Approach to the Patient with a Lipid Disorder
Treatment of hypercholesterolemia reduces cardiovascular morbidity and mortality, improving quality of life and extending life expectancy. The ability to slow atherosclerosis and in some instances to achieve regression of atheromatous vascular change represents one of the major accomplishments of modern medicine. The high prevalence of hypercholesterolemia and the ability to meaningfully alter its clinical impact necessitate a comprehensive approach to the problem by the primary care physician and team. The task begins with screening (see Chapter 15) and progresses to risk stratification and design of a personalized treatment program, the subjects of this chapter. Evidence-based approaches to the problem have been elucidated and promoted by the National Cholesterol Education Program (NCEP) of the National Institutes of Health through such efforts as the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults—Adult Treatment Panel III (ATP III). Since the panel’s last report of over a decade ago, continued progress has been made. This chapter builds on the foundation provided by ATP III and incorporates advances in treatment of lipid disorders, particularly the benefits of more intensive therapy, that form the basis for new guidelines issued by the American Heart Association (AHA) and the American College of Cardiology (ACC) Foundation. In addition, the chapter addresses the significance of both hypertriglyceridemia and low high-density lipoprotein (HDL) cholesterol, dyslipidemias that are appearing more frequently with the growing prevalence of obesity and its concomitant metabolic syndrome.
The production of atherogenic lipoproteins and the induction of atheromatous plaques by those lipoproteins involve distinct pathways. The presence of an elevated serum cholesterol level does not, by itself, guarantee the development of atherosclerotic lesions that will become clinically important any more than a normal cholesterol concentration ensures plaque-free coronary arteries. The formation and subsequent rupture of atherosclerotic lesions, leading to the acute coronary syndromes of unstable angina and myocardial infarction, depend on complex cellular and metabolic interactions. Serum lipids, inflammatory cells recruited to the sites of lipid deposition, the normal cellular constituents of the artery wall, and components of the blood coagulation system all contribute to the pathogenesis of atherosclerosis and its clinical consequences.
Lipoproteins (Table 27-1)
An understanding of lipoproteins and their metabolism helps guide physicians in evaluating and treating lipid disorders. To circulate in the aqueous environment of the blood, nonpolar lipids such as cholesterol and triglyceride are complexed with proteins and the more polar phospholipids into spheres called lipoproteins. The protein components of the lipoproteins are known as apoproteins, which play both structural and functional roles in the metabolism of lipid particles. Genetically inherited mutations in either the structure of apoproteins or the receptors that bind them account for many of the most severe forms of hyperlipidemia. The lipoproteins are usually divided into four major classes based on particle density, which is a reflection of their relative protein and lipid content: chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). There are also subdivisions and minor classes of lipoproteins.
TABLE 27-1 Lipoprotein Composition | ||||||||||||||||||||||||||||||||||||||||||||||||
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Chylomicrons
Chylomicrons derive from dietary fat and carry triglycerides throughout the body. They have the lowest density of all lipoproteins and float to the top of a plasma specimen left in the refrigerator overnight. The chylomicron itself is probably not atherogenic, but the role of the triglyceride-depleted chylomicron remnant is uncertain. Triglyceride makes up most of the chylomicron and is removed by the action of lipoprotein lipase. Patients deficient in this enzyme or its cofactors (insulin and apolipoprotein C-II) have very high serum triglyceride levels and increased risk of acute pancreatitis.
Very-Low-Density Lipoproteins
VLDLs are also triglyceride rich and are acted on by lipoprotein lipase. Their function is to carry triglycerides synthesized in the liver and intestines to capillary beds in adipose tissue and muscle, where they are hydrolyzed. After removal of their triglyceride, VLDL remnants can be further metabolized to LDLs. The atherogenicity of native VLDL is controversial, but the metabolism of VLDL to atherogenic lipoproteins is not in doubt. VLDLs serve as acceptors of cholesterol transferred from HDLs, possibly accounting in part for the inverse relation between HDL cholesterol and VLDL triglyceride. The serum enzyme cholesterol ester transfer protein (CETP) mediates this transfer process, and inhibitors of CETP raise HDL cholesterol levels. It is not clear whether such inhibitors favorably alter the development of atherosclerosis, despite the substantial impact they have on raising HDL levels.
Low-Density Lipoproteins
LDLs are the major carriers of cholesterol in humans. They carry cholesterol to tissues and deliver it via receptors on the cell surface that bind and internalize the LDL particle. LDLs are the lipoproteins most clearly implicated in atherogenesis. LDL levels are increased in individuals who consume large amounts of saturated fat and/or cholesterol. There are also several mendelian genetic disorders that result in increased LDL levels. These disorders encompass mutations that produce defective LDL receptors (familial hypercholesterolemia) or mutant proteins that interact with the LDL receptor (PCSK9 and autosomal recessive hypercholesterolemia proteins). LDL levels can also result from genetically encoded abnormalities in the structure of LDL’s major protein constituent, apoprotein B (familial defective Apo B). Finally, there are non-mendelian, polygenic disorders that cause increases in LDL.
When serum LDLs exceed a threshold concentration, they traverse the endothelial wall and can become trapped in the arterial intima. There, they may undergo oxidation, aggregation, or other modifications that enhance their uptake by macrophages. The accumulation of lipid in macrophages that has derived from native and modified LDL uptake appears to be an important initiating step in atherogenesis. The association of serum total cholesterol with coronary heart disease (CHD) is predominantly a reflection of the role of LDL because LDL cholesterol constitutes the bulk of serum cholesterol in most humans. Many well-designed studies demonstrate that lowering the LDL cholesterol can dramatically reduce subsequent coronary events and all-cause mortality in hypercholesterolemic patients.
High-Density Lipoproteins
HDLs appear to function in peripheral tissues as an acceptor of free cholesterol that has been transported out of the cellular membrane. The cholesterol is esterified and stored in the central core of the HDLs and may be further metabolized. This movement of cholesterol from peripheral cells back to HDLs and then ultimately to the liver for excretion is termed reverse cholesterol transport. The activity of this pathway may explain why patients with very high HDL levels have a reduced risk of developing CHD, even if their LDL levels are elevated. Recent investigations have also attributed direct anti-inflammatory and antioxidant properties to HDLs, apparently mediated by an extremely complex mixture of proteins carried in HDLs that may vary in individuals with differing risks of coronary disease. Apolipoprotein A1 is the major apoprotein of HDL, and its level also inversely correlates with the risk of CHD.
Women have higher levels of HDL cholesterol than men, in part because of their higher estrogen levels. Exercise increases HDL, whereas obesity, hypertriglyceridemia, and smoking lower HDL. In several epidemiologic studies, the HDL cholesterol concentration is the most powerful lipid predictor of CHD risk, but therapies that raise HDL cholesterol levels have proven difficult to develop, and the significance of such an intervention on coronary disease outcomes is uncertain. There is a growing appreciation of the complexity of the role of HDLs in atherosclerosis, which has led to the view that simply raising HDL cholesterol levels, unlike lowering LDL cholesterol values, may not reliably translate into a clinical benefit.
Dietary Influences
Dietary fat and cholesterol have a substantial influence on serum cholesterol and LDL cholesterol levels. Saturated fat intake has a greater effect on serum cholesterol than does dietary cholesterol intake. For each increase in percentage of total calories contributed by saturated fats, serum cholesterol increases by a factor of 2.16, whereas the serum cholesterol increases by only 0.068 times the percentage increase in dietary cholesterol. This relationship is summarized in the equation of Hegsted:
Change in total cholesterol = 2.16 ΔS + 1.65 ΔP + 0.068 ΔC
where ΔS, ΔP, and ΔC are the changes in the percentage of total calories contributed by saturated fats, polyunsaturated fats, and cholesterol, respectively. Fats are characterized by their constituent fatty acid composition. The fatty acids are characterized as saturated, polyunsaturated, or monounsaturated. The state of saturation refers to the number of carbon-carbon double bonds contained in the fatty acid.
Saturated Fatty Acids
These fatty acids can raise LDL cholesterol, in part by altering the LDL receptor’s catabolic activity. The long-chain saturated fatty acids common to the US diet—lauric (12 carbons), myristic (14 carbons), palmitic (16 carbons), and stearic (18 carbons)—have no double bonds and are not essential dietary components for human growth and development. Not all saturated fatty acids trigger rises in LDL cholesterol. For example, stearic acid and some shorter-chain fatty acids (caproic and caprylic) do not. In the typical US diet, about one third of the saturated fat content of the diet derives from meat and meat products, whereas another third comes from dairy products and eggs and 10% from baked goods. Vegetable oils also may contain saturated fat (see Appendix Table 27-13), especially the so-called tropical oils (coconut and palm) and cocoa butter, which are commonly used in commercial food preparation. Even when unsaturated oils (see later discussion) are used in processed foods, they usually undergo partial hydrogenation, which adds back hydrogens to the carbon-carbon double bonds, eliminating some double bonds and making the fatty acids more saturated. This saturation process is performed to make these oils more solid at room temperature, but it also makes them more hypercholesterolemic.
Monounsaturated Fatty Acids
Monounsaturated fatty acids are present in all animal and vegetable fats. The most common dietary form is oleic acid, which is plentiful in peanuts, almonds, olives, and avocados. Oils derived from these sources neither raise nor lower LDL cholesterol by themselves, although cholesterol and CHD risk fall if they are used as substitutes for saturated fat. Mediterranean diets rich in olive oil and other sources of monounsaturated fatty acids appear to be relatively nonatherogenic, even though they are not low in fat.
Polyunsaturated Fatty Acids
Unlike saturated and monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs) are not synthesized by the body. They must be present in the diet and are referred to as essential fatty acids. The location of the first double bond from the methyl end of the molecule determines the nomenclature of the PUFAs. The major dietary fatty acids contain either an n-6 or n-3 first double bond. Linoleic and arachidonic acids are the common omega-6 PUFAs, found in considerable quantities in liquid vegetable oils (sunflower, safflower, corn, and soybean). The omega-3 fatty acids are represented by linoleic acid (found in canola oil and leafy vegetables) and the omega-3 fish oils (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]). The latter attracted considerable interest when epidemiologic studies found a link between diets rich in oily fish and reduced rates of CHD mortality.
When vegetable oils rich in PUFAs are subjected to partial hydrogenation in commercial food processing, not only do some of their double carbon bonds get converted to single bonds, but shifts from the cis configuration into the trans configuration also occur, which increases the atherogenicity and associated CHD risk of these fats. Intake of such substances increases LDL cholesterol, lipoprotein(a), and triglycerides and reduces HDL cholesterol. Data from the Nurses’ Health Study suggest that replacing trans unsaturated fats in the diet with polyunsaturated fats can reduce CHD risk by nearly 60%, a much greater reduction than that achieved by reducing overall fat intake. Studies in which the total fat content of the diet has been lowered have not shown consistently reproducible benefits on serum cholesterol levels and/or coronary disease outcomes. This may be because most attempts to reduce total fat lead to reductions in both saturated and unsaturated fat intake, producing no net benefit. Current evidence suggests that only reductions of saturated and trans fat intake would be beneficial.
Cholesterol
As the Hegsted formula indicates, dietary cholesterol has a much smaller effect than saturated fatty acids on raising total cholesterol. For every additional 100 mg of dietary cholesterol consumed per day, the serum cholesterol will rise by about 8 to 10 mg/dL. However, organ meats (e.g., brain, kidney, heart, sweetbreads) and egg yolks are concentrated sources of dietary cholesterol (see Appendix Table 27-14) and can have a substantial effect on serum cholesterol levels. Although shellfish contain moderate amounts of cholesterol, they have relatively small amounts of saturated fat and are sources of omega-3 PUFAs. Cholesterol is absent from food derived from plants. Plant stanols and sterols can actually block cholesterol absorption in the intestine, and a commercially available margarine containing the plant stanol sitostanol is available as a cholesterol-lowering agent. It reduces serum cholesterol levels by 10% to 15%. Recently released NCEP guidelines ATP III encourage the use of these plant stanols in dietary programs aimed at reducing blood cholesterol levels.
Other Dietary Factors
Low-fat, high-carbohydrate diets in which saturated fat is replaced by carbohydrate can reduce HDL cholesterol and increase triglycerides. Especially in obese persons, increased total caloric intake may induce overproduction of VLDL triglycerides while reducing HDL cholesterol levels. Data from the Nurses’ Health Study suggest that substituting carbohydrate for saturated fat in the diet may reduce CHD risk by about 15%, but substituting carbohydrates with a high glycemic index increases CHD risk by greater than 50%. An atherogenic lipid profile of increased triglycerides, small LDL particles, and reduced HDL cholesterol similar to that associated with insulin resistance and obesity has been observed in persons with excessive intake of refined or processed carbohydrates. No adverse lipid effect has been associated with intake of less processed forms of carbohydrate.
The fiber content of food has generated much interest. Insoluble fiber (typically cellulose found in wheat bran) has no cholesterol-lowering effect, although it is beneficial for lowering the risk of diverticular disease and colon cancer (see Chapter 65). Soluble fiber (pectins, certain gums, psyllium) has received much attention in the lay press stimulated by claims about oat bran, which contains the gum β-glycan. Initial studies were encouraging, but subsequent data suggested that the cholesterol decreases observed were no greater than those found with the use of insoluble fiber and probably resulted from the replacement of dietary fat in the diet rather than from a direct effect on lipid metabolism. When studied in patients already taking a low-fat diet, high-soluble fiber intake appeared to lower serum cholesterol by a modest amount (3% to 7%).
Lifestyle Contributions
Lack of exercise and caloric excess are epidemic in the United States and major contributors to lipid abnormalities and CHD risk. The obesity that results from an unhealthy lifestyle leads to the metabolic syndrome, characterized by hyperinsulinism and elevations in triglycerides, reductions in HDL cholesterol, and increases in LDL cholesterol; in addition, blood pressure rises along with the risk of developing type 2 diabetes. The net result is a marked increase in CHD risk.
Diagnosis
The diagnosis of a lipid disorder should never be based on a single serum lipid determination, because combined analytic and biologic variations in serum lipids range from 10% to 20%. A confirmatory fasting determination is required.
Measurement of the Lipid Profile
A venous sample processed in a laboratory meeting Centers for Disease Control and Prevention standards for cholesterol determination (see Chapter 15) is recommended. The ATP III guidelines suggest that a fasting lipid profile be done at the initial assessment whenever possible. The fasting venous sample is processed for direct determination of serum total cholesterol, HDL cholesterol, and triglycerides, with calculation of LDL cholesterol and non-HDL cholesterol derived from direct measurements of these components (see below). If a fasting lipid profile cannot be readily arranged, then a practical alternative in persons at low CHD risk is to obtain nonfasting determinations of total cholesterol and HDL cholesterol and reserve for a full lipid profile only those persons with a nonfasting total cholesterol greater than 200 mg/dL or an HDL cholesterol less than 40 mg/dL (see Chapter 15).
Estimation of VLDL cholesterol and calculation of LDL cholesterol and non-HDL cholesterol are derived from direct measurements of total and HDL cholesterol levels and the triglyceride concentration using the following formulae:
LDL cholesterol = total cholesterol — (HDL cholesterol + triglyceride/5)
The triglyceride/5 factor represents a close estimate of VLDL cholesterol and derives from the observation that VLDL cholesterol is usually 20% of the serum triglyceride value. The validity of this formula for estimating LDL cholesterol has been confirmed by direct LDL cholesterol measurement and remains fairly accurate so long as the total triglyceride is less than 400 mg/dL. A fasting sample is required for accurate results because chylomicrons appearing in the blood after a meal do not contain the same ratio of triglyceride to cholesterol found in VLDL.
If the triglyceride level is greater than 400 mg/dL, direct measurement of LDL cholesterol is required to determine its serum concentration. The direct measurement of LDL cholesterol is a much more expensive procedure reserved for patients with elevated triglycerides or unusual clinical presentations.
Non-HDL cholesterol is determined by subtracting HDL cholesterol from total cholesterol. It represents the atherogenic portion of the serum cholesterol (i.e., LDL cholesterol plus VLDL cholesterol). It is calculated by the formula:
Non-HDL cholesterol = Total cholesterol — HDL cholesterol
The accuracy of the non-HDL determination depends in part on the accuracy of the HDL determination. It is important to keep in mind that in clinical practice, measurement of HDL cholesterol may differ from that in research studies.
Excluding Secondary Causes
Before embarking on a treatment plan, one must exclude conditions that might secondarily lead to hyperlipidemia. The most important are hypothyroidism, nephrotic syndrome, and diabetes, which are best screened for by a serum thyroid-stimulating hormone, urine dipstick for protein, and serum hemoglobin A1c, respectively (see Chapters 93, 104, and 130). Drugs can affect lipid levels as well, with LDL elevations occurring with thiazide use and triglyceride levels rising with beta-blockers. Postmenopausal estrogen replacement lowers LDL and increases HDL and triglyceride. Antiviral protease inhibitors used in the treatment of AIDS often cause hyperlipidemia as well.
Diagnostic Definitions and Classification (Tables 27-2 and 27-3)
Definitions of abnormality for lipid serum concentrations are somewhat arbitrary since risk exists along a continuum of lipid levels, but consensus definitions that reflect population distributions and associated levels of CHD risk are helpful. US and European consensus definitions of abnormal levels differ slightly as do the units used to define serum concentrations (Table 27-2).
For purposes of clinical classification, separating patients into three broad categories usually suffices: those with elevated cholesterol, those with elevated cholesterol and triglyceride, and those with elevated triglyceride only (Table 27-3). The possibility of a genetic disorder should be considered if extremes of any lipid level are encountered or if there is a history of premature CHD in the patient or family.
The need for and benefit from treatment of lipid disorders are closely linked to the patient’s overall risk of an adverse cardiovascular event. Focusing only on lipoprotein cholesterol levels for both risk stratification and treatment misses the point, putting the patient at risk for under- or overtreatment and suboptimal outcomes. The risk assessment and treatment plan need to be comprehensive, taking into account all independent determinants of cardiovascular risk.
Role of Established CHD Risk Factors in Risk Stratification
The comprehensive CHD/CVD risk assessment for patients with a lipid disorder starts with consideration of lipid levels (Table 27-4), but must attend to the full spectrum of validated CHD/CVD risk factors (Table 27-5), particularly those identified and represented by the Framingham Risk Score (see Chapter 18). These include hypertension, smoking, diabetes, family history of premature CHD, age, sex, and presence of established CHD or other atherosclerotic disease (e.g., peripheral arterial insufficiency, symptomatic carotid disease). Diabetes is notable for being increasingly recognized as a major risk factor for CHD events, now designated as a “CHD equivalent” for risk assessment purposes. The appreciation for elevated HDL cholesterol (HDL >60 mg/dL) as a factor in reducing CHD risk has led to its designation as a negative risk factor; conversely, a low HDL cholesterol (<40 mg/dL) has been added to the list of positive risk factors (Table 27-5). While HDL cholesterol appears to be
a useful biomarker of risk, its importance regarding treatment decisions remains the subject of debate, because of conflicting evidence regarding its biologic significance.
a useful biomarker of risk, its importance regarding treatment decisions remains the subject of debate, because of conflicting evidence regarding its biologic significance.
TABLE 27-2 Designations of Serum Lipid Levelsa,b | ||||||||||||||||||||||||||||||
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For a given elevation in LDL cholesterol level, patients considered at highest risk are those with established CHD or CHD equivalent disease. Next come patients free of CHD and CHD equivalent disease who have two or more CHD risk factors in addition to their lipid disorder, followed by those having no CHD and zero or one risk factor (Table 27-6).
Refining risk stratification and translating it into semiquantitative terms of 10-year CHD event risk can be helpful and readily performed by both physician and patient using such tools as a Framingham Risk Score calculator (e.g., http://hp2010.nhlbihin. net/ATPiii/calculator.asp). It makes for a more precise estimate of CHD event risk and helps with evidence-based program design and patient education, particularly in persons who initially fall into the rather broad “intermediate-risk” category (Table 27-5).
Other Risk Factors
Risk stratification by use of the established risk factors accounts for up to 80% of observed CHD risk. Efforts to identify other independent risk factors for CHD continue.
Non-HDL Cholesterol.
This component of the lipid profile represents the atherogenic apolipoprotein fraction (VLDL cholesterol + LDL cholesterol). In persons with elevated triglycerides and in those taking statins, it correlates better than LDL cholesterol with CHD risk. Direct measurement of apolipoprotein B provides similar risk assessment in statin users.
Triglycerides.
Elevations in triglycerides have long been suspected as a CHD risk factor, often found in persons and families with premature coronary disease, but only recently has evidence been accumulating to suggest an independent contribution to risk and not just an epiphenomenon of the metabolic syndrome and low HDL cholesterol. Associated with hypertriglyceridemia are other lipid profile abnormalities seen with accelerated atherosclerosis, including reduction in HDL2 and increase in small dense LDL cholesterol particles. The degree of risk that is emerging is modest, which might account for the conflicting findings in the literature, but the most recent meta-analysis found the relative risk for CHD to be 1.7 when comparing persons in the top triglyceride quartile with those in the bottom one. Risk appears independent of other traditional CHD risk factors, but less so after adjusting for LDL cholesterol or HDL cholesterol subfractions. Risk appears greatest in young persons, women, and those with diabetes. Persons with a family history of hypertriglyceridemia who are at risk for premature heart disease often have an increase in apolipoprotein B and non-HDL cholesterol, characteristic familial combined hyperlipidemia, distinguishing them from those with familial hypertriglyceridemia, who have much less risk of premature CHD.
C-Reactive Protein (see also Chapters 15 and 18).
C-reactive protein (CRP) is an acute-phase reactant protein that is primarily produced in the liver in response to elevations in blood cytokines, such as interleukin-6 and tumor necrosis factor-a. The inflammatory nature of the developing atherosclerotic lesion provides a plausible link between production of activating cytokines in the atheroma and the generation of hepatically produced CRP. Evidence is beginning to accumulate suggesting that CRP may play a direct role in exacerbating atherosclerosis and raising cardiovascular event risk.
A substantial body of epidemiologic evidence supports CRP as an independent predictor of CHD events in both men and women. CRP has also been used as a prognostic indicator in patients presenting with both acute coronary syndromes and more stable, chronic coronary disease. In some subgroups (such as older women with intermediate CHD risk), the CRP level appears to be as predictive as LDL cholesterol, but overall, the association between CHD risk and CRP elevation appears to be less pronounced than originally proposed (relative risk on the order of 1.5 vs. previous estimates of 2.0 to 2.5) and weaker than that for several of the more established CHD risk factors (e.g., LDL cholesterol, smoking history, hypertension).
Data from placebo-controlled randomized clinical trials are emerging that support the clinical significance of CPR. In the landmark JUPITER study of healthy normocholesterolemic persons (LDL cholesterol <130 mg/dL and median 108 mg/dL) with high levels of CRP (highly sensitive CPR >2.0 mg/L), treatment with a potent statin that lowers CRP resulted in a significant reduction in cardiovascular events, twice that which would be expected from the reduction in LDL cholesterol alone. Similar results have been found in studies of statin therapy in patients with coronary disease: Those with the greatest CRP reductions have the best cardiovascular outcomes, independent of LDL lowering.
The optimal approach to application of CRP determination for CHD risk stratification continues to be a work in progress, but use in “intermediate-risk” persons (by Framingham Score) helps refine classification and guide intensity of treatment. Until definitive means of treating CRP elevation are established, its determination may be helpful in selective instances in which the results will change management of established treatable CHD risk factors (e.g., motivate the patient to make substantive lifestyle changes and/or trigger more aggressive pharmacologic treatment of modifiable CHD risk factors such as LDL cholesterol). If CRP levels are determined, at least two values, obtained several weeks apart, should be measured using a reliable, high-sensitivity assay (hsCRP).
TABLE 27-3 Classification of Lipoprotein Disorders | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Homocysteine.
Elevations in homocysteine (see also Chapter 15) appear to be associated with statistically significant but clinically modest increases in the risk of atherosclerotic events affecting the cerebral, peripheral, and coronary vessels. Early data suggesting a more powerful association with atherosclerosis and ability to reduce homocysteine levels with vitamin supplementation (folate, B12, and B6) led to a period of enthusiasm for screening and treating hyperhomocysteinemia, especially in persons with established CHD. However, prospective, randomized trials of vitamin supplementation failed to achieve any reduction in risk of CHD events, either in those with established CHD or as a primary preventive therapy. In some studies, paradoxical increases in CHD risk were observed. Therefore, routine measurement and treatment of homocysteine levels are not warranted at this time, but selective testing may be worth considering (e.g., strong family history of CHD, premature onset of CHD, or CHD with no identifiable risk factors).
TABLE 27-4 Coronary Heart Disease Risk Associated with Lipoprotein Cholesterol Abnormalities | |||||||||||||||||||||||||||
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Genetic Determinants.
Uncovering the genetic determinants of CHD risk that present as lipid abnormalities and premature cardiovascular disease (CVD) is an area of active research. Its principal contributions so far have been in elucidation of disease mechanisms. Incorporating genetic profiles into CHD risk assessment has yet to enhance risk stratification beyond that
contributed by a positive family history of premature CVD (see Chapter 18), but the literature should be watched closely for future developments.
contributed by a positive family history of premature CVD (see Chapter 18), but the literature should be watched closely for future developments.
TABLE 27-5 Coronary Disease Risk Factors and Coronary Heart Disease Risk Status | ||
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TABLE 27-6 LDL Cholesterol Goals and Thresholds for Treatment Based on Total Cardiovascular Risk | ||||||||||||||||||||||||
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PRINCIPLES OF MANAGEMENT (17,18,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78)
Overall Approach
The goal is to reduce cardiovascular morbidity and mortality, which requires attention not only to lipid abnormalities but also to the full spectrum of treatable atherosclerotic risk factors, ranging from hypertension and smoking to diabetes and obesity. Both primary prevention (reducing the risk of having a first event) and secondary prevention (reducing the risk of a new event in a person with established disease) are sought. The most impressive reductions in risk are achieved in patients at greatest risk (see later discussion), and the greatest reductions are being increasingly realized with multifaceted treatment programs that include intensive lipid-lowering therapy in such persons.
The approach to treatment that follows uses the ATP III guidelines of the NCEP as a foundation, supplemented by the new AHA/ACC recommendations based on evidence that has emerged since ATP III’s publication over a decade ago. The new guidelines (see Recommendations) follow the trends of the past several years of lower thresholds for pharmacologic intervention, more intensive statin therapy, and more ambitious treatment targets for lowering of LDL cholesterol. These derive from ability to achieve better outcomes more cost-effectively and with reasonable safety through use of potent statins that are now available generically.
As noted earlier, the approach to the treatment of hyperlipidemia is guided by an assessment of total CHD risk, not just that associated with the lipid abnormality. In both ATP III and AHA/ACC guidelines, as total CHD risk increases, the threshold for initiation of therapy decreases. The two guidelines differ in that ATP III recommends specific LDL- and nonHDL-cholesterol goals (Tables 27-6 and 27-7), whereas AHA/ACC does not.
TABLE 27-7 Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for Three Risk Categories | |||||||||||||||
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The NCEP and AHA/ACC treatment recommendations are listed by degree of estimated CHD risk (see Recommendations). Lifestyle modification with emphasis on dietary measures and exercise is a sole mode of therapy for patients at the lower end of the CHD risk spectrum, whereas pharmacologic measures are reserved for patients at increased risk or for those who fail dietary intervention. Additional considerations include possible adverse effects of long-term pharmacologic therapy (an issue when dealing with young persons) and appropriateness of the patient for treatment (an issue in the frail elderly and seriously ill). Again, dietary modification, complemented by exercise and weight reduction, is the core of the lipid treatment program, with pharmacologic therapy reserved for those at higher risk and for persons failing to reach goals with lifestyle modification alone.
Dietary Modification, Exercise, and Weight Loss
Dietary modification and exercise remain the cornerstones of treatment, effective for both treatment and prevention of hypercholesterolemia and the metabolic syndrome. As suggested by the Hegsted equation given earlier, the greatest contributor to hypercholesterolemia is the consumption of saturated fat, with excess cholesterol contributing to a lesser extent. Reductions in total fat, saturated fat, partially hydrogenated unsaturated fatty acids, and dietary cholesterol are recommended for all adults. Because the benefits of reducing total fat are unproven, it is more critical that lipid-lowering diet plans substitute foods that provide polyunsaturated and monounsaturated fats for those rich in saturated and trans unsaturated fat (see Appendices 27-1 to 27-3).
In conjunction with exercise and weight loss (which contribute to reductions in lipid levels and ameliorate other cardiac risk factors), dietary modification provides an excellent nonpharmacologic means of improving the patient’s lipid profile and reducing CHD risk. The adverse effects are nil, making it the safest of treatments for hypercholesterolemia and especially well-suited for persons with only a modest increase in CHD risk (e.g., hypercholesterolemic young men and premenopausal women with no other CHD risk factors). Even for high-risk patients, dietary therapies are central to the treatment program and almost always have an additive effect to pharmacologic treatments.
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