Lipid Disorders

Lipid Disorders
CURRENT Diagnosis & Treatment in Cardiology

Peter C. Chien, MD & William H. Frishman, MD

General Considerations
Clinical Findings

ESSENTIALS OF DIAGNOSIS

Total serum cholesterol greater than 200 mg/dL on two samples at least 2 weeks apart

LDL cholesterol greater than 100 mg/dL

HDL cholesterol less than 40 mg/dL

Triglycerides greater than 200 mg/dL


General Considerations
In recent years, a great deal of emphasis has been placed on the relationship between elevated serum cholesterol levels—especially low-density lipoprotein cholesterol (LDL-C)—and the incidence of coronary artery disease (CAD). Hyperlipidemia represents a public health epidemic that continues to parallel the increased prevalence of obesity and is intimately implicated in the development of CAD. It is estimated that approximately 100 million American adults have total serum cholesterol levels in excess of 200 mg/dL and more than 12 million adults would qualify for lipid-lowering therapy by current national standards. Lowering LDL levels through diet and medication has been shown to reduce the progression of CAD and CAD mortality. According to the Framingham study, a 10% decrease in cholesterol level is associated with a 2% decrease in incidence of CAD morbidity and mortality.
A. LIPOPROTEINS

The major circulatory forms of cholesterol, cholesterol ester and triglyceride, are both insoluble in water; to circulate in an aqueous environment they combine with phospholipids and proteins in complexes known as lipoproteins. The protein components of these complexes, apoproteins, play an important role in the interaction between cell surface lipases and the lipoprotein receptors necessary for lipid catabolism. The six major classes of lipoproteins are listed in Table 2–1.

Table 2–1. Lipoprotein classes and composition.

1. Lipoprotein metabolism—Lipoprotein metabolism can be divided into exogenous and endogenous pathways, as shown in Figure 2–1.

Figure 2–1. Exogenous and endogenous pathways of lipoprotein metabolism. C = cholesterol; TG = triglyceride; MG = monoglyceride; DG = diglyceride; FFA = free fatty acid; LPL = lipoprotein lipase; APO = apolipoprotein; PL = phospholipids. Reproduced, with permission, from Mitchel Y: Evaluation and treatment of lipid disorders. Prac Diabetol 1987;6:6.


a. Exogenous pathway—The exogenous pathway is mainly responsible for absorption of dietary fat in the postprandial state and its subsequent distribution to the tissues. It begins with the absorption of dietary cholesterol and free fatty acids in intestinal microvilli, where they are converted to cholesterol esters and triglycerides, respectively, and packaged into chylomicrons that are secreted into the lymphatic system and enter the systemic circulation. In the capillaries of adipose tissue and muscle, the chylomicrons interact with an enzyme, lipoprotein lipase, which cleaves core triglycerides into mono- and diglycerides and free fatty acids that are taken up by surrounding tissue. Triglyceride hydrolysis reduces the core size of the chylomicron, resulting in an excess of surface components that are transferred to high-density lipoprotein (HDL). The remaining particle, a chylomicron remnant, is greatly reduced in size; it contains approximately equal amounts of cholesterol and triglycerides, and it acquires atherogenic potential.
The chylomicrons are rapidly removed from the circulation by the liver in a receptor-mediated process. The cholesterol can also be secreted, as bile acids, into the bile.
b. Endogenous pathway—The endogenous pathway delivers cholesterol and triglyceride to the tissues in the fasting state. It begins with the synthesis and secretion of very-low-density lipoprotein (VLDL) by the liver. This triglyceride-rich lipoprotein, which is smaller than the chylomicron, also interacts with lipoprotein lipase in the capillaries, adipose tissue, and muscle. Triglycerides within the core of the particle are cleaved and taken up by the surrounding fat and muscle; the redundant surface components are transferred to the HDL fractions. The remaining particle (VLDL remnant, or intermediate-density lipoprotein [IDL]), is a smaller lipoprotein, similar to the chylomicron remnant in its lipid composition and atherogenic potential. Approximately 50% of VLDL remnants are removed by the liver through the LDL receptor, which recognizes apoprotein E or the VLDL remnant. The highly atherogenic LDL contains mostly cholesterol ester and only one apoprotein, B-100. Its function is the delivery of cholesterol to tissues that require it (gonads, adrenals, rapidly dividing cells). The liver also plays a role in removing LDL from the blood via the LDL receptor. Two thirds of LDL is removed in this fashion; the remainder is removed by a non-LDL-receptor-mediated pathway in Kupffer cells, smooth muscle cells, and macrophages. It is believed that this mode of LDL uptake contributes to the development of foam cells and atherosclerosis. HDL, which seems to exert a protective effect against the development of atherosclerosis, is synthesized in both the liver and intestine and receives components during the lipoprotein lipase reaction. HDL is composed of approximately 50% protein (apoprotein A-I, A-II) and 20% cholesterol and comprises two major subfractions in the blood: HDL2 and HDL3. The latter is a small, dense particle that is believed to be the precursor of the larger cholesterol-enriched HDL2. The transfer of surface components during the lipoprotein lipase reaction is felt to be important in the formation of HDL2 and HDL3. HDL2 is believed to exert its protective effect through its participation in reverse cholesterol transport (picking up cholesterol from the cells involved in the atherosclerotic process and delivering them to the liver for excretion). HDL levels are higher in premenopausal women than in men, contributing to the lower incidence of CAD in women. There has been recent interest in cholesterol ester transfer protein, which is involved with the enzyme lecithin cholesterol acyl transferase in driving the reverse cholesterol transport process in moving cholesterol from peripheral tissues into plasma and then back into the liver.
B. LIPOPROTEIN(A)

Lipoprotein(a), a variation of LDL, is formed by two components: an LDL-like particle with apoprotein B-100 and a hydrophilic protein moiety known as apoprotein(a), which has a close structural homology with plasminogen. It may cause a perturbation in the thrombolytic system by binding to and displacing plasminogen from binding sites on fibrin, fibrinogen, and cell surfaces. It inhibits plasminogen activation by tPA through stearic hindrance of tPA-binding sites.
Accumulation of lipoprotein(a) has been found in atherosclerotic lesions, and it is now believed to be an atherogenic lipoprotein. Elevated plasma levels greater than 30 mg/dL in humans appear to be associated with an increased risk for the development of CAD, with a rate of occurrence estimated to be two to five times greater than in normal controls. Lipoprotein(a) is thought to be inherited by autosomal codominance. Some studies restrict identification of lipoprotein(a) as a risk factor for CAD only in the setting of elevated plasma LDL levels. Others have found the condition to be an independent risk factor. Diet, age, sex, smoking, body mass index, and apoprotein E polymorphism have not been found to correlate with plasma levels of lipoprotein(a). Increased lipoprotein(a) levels have been noted in patients with diabetes mellitus or nephrotic syndrome and immediately following myocardial infarction. In other studies, no changes have been observed in lipoprotein(a) levels in patients with acute myocardial infarction or unstable angina. Of the hypolipidemic interventions, niacin, neomycin, and extracorporeal removal of cholesterol have been shown to affect elevated lipoprotein(a) levels. Estrogen and fenofibrate may also reduce lipoprotein(a) levels.
C. LIPOPROTEINS AND ATHEROSCLEROSIS

Current concepts in atherosclerosis suggest that oxidation of LDL is involved in its pathogenesis. It is hypothesized that the critical role of oxidized LDL in atherogenesis is due to its rapid uptake by the foam cells lining the arterial intima, which are thought to have macrophage-like properties. The LDL is then oxidized, exerting a chemotactic effect on monocytes, leading to more uptake of LDL and thus to the formation of the atherosclerotic plaque. The endothelial cells and smooth muscles can also oxidize LDL.
Support for this lipid oxidation hypothesis comes from evidence that antioxidants such as vitamin E inhibit formation of lesions in hypercholesterolemic rabbits. Observations in some population studies also show an association between low plasma vitamin E levels and CAD incidence. However, clinical trials have not substantiated a reduction in the rates of fatal or nonfatal myocardial infarction with daily vitamin E use.
Clinical Findings
A. HISTORY

A history of lipid disorders should be sought in all routine evaluations and in patients with suspected or overt cardiovascular disease. Many individuals already know they have high cholesterol levels from screening tests performed at shopping malls, in other physicians' offices, or during prior hospitalization. A family history of premature cardiovascular disease is also useful. A history compatible with overt cardiovascular disease, especially in a young man or a premenopausal woman is highly suggestive of a lipoprotein disorder. In addition, a history or symptoms of other diseases associated with lipoprotein abnormalities (eg, diabetes mellitus, hypothyroidism, end-stage renal disease) should be sought (Table 2–2). Other risk factors for CAD should also be identified because they multiply the risk caused by lipid disorders (Table 2–3).

Table 2–2. Some acquired causes of hyperlipidemia.

Table 2–3. Risk factors that modify LDL-cholesterol goalsa

B. PHYSICAL EXAMINATION

Most individuals with lipid disorders have no specific physical findings. Depending on the duration and severity of the lipid disorder, they may have overt evidence of lipid deposition in the integument that follows certain phenotypes (I–V), as originally proposed by Frederickson and Lees. Eruptive xanthomas occur when triglyceride levels are high; they are seen in types I (increased chylomicrons caused by lipoprotein lipase deficiency), IV (familial combined hyperlipidemia), and V (familial hypertriglyceridemia). Tendon xanthomas are characteristic of type II (familial hypercholesterolemia) patients, who can also have tuberous xanthomas and xanthelasma; the latter, however, is nonspecific and can be found in individuals with normal lipid levels. Palmar and tuberoeruptive xanthomas are characteristic of type III (familial dysbetalipoproteinemia).
C. LABORATORY ASSESSMENT

The Expert Panel Report of the National Cholesterol Education Program on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP) suggests that a fasting lipid profile should be obtained in all adults 20 years of age or older at least once every 5 years. Without a family history of premature CAD or a history of familial hyperlipidemia, cholesterol screening should not be done routinely in children. Cholesterol values in the general pediatric population may not always predict the future development of hypercholesterolemia in adults.
For many years clinicians depended on total cholesterol and triglyceride measurements to determine specific patient treatment regimens. More sophisticated lipoprotein measurements were available only in research facilities. Recent advances have made lipoprotein subclass and apoprotein determinations available from many clinical laboratories.
LDL-C has been shown to be a more accurate predictor of CAD risk than is total-C. Low levels of HDL-C and the subfractions HDL2 and HDL3 have also been shown to be more powerful than total-C in predicting CAD. Levels of plasma apoproteins are also accurate predictors of CAD risk. It is controversial whether increases in plasma apoprotein B levels (the major apoprotein of LDL) and decreases in levels of apoproteins A-I and A-II (the major apoproteins of HDL) are better predictors of increased coronary risk than are total-C, HDL-C, LDL-C, or the ratio of total-C to HDL-C.
Nonetheless, a patient's risk of CAD can be adequately estimated by an accurate total-C measurement and a calculated LDL-C determination. (Mean serum cholesterol and calculated LDL-C values for various population groups have been reported on by the National Center for Health Statistics.)
Serum total-C levels can be measured at any time of day in the nonfasting state because total-C concentrations do not vary appreciably after eating. Patients who are acutely ill, losing weight, or pregnant or who recently had a myocardial infarction or stroke should be studied at a later time because cholesterol levels may be suppressed. Venipuncture should be carried out in patients who have been in the sitting position for at least 5 min, with the tourniquet applied for the briefest time possible. The blood may be collected as either serum or plasma. The National Cholesterol Education Program has established guidelines for standardization of lipid and lipoprotein measurements because of the great variations in accuracy at different laboratories that have been reported. The recommendation is that intralaboratory precision and accuracy for cholesterol determinations be no more than 3%. In a recent study assessing compact chemical analyzers for routine office determinations, some of the machines tested were shown to have accuracy and precision above the older (l988) target of 5% variance. A rapid capillary blood (fingerstick) methodology for cholesterol measurement is currently under development and evaluation.

LDL-C measurements are usually indirectly derived from the following formula:

LDL–C (mg/dL) = Total–C (mg/dL) – HDL–C (mg/dL) – triglyceride (mg/dL) ÷ 5

When using this formula with mm/L units, divide the triglyceride value by 2.3.

A reliable direct method for measuring LDL-C is needed because the accuracy of indirect estimates of LDL-C reflects measurements of total-C, HDL-C, and triglycerides, each of which contributes some degree of imprecision. Because triglyceride values are influenced by food, the patient should fast for at least 12 h before blood is taken for the LDL-C determination. If the triglyceride values are higher than 4.52 mm/L (> 400 mg/dL), the LDL-C value will be even less accurate. Direct measurement of LDL in a specialized laboratory, using ultracentrifugation, may be necessary when significant hypertriglyceridemia persists despite fasting.
Tests are now available for specific apolipoproteins. These tests have proven to be accurate predictors of cardiovascular risk in various research studies. Unfortunately, until more is known about their utility in clinical practice, they should not be used in routine clinical management.

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