be identified (Table 82.4) and treated. If the cause of a secondary disorder is not reversible, or if a primary disorder exists, treatment may be required that is specifically directed at the abnormal lipoprotein pattern.
Such treatment should be part of the comprehensive management of other coexisting CAD risk factors (e.g., cigarette smoking, hypertension, diabetes mellitus, obesity, inactivity). It probably will require behavioral change on the part of the patient and lifelong management, emphasizing the need for a positive patient–clinician relationship, appropriate patient education, and skill on the part of the clinician in promoting patient compliance (see Chapters 3 and 4). Long-term followup and monitoring of such patients are necessary to enhance compliance, to assess the effectiveness of therapy, and to detect drug toxicity or the effect of concomitant therapy (e.g., diuretics, other antihypertensive agents) on plasma lipids.
Patients without CAD who are classified as having a desirable total cholesterol level (less than 200 mg/dL) and an HDL cholesterol level higher than 40 mg/dL are usually instructed on the principles of a prudent diet and healthy lifestyle, educated about CAD risk factors (Table 82.2), and advised to have their total cholesterol level rechecked at least once every 5 years.
Patients with CAD, diabetes, secondary causes of lipid disorders, a total cholesterol level higher than 200 mg/dL, an HDL cholesterol level lower than 40 mg/dL, or risk factors (Table 82.2) should have a fasting lipid panel performed (fasting total cholesterol, triglycerides, and HDL cholesterol, and calculation of LDL; see previous discussion). Treatment is then based primarily on LDL cholesterol levels according to guidelines provided by the NCEP (Table 82.7). The guidelines also emphasize the need to assess CAD risk for patients with more than two risk factors and an LDL cholesterol level between 130 and 159 mg/dL (see National Heart, Lung and Blood Institute website inhttp://www.hopkinsbayview.org/PAMreferences for instructions on how to calculate risk according to the Framingham scoring system). Drug therapy is suggested for patients who have a 10-year risk of developing ischemic heart disease of more than 10% (Table 82.7).
For patients with a borderline high total cholesterol of 200 to 239 mg/dL, HDL cholesterol greater than 40 mg/dL, and fewer than two risk factors, it is also reasonable to provide education about diet, exercise, and other lifestyle modifications and to recheck the total and HDL cholesterol in 1 to 2 years, in the absence of a fasting lipid profile.
Patients with isolated reductions in HDL cholesterol (less than 40 mg/dL) should be instructed in the value of weight loss, aerobic exercise, and discontinuation of cigarette smoking (see Nonpharmacologic Therapy). Although certain drugs used for treatment of increased levels of LDL cholesterol or of triglycerides may also raise HDL levels, at present no data support their use in the healthy patient whose only lipid abnormality is a reduction in the level of HDL.
Management of hypertriglyceridemia must be individualized. When familial combined hyperlipidemia or familial dysbetalipoproteinemia is diagnosed, specific treatment is required. Patients with fasting triglyceride levels greater than 500 mg/dL sometimes accumulate chylomicrons and develop pancreatitis. The risk becomes substantial when triglyceride levels exceed 1,000 mg/dL. The plasma triglyceride level should therefore be lowered in patients whose triglyceride levels exceed 500 mg/dL. For patients with fasting triglyceride levels in the 200- to 499-mg/dL range, control of LDL cholesterol remains the primary goal but
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control of triglyceride level becomes a secondary goal. Diet, weight control, and regular exercise should be encouraged. Drug therapy should also be considered if treatment goals are not reached through lifestyle change, especially when CAD, diabetes, or coexistent risk factors (see 82.2) are present. The presence of the metabolic syndrome, which is associated with a very high risk of CAD, should probably also sway the clinician toward the use of drug therapy if treatment goals cannot be achieved by lifestyle change. The metabolic syndrome (also called metabolic syndrome X or insulin resistance syndrome) is characterized by abdominal obesity (see Chapter 83), low HDL cholesterol (less than 40 mg/dL in men, 50 mg/dL in women), hypertension (130/85 mm Hg or higher), fasting plasma glucose concentration 110 mg/dL or higher, and fasting triglycerides 150 mg/dL or higher. Treatment goals are defined by a non-HDL cholesterol concentration (i.e., total cholesterol minus HDL cholesterol) that is 30 mg/dL greater than the treatment goals for LDL cholesterol; that is, less than 190 mg/dL for one or no risk factors, 160 mg/dL for two or more risk factors and 10-year risk greater than 20%, and less than 130 mg/dL for CAD or CAD risk equivalent.
Nonpharmacologic Therapy
Diet
It is now well established that plasma lipid levels can be altered by dietary manipulations (Tables 82.8 and 82.9). Under strictly controlled conditions (e.g., in a metabolic research unit), increased plasma levels of total (or LDL) cholesterol may be reduced by as much as 30% or more, and levels of triglyceride or VLDL (in the presence of marked elevations) by as much as 80% or more. Fasting chylomicronemia can also be eliminated. Under ambulatory conditions, in which diets tend to be less restrictive and noncompliance more common, reductions in lipid levels are less dramatic. For example, among prospective studies of cholesterol-lowering diets, the decrease in plasma cholesterol averaged 15% (range: 8.5% to 22%).
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TABLE 82.8 Nutrient Composition of the Therapeutic Lifestyle Changes (TLC) Diet |
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Single-Diet Approach
The ATP of the NCEP (see http://www.hopkinsbayview.org/PAMreferences) continues to highlight dietary therapy as the first line of treatment of elevated blood cholesterol levels (Table 82.8). In primary prevention trials to date, dietary therapy has not been associated with decreased all-cause mortality. There is insufficient evidence to support treatment of healthy normolipidemic individuals with restrictive diets. Studies have shown little change in the lipid profiles of healthy subjects with intake of either a high- or a low-cholesterol diet (56). Dietary therapy has more impact in those who are dyslipidemic and have risk factors for CAD. It is now appreciated that one diet can be used to treat all of the common forms of hyperlipoproteinemia (Table 82.8). The classification of diets as Step 1 and Step 2 has been eliminated and replaced with the Therapeutic Lifestyle Changes (TLC) diet. Using the principle of graduated regimen implementation (seeChapter 4), the diet can be introduced in a step-wise fashion. If severe chylomicronemia is present, dietary fat must be more severely restricted (see Cholesterol Reduction).
The AHA and other organizations publish useful booklets on this diet for the patient, physician, and nutritionist (seehttp://www.hopkinsbayview.org/PAMreferences). Most patients with hyperlipoproteinemia benefit from referral to a suitably trained dietitian. The TLC diet actually incorporates several nutritional strategies, each of which tends to have a selective effect on plasma lipoprotein levels. It is helpful to consider each strategy separately.
Cholesterol Reduction
The TLC diet to lower serum cholesterol levels (Tables 82.8 and 82.9) is characterized by a restriction of dietary cholesterol to less than 200 mg per day and reductions in daily total and saturated fat intake to less than 35% and 7% of caloric intake, respectively. The total fat allowance can range from 25% to 35% as long as the intake of saturated fats and trans fatty acids is low. The other feature of the TLC diet is encouragement of the consumption of plant stanols/sterols (2 g/day) and soluble fiber (10 to 25 g/day). Caloric allowance is adjusted to ensure loss of excess weight or maintenance of ideal body weight (see Chapter 83). Restrictions in dietary cholesterol and
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saturated fats independently contribute to the reduction in plasma cholesterol levels. A modest increase in dietary polyunsaturated fat results in further, although less marked, reduction in plasma cholesterol level.
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TABLE 82.9 Dietary Guidelines to Lower Blood Cholesterol |
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The two major categories of polyunsaturated fatty acids are the omega-6 and omega-3 types. Linoleic acid is the principal omega-6 fatty acid; when consumed in large amounts, it can decrease levels of total cholesterol. Lecithin, a phospholipid derived from soybeans, is a widely publicized, popular remedy for hypercholesterolemia and is commonly sold in health food stores. Because it is not absorbed as such from the gastrointestinal tract, any hypocholesterolemic effect probably derives from its high content of linoleic acid. Vegetable oils rich in linoleic acid, such as safflower oil, soybean oil, sunflower oil, and corn oil, are the preferred dietary sources of the omega-6 fatty acids.
The major sources of the omega-3 fatty acids are the fish oils. Taken as dietary supplements, high dosages of fish oil lower elevated triglyceride concentrations but do not reduce levels of total or LDL cholesterol. Nevertheless, epidemiologic studies have shown an inverse relationship between the consumption of fish and the risk of adverse cardiac and other cerebrovascular events, in persons with and without ischemic heart disease (57,58). Also, several randomized controlled trials have demonstrated a modest reduction in cardiac events (1% to 3% absolute risk reduction) in patients with documented CAD who were prescribed omega-3 fatty acids (32,59). Side effects are predominantly gastrointestinal (nausea, bloating, flatulence, eructation, diarrhea, fishy aftertaste). Concerns that fish oil supplements may worsen hyperinsulinemia and increase insulin resistance were diminished by a meta-analysis that showed no adverse effects of these supplements on glycosylated hemoglobin levels (60).
The typical North American diet has an unfavorable polyunsaturated-to-saturated fat (P/S) ratio of 0.4. On the other hand, there is no historical precedent that attests to the safety of diets that are very rich in polyunsaturated fats (e.g., P/S ratio of 1.5 or more). It does appear that the latter diets can promote the formation of lithogenic bile and actually increase the incidence of symptomatic biliary tract disease. Although there was a concern that such diets are associated with an increased risk of malignant disease, this finding was not supported when data from several trials were pooled (61). Another disadvantage to substantially increasing dietary intake of polyunsaturated fat is that the resultant high caloric intake might promote obesity. Finally, it should be noted that diets with very high P/S ratios (e.g., 3 or more) may decrease HDL levels and lead to an unfavorable increase in the LDL/HDL ratio. For all of these reasons, a P/S ratio of about 1.0 is recommended in most hypocholesterolemic diets.
Monounsaturated fatty acids, principally oleic acid, found in canola oil, olive oil, and certain forms of safflower and sunflower seed oil, lower levels of LDL cholesterol as effectively as do polyunsaturated fatty acids such as linoleic acid. Therefore, it is now recommended that the TLC diet contain approximately 20% monounsaturated fatty acids, derived mainly from these vegetable oils.
The influence of dietary fiber on plasma cholesterol levels is complex, dependent on the type of fiber, and somewhat controversial. Guar, pectin, and unprocessed high-fiber foods, such as legumes and oats, lower plasma total cholesterol levels, whereas other fibers, such as wheat bran, do not. Effects on levels of HDL cholesterol and triglyceride are minimal. In the amounts consumed in a palatable diet, fiber plays a minor role compared with control of dietary fats and cholesterol.
Although garlic supplements are effective in reducing total cholesterol, LDL cholesterol, and triglyceride concentrations modestly (approximately 5%) (62), reductions may not persist. The impact on clinical outcomes is unknown. Known side effects are malodorous breath and body odor; there may also be gastrointestinal side effects such as abdominal pain, fullness, anorexia, and flatulence.
Margarines enriched with plant sterols (sitostanol and campestanol in Benecol, sitosterol and campesterol in Take Control) have been shown in a few studies to lower total and LDL cholesterol by approximately 10%. They are very poorly absorbed and probably act through the inhibition of cholesterol absorption. Their impact on cardiovascular outcomes is unknown. Although short-term studies have not demonstrated adverse clinical effects, the absorption of fat-soluble vitamins may be affected. A long-term safety profile has not been established. Because of this, the AHA does not recommend their consumption by the general population, but recommends reserving their use for secondary prevention and for patients with moderate to severe hypercholesterolemia (63). Margarines enriched with plant sterols are several times more expensive than ordinary margarines.
Soy proteins, which are found in tofu and soy milk, lower total cholesterol, LDL cholesterol, and triglyceride by approximately 10% (64) and may contribute to the lower risk of heart disease in Asian, as compared to Western, societies. An advisory from the Nutrition Committee of the AHA concluded that 25 to 50 g per day of soy protein is both safe and effective in modestly reducing LDL cholesterol by 4% to 8% (65). The impact of such a diet on health has not been established.
Monitoring and Adjusting Diet
Results of the TLC diet should be monitored after 4 to 6 weeks and again at 3 months, when the effects should be maximal. In general, formal consultation with a dietitian is not required during implementation of the TLC diet, and the physician and other health care providers should serve as the primary sources of education, compliance monitoring, and encouragement for the patient. It is important to
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emphasize to all patients that dietary treatment of hypercholesterolemia implies permanent, rather than temporary, changes in eating behavior. If the goals of diet therapy are not met after 3 months, it is recommended that the patient continue on the TLC diet and that consideration be given to initiating drug treatment. Patients should also be referred to a dietitian for formal nutritional counseling. For patients with known CAD and for those with diabetes mellitus, it is recommended that pharmacologic and dietary therapy be initiated simultaneously.
Dietary and Drug Therapy
Dietary therapy alone is effective in lowering cholesterol levels in many of the almost 85% of hypercholesterolemic patients with polygenic or nonhereditary forms of hypercholesterolemia. However, numerous studies indicate that dietary therapy alone is less effective in lowering total or LDL cholesterol levels than is the combination of dietary therapy plus drug treatment. For example, in a multicenter trial comparing the separate and combined effects of intensive dietary therapy and low-dose lovastatin in outpatients with moderate hypercholesterolemia, a low-fat diet alone reduced LDL cholesterol by 5%, lovastatin alone lowered LDL by 27%, and lovastatin plus dietary therapy reduced LDL by 32% (66). In elderly patients with hypercholesterolemia, the benefits of diet therapy should be weighed against the possibility of inadequate nutrition.
Triglyceride Reduction
Diets designed to reduce plasma triglyceride and VLDL levels emphasize the loss of excess weight by total caloric restriction. Plasma triglyceride levels usually fall, often to normal, after a few days of caloric restriction. The reduction is maintained as long as weight loss continues at a rate of 1 to 2 lb (0.5 to 1 kg) per week. If normal weight is attained and maintained, further therapy may not be necessary. If hypertriglyceridemia persists or occurs in individuals of normal weight, a cholesterol-lowering diet, as outlined earlier, may be effective. Alcohol intake should be restricted, because it can cause a striking rise in triglyceride levels in some patients with hypertriglyceridemia. Although extreme increases in the carbohydrate content of a diet can cause transient and, rarely, sustained hypertriglyceridemia, there is no firm evidence to suggest that total carbohydrate restriction is helpful in the treatment of hypertriglyceridemia. There are conflicting data regarding the effect on plasma triglyceride level of excessive intake of sucrose (common sugar) and simple sugars. In most studies, especially in patients who are already hypertriglyceridemic, they do raise plasma levels of triglycerides and lower those of HDL cholesterol, but the effect is small. The rationale for dietary restriction of sugar is based more on the need to avoid excessive caloric intake (and to prevent caries) than on any direct effect on plasma lipids. Like alcohol, sucrose provides empty calories in that it contains none of the valuable nutrients (e.g., protein, fiber, minerals, vitamins). Therefore the substitution of complex carbohydrates (e.g., starches) for simple carbohydrates in the diet is recommended. A triglyceride-lowering diet should favorably affect plasma HDL cholesterol levels in most individuals, because obesity and triglyceride concentration are inversely correlated with the level of HDL cholesterol and plasma HDL usually rises during weight reduction. Plasma levels of total (and LDL) cholesterol often fall with loss of excess weight; if they rise, familial combined hyperlipoproteinemia may be present.
Chylomicron Reduction
Treatment of fasting chylomicronemia (type I) involves the restriction of dietary fat intake to 5% to 20% of total calories (0.5 g of fat per kilogram of body weight is a reasonable starting point). The fat deficit should be corrected predominantly by substitution of complex carbohydrates. Because medium-chain triglycerides (available as MCT oil) are transported directly from the intestine to the liver in the portal circulation without incorporation into chylomicrons, they may be added to the diet to provide calories. The recommended dose of MCT oil (available at most pharmacies) is 1 tablespoonful three to four times daily, mixed with foods. Five grams of vegetable fat rich in polyunsaturates should be included to prevent essential fatty acid deficiency.
Dietary fat is severely restricted until fasting chylomicronemia is eliminated and clinical symptoms are prevented or reduced in frequency; dietary fat is then chronically restricted to whatever degree is necessary to prevent fasting chylomicronemia. The efficacy of fat restriction in preventing recurrent abdominal pain is supported by clinical observations in individual patients.
If fasting chylomicronemia is accompanied by increased VLDL triglyceride levels, therapy is initiated with restriction of dietary fat intake and correction of coexistent secondary causes for the disorder. Once chylomicronemia has been eliminated, a triglyceride-lowering diet with a modest reduction in total fat intake (to approximately 30% of total calories) is all that is usually required to prevent recurrence. Total abstinence from alcohol is usually necessary.
Diets to Raise the HDL Level
Some studies have reported that low-fat, low-cholesterol diets have resulted in decreased levels of HDL cholesterol (67), whereas others have found increased HDL values (68). The dietary approach to the patient with an HDL cholesterol level lower than 40 mg/dL should incorporate loss of excess weight with an aerobic exercise program. Although moderate alcohol consumption (2 to 3 oz/ day) is positively correlated with HDL cholesterol concentration and negatively correlated with CAD, it is discouraged for three reasons: Excessive use (more than two or
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three drinks per day) increases the overall risk of morbidity and mortality; its use may interfere with attempts to control obesity and hypertriglyceridemia; and evidence is not conclusive that modest intake results in an overall health advantage.
Exercise
During the past decade, evidence has accumulated that regular isotonic exercise enhances fatty acid oxidation and glycogen storage, thus increasing HDL formation, triglyceride clearance, and insulin sensitivity. These metabolic changes favorably affect plasma lipid levels. Most of the exercise programs that have been evaluated, including jogging, rapid walking, swimming, bicycling, cross-country skiing, and mountain climbing, have involved 30 minutes or more of continued effort at 70% to 85% of maximal heart rate at least three times weekly. In most studies, levels of HDL cholesterol have been shown to rise (approximately 20%) and triglyceride levels to fall (approximately 25%) with exercise (45). Although levels of LDL cholesterol usually do not fall in normal subjects, reductions of as much as 10% may occur in individuals with increased concentrations of total and LDL cholesterol.
Resistive training programs conducted in normolipidemic individuals have resulted in increases in HDL cholesterol of 10% to 15% and decreases in LDL cholesterol of 5% to 39% (69). In contrast, in one well-controlled prospective study of resistive training in subjects at risk for CAD (70), no changes in lipid profiles were observed after 20 weeks. Both aerobic and resistive exercise training improve glucose tolerance and insulin sensitivity, reduce blood pressure, and improve body composition (71,72).
To date, most prospective exercise studies have been performed in men. A meta-analysis of the existing longitudinal exercise investigations in women revealed an overall decrease in levels of total cholesterol and triglycerides with little or no change in values of HDL or LDL cholesterol (73). Gender-related differences in the lipoprotein response to exercise may reflect the generally higher endogenous levels of HDL cholesterol in women or differences in metabolic factors such as levels of sex steroids or regulatory enzymes.
It has been demonstrated in both cross-sectional and longitudinal epidemiologic studies that people who exercise regularly have a reduced risk for CAD. Exercise also improves glucose metabolism, assists in weight reduction, and may reduce blood pressure (74,75). Thus exercise counseling (see Chapters 16 and 63) is an important part of the management of patients with abnormalities in lipoprotein metabolism.
Smoking Cessation
Plasma levels of HDL cholesterol have been found to be lower and levels of VLDL triglyceride higher in people who smoke cigarettes than in nonsmokers or ex-smokers. Moreover, an inverse relationship exists between the number of cigarettes smoked daily and the level of HDL cholesterol. Smoking cessation has been associated with a modest rise in plasma HDL concentration. It is not known how much of the increased risk of CAD associated with smoking is mediated through alteration in the plasma lipids and how much via other mechanisms. There is, however, substantial evidence that smoking cessation reduces CAD risk. There is also evidence that counseling of patients increases cessation rates. Therefore, all patients who smoke cigarettes should be counseled to quit, regardless of their lipid profile (seeChapter 27).
Drug Therapy
The recommendations for drug therapy for primary prevention by the ATP (44) are discussed here. Candidates for drug therapy should always continue dietary interventions, because the effects of each mode of treatment are often additive. For all patients, additional lifestyle changes such as weight control, habitual exercise, and cessation of cigarette smoking should be maximized. Table 82.10 provides detailed information on lipid-lowering drugs.
Hypercholesterolemia
In general, the NCEP guidelines suggest a need for drug therapy (Table 82.7) when, despite 3 months of dietary intervention, the LDL level is still higher than the desired range. Patients with marked elevations of LDL cholesterol, in whom dietary therapy alone is unlikely to normalize LDL cholesterol levels, may be considered for drug therapy simultaneously with the initiation of dietary modification. After drugs have been started, LDL cholesterol levels should be checked at 4 to 6 weeks and at 3 months. Once target levels have been achieved, patients should be evaluated with measurement of LDL cholesterol every 4 to 6 months.
For patients at highest risk of adverse cardiovascular events, a recent update from the NCEP suggested that a lower LDL cholesterol target of 70 mg/dL may be appropriate (51). Such patients include those with diagnosed CAD, peripheral arterial disease, or carotid artery disease; diabetes; or 2 or more risk factors for CAD with a calculated 10-year risk more than 20%. In such patients, it is suggested that drug therapy be initiated if the baseline LDL is 100 mg/dL or greater and should even be considered as an option if the LDL is <100 mg/dL but >70 mg/dL. Drug therapy may be delayed in the lowest-risk patients. These include men younger than 35 years of age (with the exception of smokers whose LDL levels are 160 mg/dL or higher and all men whose LDL levels are 190 mg/dL or higher) (44); premenopausal women without other risk factors whose LDL cholesterol levels are less than 220 mg/dL; patients
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with fewer than two other risk factors and LDL cholesterol levels less than 190 mg/dL; and patients with two other risk factors and LDL cholesterol levels less than 160 mg/dL who have embarked on a trial of adequate diet.
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TABLE 82.10 Commonly Used Lipid-Lowering Drugsa |
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Cholesterol-lowering drugs are categorized into two groups: (a) first-choice agents, such as HMG-CoA reductase inhibitors, bile acid sequestrants, and nicotinic acid, which are effective in lowering total and LDL cholesterol levels, reducing CAD risk, and are generally safe for long-term use; and (b) other drugs, such as gemfibrozil, fenofibrate, and ezetimibe.
HMG-CoA Reductase Inhibitors
The statins (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin) are specific, potent, competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. These drugs increase hepatic LDL receptor activity and LDL clearance from the circulation and, in addition, decrease production of LDL (76). More than 15 years of clinical experience with this class of drugs has confirmed their effectiveness in reducing levels of total and LDL cholesterol by 20% to 50%, in decreasing triglyceride levels slightly, and in modestly increasing the levels of HDL cholesterol in some patients (76,77). They appear to be equally effective in individuals with familial and nonfamilial hypercholesterolemia. When compared with bile acid sequestrants and nicotinic acid in the treatment of patients with type IIa hyperlipidemia, statins induce a greater reduction in LDL cholesterol concentrations and better compliance.
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A 5-year study demonstrated lovastatin to be comparable in safety to the other major cholesterol-lowering drugs (78). The safety profiles are similar for the other statins, with drug-related adverse events occurring in approximately 2% to 3% of patients. Side effects include increase in aminotransferase activity, myopathy, insomnia, myalgia, arthralgia, and gastrointestinal disturbances. No study has shown a significant increase in the development of lens opacities; consequently, routine ophthalmologic monitoring is not required. Periodic tests of liver function are now suggested before initiation of statin therapy, at weeks 6 and 12, and then semiannually. In general, statin therapy should be reduced or discontinued when aminotransferase levels rise three times above the upper limit of normal. There is no compelling evidence that one statin is superior to another in regard to problems with hepatic toxicity. The same is true for problems with myalgias or myositis. If the patient complains of painful muscles, the serum creatinine kinase (CK) level should be measured. It is prudent to check CK levels before initiating statin therapy as it avoids confusion later if the patient complains of myalgia and then is found to have an elevated CK. Statin therapy should be reduced or discontinued when CK levels rise three times above the upper limit of normal. The incidence of myositis rises when statins are used in combination with gemfibrozil (especially in older females with renal insufficiency), erythromycin, antifungals, or cyclosporine.
Bile Acid Sequestering Resins
The bile acid-binding resins cholestyramine and colestipol are among the oldest agents used to treat hypercholesterolemia. They are useful for primary prevention therapy in young men and premenopausal women without other risk factors who have moderately increased LDL cholesterol levels. They enhance LDL catabolism and excretion and prevent intestinal absorption by diverting cholesterol and bile acids into the feces. They also increase levels of triglycerides and HDL, particularly HDL2. At dosages of 20 to 24 g per day, a 20% to 30% reduction in LDL cholesterol may be achieved. Although the resins may be the safest of all of the hypolipidemic drugs, compliance with the older agents was a problem because taste and gastrointestinal side effects prevented many patients from taking a full dose. As many as 30% of clinical trial participants admitted to taking less than half of the prescribed dosage of bile acid-binding resins (36). Gradual increase of dose, continuation of therapy, and concomitant symptomatic management of constipation may diminish side effects. The resins are better tolerated when used at lower dosages in combination with other lipid-lowering agents. They should not be overlooked as adjuvant therapy when other lipid-lowering agents fail to achieve the desired results. Another bile acid resin, now available for prescription, is colesevelam (WelChol), a more palatable preparation and one that has fewer drug interactions than the older bile acid resins. It can be given concurrently with statins and does not interfere with the absorption of vitamins A, D, E, or K (79).
Cholesterol Absorption Inhibitors
Ezetimibe is a relatively new medication that impairs cholesterol absorption in the intestine (80). The standard dose is 10 mg daily and can be prescribed as monotherapy or in combination with other lipid lowering medications. In combination with simvastatin, it is marketed as Vytorin and is available in multiple doses (10 mg of ezetimibe with 10 to 80 mg of simvastatin). It is generally free of major side effects and does not impair absorption of vitamins.
Nicotinic Acid (Niacin)
Nicotinic acid (3 to 6 g/day) significantly lowers plasma levels of LDL and VLDL while raising the level of HDL cholesterol. It is therefore the drug of first choice for patients with concomitant elevations in LDL cholesterol and triglycerides. It is the first lipid-lowering drug shown to lower levels of Lp(a) (26), and it is also one of the most potent agents in elevating HDL cholesterol levels. There is evidence in secondary prevention trials that nicotinic acid may reduce total mortality. Its use is often limited, however, by unpleasant side effects and the frequent presence of coexisting contraindications (see Table 82.10). Therapy should be discontinued if gout, hyperglycemia, or hepatotoxicity develops. By starting at a very low dosage of 100 to 200 mg/day and gradually increasing the dosage of the drug and adding aspirin, increased tolerance often develops to the common side effects of cutaneous flushing, rashes, hives, and pruritus. Sustained-release forms of nicotinic acid were initially thought to produce fewer side effects than immediate-release forms. However, because of reports of irreversible chronic liver disease and fulminant hepatic failure with sustained-release nicotinic acid, immediate-release forms are strongly preferred (81,82).
Fibrates
Gemfibrozil is the most commonly used drug in this class in the United States. Clofibrate, rarely used since the World Health Organization Cooperative Trial reported significantly increased all-cause mortality in patients taking the drug (83), and fenofibrate are also available in the United States, whereas bezafibrate and ciprofibrate are available in Europe. Although gemfibrozil is approved for the treatment of hypertriglyceridemia, data from the Helsinki Heart and VA-HIT studies (37,42) revealed it to be effective in raising HDL cholesterol and reducing morbidity and mortality from CAD. In general, gemfibrozil is not considered as useful for secondary prevention as other drugs such as the statins, because it does not achieve maximal reductions in LDL cholesterol. Diabetic patients with elevated triglycerides and patients with type III
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hyperlipoproteinemia are excellent candidates for treatment with this drug. The VA-HIT study showed that gemfibrozil is associated with significant risk reductions for stroke, nonfatal MI, and CAD death in patients with known CAD and low HDL cholesterol levels (42). However, in patients with primary hypertriglyceridemia gemfibrozil may increase LDL cholesterol levels, whereas in patients with elevations of both cholesterol and triglycerides, this drug can cause either an increase or a decrease in LDL cholesterol levels. The newer fibrates may lower LDL cholesterol more effectively than gemfibrozil does (84). A significant side effect of gemfibrozil is its tendency to increase bile lithogenicity.
Combination Drug Therapy
If the response to one of the first-line drugs proves to be inadequate, combined therapy with two drugs with complementary or synergistic mechanisms of action should be considered. The use of a bile acid sequestrant or ezetimibe in combination with either nicotinic acid or a statin can lower levels of LDL cholesterol by 45% to 60% in patients with hypercholesterolemia and normal triglyceride levels (85). These regimens have been well tolerated, with synergistic effects on LDL cholesterol without an additive effect on drug-related toxicity. Fibrates may also be used in combination with a bile acid-sequestering resin, although these regimens are less effective. The combination of a statin and fibrate causes an increased risk of myopathy, and rhabdomyolysis has been reported with the combination of lovastatin and nicotinic acid (86).
Two placebo-controlled studies of intensive lipid-lowering therapy using combined colestipol and niacin therapy or combined lovastatin and niacin treatment for men with documented CAD showed reduced frequency of progression of coronary lesions, increased frequency of regression, and reduced incidence of cardiovascular events in the active drug groups, without cases of rhabdomyolysis (87,88). Patients with homozygous familial hypercholesterolemia may respond less well to treatment with drugs and diet than patients with heterozygous monogenic, polygenic, or nonhereditary hypercholesterolemia.
Obviously, it is prudent to carefully monitor patients treated with combination therapy. This requires frequent followup visits and advising patients to call the caregiver should they experience excessive muscle aches or weakness. Consultation with a lipid disorders specialist may be helpful in considering and initiating combination drug therapy.
Other Hypocholesterolemic Drugs
The use of estrogen replacement therapy (ERT) in postmenopausal women has a number of effects on cholesterol metabolism (see Chapters 103 and 106). Treatment with oral estrogens usually lowers levels of LDL cholesterol and raises those of HDL cholesterol, but the dosages required for these effects probably exceed those for physiologic replacement therapy. In contrast, administration of transdermal estrogens usually results in lower LDL cholesterol levels but unaltered levels of HDL cholesterol. Both oral and transdermal ERT have been shown to significantly lower Lp(a) levels (31% and 16%, respectively) in postmenopausal women. Concomitant use of the progestin medroxyprogesterone acetate (Provera) with either form of ERT appears not to influence either form of ERT adversely. The primary side effect of unopposed estrogen is the increased risk of endometrial cancer, a risk that is greatly attenuated by cotreatment with progestogens (see Chapter 106).
Phytoestrogens, plant-derived estrogens, are substances that have attracted the attention of the American population. These plant derivatives are comprised mainly of three classes: isoflavones, coumestans, and lignans (89). In most studies, phytoestrogens have been reported to exert a favorable effect in improving lipid profiles (89).
The results from the Heart and Estrogen/Progestin Replacement Study (HERS) dampened the enthusiasm for hormone replacement therapy (HRT) in the treatment of women with known CAD. The participants were postmenopausal women younger than 80 years of age with known CAD and an intact uterus. Study participants were treated with either an estrogen/progestin preparation or placebo for an average followup of 4.1 years (90). The results showed no statistically significant difference between the occurrences of nonfatal MI and coronary heart disease death between the two groups. There was an increase in thromboembolic and gallbladder disease among study participants taking the hormone supplements.
In addition, the results from the Women's Health Initiative Study have raised concern that there is an increased risk of invasive breast cancer and of cardiovascular disease associated with hormone replacement therapy (91). The study found excess risk in incident cases of coronary heart disease, stroke, pulmonary embolism, and invasive breast cancer in healthy women using HRT (Premarin 0.625 mg/day plus medroxyprogesterone 2.5 mg/day), but there was also a significant reduction in the risk of colorectal cancer and fracture. It should also be noted that there has been disagreement on whether hormone replacement therapy should be withheld in women at increased risk for coronary disease (92). The most prudent advice for the health care provider is to engage in a candid discussion with the patient regarding the pros and cons of HRT.
Hypertriglyceridemia
Drugs that decrease hepatic production of VLDL and apo B, enhance VLDL clearance by stimulating LPL activity, or both are generally effective in treating hypertriglyceridemia. Fibrates and nicotinic acid do both.
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Although nicotinic acid may be most efficacious, its use is limited by its side effects and the presence of coexisting contraindications. The fibric acid derivatives gemfibrozil and fenofibrate are therefore the drugs most commonly used. Although gemfibrozil is generally well tolerated, an acute myositis, which is occasionally associated with renal failure, may occur, particularly in patients with impaired renal clearance or hypoalbuminemia. Either the drug should not be used or the dosage should be reduced by 70% to 90% in azotemic patients. Periodic monitoring of muscle enzymes (creatine kinase, aldolase) is required to avoid toxicity. If the level of LDL cholesterol rises in a patient taking gemfibrozil, the diagnosis of familial combined hyperlipoproteinemia should be considered.
For compliant patients who remain hypertriglyceridemic with diet and a single drug, combined therapy with a fibric acid drug and nicotinic acid may be useful. Rarely, after consultation with a specialist in lipid disorders, the progestational agent norethindrone acetate or the androgenic anabolic steroid oxandrolone—in women or men, respectively—may be required to treat persistent hypertriglyceridemia plus chylomicronemia.
Dysbetalipoproteinemia
The decreased remnant catabolism characteristic of this clinically uncommon disorder can be corrected or improved by drug therapy.Gemfibrozil appears to normalize lipid levels and to enhance remnant clearance in patients with dysbetalipoproteinemia. It is the drug of choice in this disorder. Ethinyl estradiol has a similar and even more dramatic effect, but at dosages that greatly exceed those used for postmenopausal replacement therapy. Hence, its use requires careful monitoring for possible adverse estrogenic effects that would necessitate discontinuation of the drug. Nicotinic acid is the drug of second choice.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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