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The ubiquitous, lipids and related diseases: A laboratory perspective.

Efforts to reduce the incidence of heart disease and Alzheimer's disease in this country must include regular measuring of patients' lipid, lipoprotein, and apolipoprotein concentrations.

Coronary heart disease (CHD) and stroke continue to be weighty medical problems in the U.S. and abroad. In addition to contributing to numerous deaths, these conditions are primary causes of disability and contribute significantly to rising health care costs in this country. CUD accounts for the largest proportion of heart disease; about 12 million people are afflicted. [1] Furthermore, some 600,000 cases of acute myocardial infarction (AMI) are reported each year, with direct medical costs exceeding $16 billion annually.

A high concentration of total cholesterol (TC) in the blood has been found to contribute to the development of atherosclerosis and CUD. More than 50 million U.S. adults have blood cholesterol levels that require medical attention. [2] Approximately 90 million adults have cholesterol levels that place them at risk of heart disease. Most heart attacks occur in patients with CHD and coronary artery disease (CAD), both of which are associated with atherosclerosis, caused by plaque build-up on the walls of the coronary arteries.

Generally speaking, atherosclerotic lesions consist of fatty streaks that develop into fibrous plaques) [3,4] Foam cells consisting mainly of macrophages (laden with lipids) characterize initial fatty streaks, which either regress or progress through a transitional lesion to fibrous plaques. A build-up of plaque creates blockages in coronary arteries and results in a decrease, or complete halt, of blood supply to a portion(s) of the heart. The lodging of blood clots in the arteries also can cause obstructions in the coronary artery, sometimes referred to as coronary;' thrombosis or coronary occlusion.

Epidemiological, genetic, and environmental factors contribute to the development and progression of atherosclerotic vascular disease. Major independent risk factors for CUD include adverse levels of plasma lipids and lipoproteins. [5] Lipoproteins also contribute to the development of neurodegenerative diseases, although the mechanism involved currently remains unknown. Nevertheless, lipid alterations are reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Also not well understood is the mechanism that underlies the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer's disease (AD). Some researchers believe disturbances in brain lipoprotein metabolism play a role. [6]

Experts recommend that all patients 20 years of age and older have their cholesterol levels checked at least once every five years to help them prevent or lower their risk of CHD. Among the lifestyle changes that prevent/lower high blood cholesterol: eating a diet low in saturated fat and cholesterol, increasing physical activity, and reducing excess weight. [7]

The role of lipids. lipoproteins, and apolipoproteins

Lipids, found in all tissues and cells of the body, play both functional and structural roles in all aspects of cellular life. For instance, they are hormone precursors, aid in digestion, provide fuel for metabolism, and store energy. Lipids, including fatty acids, sterol derivatives, glycerol esters, sphingosine, and terpenes, are transported to various sites in the body via lipoproteins, including very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Closely associated with lipoproteins are protein moieties called apolipoproteins, which include five major types (apo A, B, C, D, and E) as well as four minor types (apo J, H, F, and G). The liver produces about 1.5 g of lipids daily. Another 150-300 mg of lipids are produced daily from one's diet.

Triglycerides (TGs)

Most fatty acids form esters known as glycerides with glycerol, of which TGs are the most abundant. While plant TGs have linoleic acids and are liquid at 4[degrees]C, animal TGs are solid at room temperature. Many epidemiological studies investigating the association of high TGs with increased risk for CHD reveal that elevated serum TG is an important risk factor for CHD, although other studies have found inconclusive evidence regarding the association of TG with CHD. Experts point out, for example, that whether increased TO precedes the onset of disease cannot be determined. [8] Factors that may contribute to elevated TGs in the general population include excess weight and obesity; physical inactivity; cigarette smoking; excessive alcohol consumption; a high carbohydrate diet; diseases such as type 2 diabetes, chronic renal failure, and nephrotic syndrome; and certain drugs such as corticosteroids, estrogen, retinoids, and geetic disorders).

According to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, the following classification of serum TGs has been adopted:

* Concentrations [greater than]500 mg/dL are classified as very high risk.

* Concentrations 200-499 mg/dL are classified as high risk.

* Concentrations 150-199 mg/dL are classified as border-Line-high risk.

* Concentrations [less than]150 mg/dL are classified as normal. [9]

Pancreatitis may result in extremely elevated concentrations of TG; concentrations as high as 1,000 mg/dL have been reported. Alcoholics with pancreatitis may present with very elevated concentrations of TG as well.


Cholesterol has been implicated as another key risk factor for developing CHD and atherosclerosis. Despite its atherogenic properties, cholesterol is necessary for synthesis of steroid hormones, manufacture of bile salts in the liver, and maintenance of membrane fluidity. Plant sterols may compete with cholesterol for uptake by the mucosal cells of the gut, a competitive property that can be used therapeutically to lower cholesterol concentration in the blood.

Indeed, lowering blood cholesterol levels decreases CHID risk, particularly in the absence of other risk factors. [10] NCEP ATP III guidelines still recommend a TC concentration of [less than]-200 mg/dL. Concentrations between 200-239 mg/dL are considered borderline risk for CHD, and concentrations [greater tan]240 mg/dL are considered high risk. [9,11] Serum cholesterol traditionally has been considered a poor predictor of total stroke risk; owever, it is associated positively with ischemic stroke risk and associated negatively with hemorrhagic stroke risk. [12]

Two approaches that compliment one another can be taken to reduce blood cholesterol levels among the American population. A clinical approach identifies high-risk individuals who require intensive intervention efforts. Alternatively, a population approach shifts the distribution of cholesterol levels among the entire population to a lower range through changes in dietary habits.


The major physiological function of LDL particles is to transport cholesterol to the cells. The LDL particle consists of a lipid core composed of 38% cholesterol ester and 11% TG. The outer coat of the molecule consists of 22% phospholipids, 8% unesterified cholesterol, and 21% apolipoprotein. [13] The particle contains one molecule of apo B100 and variable quantities of apo C-III and apo E. The receptor-mediated catabolism of the particle is an important determinant of the concentration of LDL-cholesterol (LDL-C) in plasma.

Epidemiological, pathological, and genetic studies reveal a strong positive correlation between elevated plasma concentrations of LDL-C and risk of premature CHD. [14] Atherogenesis modifies the particles resulting in their accumulation in arterial walls. [15] According to NCEP ATP III, the following classification of LDL-C has been adopted:

* Concentrations [greater than]190 mg/dL are classified as very high risk.

* Concentrations 160-189 mg/dL are classified as high risk.

* Concentrations 130-159 mg/dL are classified as borderline-high risk.

* Concentrations 100-129 mg/dL are classified as above optimal.

* Concentrations [less than]100 mg/dL are classified as optimal. [9]


Also known as the "sinking pre-b lipoprotein," Lp(a) was first described in 1963 as lipoprotein antigen or a genetic variant of LDL that is more prevalent in the plasma of AMI survivors than in an age-matched control group of Scandinavian men. [16-18] Lp(a) belongs to a class of apo B containing lipoproteins that is highly associated with atherosclerotic diseases, stroke, and myocardial infarction. [14] It is a genetically-determined macromolecular complex that has been identified as an independent risk factor for premature CAD. Lp(a) is elevated in both diabetic and non-diabetic android obese subjects and aggravates the atherogenic effect of diabetes mellitus. [19] Interestingly, Lp(a) concentrations are lower in Caucasians than in individuals whose ancestry originated in Africa or the Indian subcontinent. [20]

Researchers investigating the relationship of plasma levels of Lp(a) and other lipid values in patients undergoing coronary arteriography in India found that Lp(a) concentrations were higher in the CAD group compared to the disease-free group. [21] Plasma values of TC, TG, apo A-1, apo B, LDL-C, LDL/HDL-C ratio, and apo A-1/B ratios were not significantly different in the groups with normal coronary arteries and CAD, possibly indicating that measuring Lp(a) provides a better marker for predicting the presence of angiographically defined CAD versus traditional measures. [21]

Lp(a) screening should be considered under these circumstances:

* Patient or family history of premature atherosclerotic heart disease

* Familial history of hyperlipidemia

* Established atherosclerotic heart disease with a normal routine lipid profile

* Hyperlipidemia refractory to therapy

* History of recurrent arterial stenosis. [22]

Oxidized Lp(a) can induce P-selectin expression in cultured human umbilical vein endothelial cells, which may thereby influence the pathogenesis of atherosclerosis. [23] A study investigating the effect of hormone replacement therapy (HRT) on Lp(a) levels in postmenopausal women with CAD showed that HRT induced a significant decrease in Lp(a) levels. [24] Another study examining the correlation of Lp(a) to the extent and severity of CAD and its relation to unstable clinical events found that elevated Lp(a) predisposes to the extent of CAD and total occlusion but not to lesion severity. [25] Patients with increased Lp(a) levels and unstable angina, therefore, are at increased risk of suffering myocardial infarction.


HDL is involved with its major protein constituent apo A-I in reverse cholesterol transport (RCT). The efficiency of RCT depends on the specific ability of apo A-I to promote cellular cholesterol efflux, bind lipids, and activate LCAT . [26] Typically, the HDL molecule contains 50% protein and 50% lipids. About 30% of HDL particle lipids are phospholipids; the remaining 70% is made up of cholesterol. [13] HDL is the smallest of the lipoproteins (9-12 nm) yet has the highest density (1.063-1.21 g/mL) of any lipoprotein due to its high protein content. This lipoprotein can be fractionated further into subfractions known as HDL2 and HDL3. [27] HDL2 is present in premenopausal women at about three times the concentration found in men.

Low HDL2 has been implicated in predisposition to CHD. HDL2 are larger in size and richer in lipids than HDL3, in addition to being more efficient vehicles for transfer of cholesterol from peripheral tissue to the liver. [28] Evidence suggests that a low HDL-C concentration imparts increased risk of CHD. According to NCEP ATP III, therefore, an HDL-C concentration [less than] 40 mg/dL is classified as a major risk factor for CHD, while an HDL-C concentration [greater than]60 mg/dL is protective against CHD. [9] Women generally have higher levels of HDL-C and lower TC than men due to higher estrogen levels. Following menopause, however, this difference disappears due to decreased estrogen. [28]


Five major types of apolipoproteins are outlined below:

Apolipoprotein B. Apo B is the sole protein component of LDL. In addition, apo B-l00 is associated with intermediate-density lipoprotein (IDL), VLDL, and LDL. LDL and IDL particles are directly related to the development of atherosclerosis. Apo B-l00 is possibly the longest single polypeptide chain known, having 4,536 amino acids. [29] Apo B is recognized by the LDL-receptor (LDL-R), which functions in the delivery of cholesterol to peripheral tissues for membrane and or steroid hormone synthesis and to the liver for removal or reuse. [30] Measuring apo B-100 and LDL-C concentrations in serum or plasma may be employed for CHD risk stratification.

Apolipoprotein A-1. Apolipoprotein A-I is the major protein moiety of HDL, determines the plasma concentration of HDL, and protects against atherogenesis. Some authorities believe measurement of apo A-I is a better marker than measurement of HDL-C in CHD risk assessment. A small amount of apo A-I may be associated with "nascent" HDL that is newly secreted from the liver and intestine. It also plays a role in the mobilization of excess cholesterol from cells that cannot metabolize or otherwise dispose of it. The transportation process of HDL and apo A-I is believed to involve both passive and second messenger pathways. [31]

Lipid-poor apolipoproteins remove cellular cholesterol and phospholipids by an active transport pathway controlled by an ATP binding cassette transporter called ABCA1. Mutations in ABCA1 are responsible for Tangier disease, a severe HDL deficiency syndrome characterized by a rapid turnover of plasma apolipoprotein A-I, accumulation of sterol in tissue macrophages, and prevalent atherosclerosis. The implication of this is that lipidation of apolipoprotein A-I by the ABCA1 pathway is necessary for the generation of HDL particles and the clearing of sterol from macrophages. Consequently, the ABCA1 pathway has become an important therapeutic target for mobilizing excess cholesterol from tissue macrophages and protecting against atherosclerosis. [32]

Apolipoprotein E. Apo E promotes the binding of lipoproteins (LDL, VLDL, and apo E-HDL) to the LDL-R and a specific chylomicron remnant receptor. Additionally, apo E 1) is associated with transport of cholesterol ester in plasma and with the redistribution of cholesterol in tissues; 2) is a major protein constituent of TG rich lipoproteins, including chylomicrons, VLDL, and their remnants; and 3) serves as a high-affinity ligand for several hepatic lipoprotein receptors, including LDL-R and LDL receptor-related protein, and for cell surface heparin sulfate proteoglycan (HSPG). By interacting with these receptors, or with HSPG, apo E mediates the clearance of chylomicrons, VLDL, and their remnants from circulation. [33, 34]

Apo E e2 and e4 are believed to be independent risk factors for CAD and predictors for the development of atherosclerosis. [35] Apo E e4 allele is associated with very high levels of LDL-C and TC, while e2 allele is associated with decreased levels of LDL-C and higher TG levels. The ability of Apo E to modulate the risk for AD, CHD, and cerebral atherosclerosis is well established. [36, 37] In addition, Apo E e4 allele has been implicated in the development of AD.

Apolipoproteins D and C. Apolipoprotein D is a 29kDa glycoprotein primarily associated with HDL in human plasma. It is an atypical apolipoprotein and, based on its primary structure, is predicted to be a member of the lipocalin family. The primary activity of apolipoprotein C is to activate lipoprotein lipase (LPL) leading to lipolysis of TG. The three major forms of apo C (i.e., apo C-I, C-II, C-III) vary in amino acid content having 57, 78, and 79 amino acids, respectively. They are synthesized in the liver and associate with VLDL and HDL particles. [27]

Lipid-related diseases

The following section highlights the numerous diseases that can develop as a result of problems involving the lipids:


Hyperlipoproteinemia results from malfunction in the synthesis and/or catabolism of lipoproteins. One classification of hyperlipoproteinemia is based on the appearance of plasma, TC, and TG concentrations. The first comprehensive classification of dyslipoproteinemia, formulated in the mid 1960s and adopted by the World Health Organization (WHO), described hyperlipoproteinemia as plasma phenotypes.

Lipoprotein disorders are classified as primary or secondary. Primary disorders are either genetic or nongenetic, whereas secondary disorders result from poor diet, use of alcohol and/or drugs, or a disease of metabolic, hormonal, infectious, or malignant etiology. [13,38]


Hypertriglyceridemia can have a primary or secondary etiology In primary forms, the origin is essentially genetic, while secondary ones are consequent upon metabolism of various pathologies, including renal, thyroid, and diabetes mellions. [39] Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low HDL-C, and often elevated LDL-C with predominance of small, dense LDL is a strong risk factor for atherosclerosis. [40]

Familial hyperchylomicronemia

Familial hyperchylomicronemia can be divided into type I and V hyperlipoproteinemia. [13] This syndrome is a hereditary disorder of lipoprotein metabolism caused by LPL deficiency, apo-CII deficiency, or LPL inhibition [41], and is characterized by hyperchylomicronemia, hypertriglyceridemia, pancreatitis, and attacks of epigastric pain. Eventually, the presence of eruptive xanthomas leads to necrotizing pancreatitis or pancreatic insufficiency. [42] Preventing hyperchylomicronemia and its sequel requires lifelong adherence to a low-fat diet.

Familial type III hyperlipoproteinemia

Familial type III hyperlipoproteinemia is a rare disorder affecting 1 to 10 in 10,000 people in the general population. [43] Patients with this disorder have premature atherosclerosis in peripheral vessels and coronary arteries, in addition to accumulations of chylomicron remnant and VLDL in the fasting state. Homozygosity for apolipoprotein e2 and accumulation of TG -rich lipoproteins in plasma characterize this disease.

Familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is a complex disorder involving several environmental factors, which interact with multiple genes. Characterized by elevated levels of total serum cholesterol and/or TO, this disorder is believed to be common in Western populations with a prevalence of up to 2%. In addition, 14% of patients with premature CHD have FCHL, which makes this disorder one of the most common genetic dyslipidemias underlying premature CHD. [44] It has been suggested that this disease is an autosomal dominant condition with age-dependent penetrance. To date, however, an underlying defective gene has yet to be elucidated.

Familial defective apolipo protein B-100 and familial hypercholesterolemia

Familial defective apolipoprotein B-100 (FDB) and familial hypercholesterolemia (FH) are common causes of monogenic primary hypercholesterolemia. Both are associated with severe hypercholesterolemia and cannot always be distinguished from one another phenotypically. FDB is the most common known mutation causing primary hypercholesterolemia. [45] More than 150 mutations exist in the LDL-R gene associated with FH, an autosoma1 dominant inherited disorder characterized by severe hypercholesterolernia, frequent presence of tendon xanthomas, and an elevated risk of premature CAD. [46]


Abetalipoproteinemia is a rare disease in which apo B is not synthesized, preventing lipoproteins containing this apolipoprotein from being formed. This results in the accumulation of lipid droplets in the intestine and the liver, due to an inability to produce chylomicrons and VLDL in the intestine and liver, respectively.

Familial hypobetalipoproteinemia

Familial hypobetalipoproteinemia is a co-dominant disorder characterized by reduced plasma levels of LDL-C. This disorder can be caused by mutations in the gene encoding apo B-100, leading to the formation of truncated apo Bs, which have a reduced capacity to export lipids from the hepatocytes as lipoprotein constituents. [47] Isolated deficiency of HDL-C, genetic in presentation, is known as familial hypoalphalipoproteinemia. Hypoalphalipoproteinemia is a common finding in patients with premature CAD (present in about 5% of these patients). Some patients with the disease exhibit decreased HIDL production.

Familial hypoalphalipoproteinemia

Familial hypoalphalipoproteinemia syndromes are phenotypically heterogeneous. One form is associated with abnormal cellular cholesterol efflux caused by heterozygous mutations at the NB CA1 gene that defines familial HDL deficiency. Homozygous mutations/compound heterozygosity, on the other hand, causes Tangier disease, [48] characterized by deficiency of HDL and their major protein constituent apo A-I as well as by the presence of low molecular mass lipoproteins and a high concentration of apo C-HI in the lipoprotein fraction. ABCA1 heterozygotes have decreased HDL-C and increased TG.

Familial hyperalphalipoproteinemia

Familial hyperalphalipoproteinemia is associated with elevated plasma concentrations of HDL-C and possibly with longevity and protection against CHD. Individuals with this condition have elevated plasma levels of HDL-C and apo A-I, possibly due to a selective upregulation of apo A-I production, which might have antiantherogenic properties. Scientists studying the production rate of apo A-I and apo A-II in FHA individuals and control subjects found the production rate of apo A-I to be markedly increased in FHA subjects, while the production rate of apo A-II was not substantially increased in this group. [49] Hyperalphalipoproteinemia due to complete deficiency of cholesteryl ester transfer activity is characterized by the presence of both small polydisperse LDL and markedly large HDL enriched with cholesteryl ester and apo E.

Laboratory testing of lipids

Discussion of specific methodologies that can be employed in the clinical laboratory to support lipid testing follows:


Traditionally, thin-layer chromatography has been used to measure phospholipids. Separation of phospholipids is based on the side chain groups and involves extracting phospholipids into solvent, drying them for concentration, spotting them onto silica gel plates, separating them with a chloroform-methanol-water solvent, and visualizing them through charring and iodination. Spectrophotometric methods can be employed to quantitate phospholipids as well, although inorganic phosphorus is used as an indicator. [50]


Measuring cholesterol involves both the ester and free forms of this steroid. In serum or plasma, two thirds of TC exist in the esterified form; the remainder exists in free form. [13] Greater intensity in the color produced by the cholesterol ester versus the free cholesterol can lead to a significant positive bias. On the other hand, in enzymatic reactions, that hydrolysis of the longer-chain cholesterol esters (e.g., cholesterol arachidonate) is not complete can lead to a negative bias. [13]

Typical cholesterol test methods include modifications of 1) Liebermann-Burchard (used most often); 2) iron-salt-acid; 3)p-toiuene-sulfonic acid; and 4) enzymatic end point. Early analytical methods used strong acids such as sulfuric and acetic acids and chemicals such as acetic anhydride and ferric chloride, which produced a measurable color with cholesterol. A current reference method uses hexane extraction after hydrolysis with alcoholic potassium hydroxide, followed by reaction with Liebermann-Burchard color reagent, which comprises sulfuric and acetic acid as well as acetic anhydride. [28]

Enzymatic methodology for cholesterol employs cholesteryl ester hydrolase, which cleaves the fatty acid residue, thus converting cholesteryl ester to unesterified or free cholesterol. Free cholesterol is reacted by cholesterol oxidase, which produces cholest-4en-3-on and hydrogen peroxide. The hydrogen peroxide produced is a substrate for an enzymatic color reaction, which employs horseradish peroxidase to couple two colorless chemicals into a colored compound. [28] This enzymatic method has been applied to automated procedures, including the dry-chemistry approach.

Use of electrode systems is another approach for quantifying cholesterol. The oxygen selective membrane is used to measure the rate of oxygen consumption when the serum is reacted with a reagent containing cholesterol oxidase. [50]


Measuring TGs and cholesterol is employed to detect genetic and other metabolic problems such as hyperlipoproteinemia. Measuring TGs also is required to estimate LDL cholesterol concentration by the Friedewald equation. [51] Most TG methods employ lipases and proteases to cleave fatty acids from glycerol. The glycerol is converted to glycerol-3-phosphate and adenosine diphosphate (ADP) in the presence of adenosine triphosphate (ATP) and glycerol kinase. ADP is reacted with phosphoenolpyruvate in the presence of pyruvate kinase to ATP and pyruvate. The pyruvate is reacted with nicotinamide adenine dinucleotide (NADH) in the presence of lactate dehydrogenase and converted to lactate and reduced NADH. The absorbance is measured at 340 nm. Other methods use fluorometric measurement in which the disappearance of NADH fluorescence is read at 460 nm after excitation at 355 nm.

Lipo proteins

In general, HDL and LDL are quantified based on their cholesterol content. Lipoproteins may be separated and quantified based on their density, size, charge, and apolipoprotein content. The range of observed densities among lipoprotein classes are a function of their lipid and protein content and allow for fractionation by ultra-centrifugation. Separation by electrophoresis is made possible by differences in charge and size. Antibodies specific for particular apolipoproteins can be used to bind and separate lipoprotein classes. [28]


Apolipoproteins may be measured by immunoassay methods using turbidimetric or nephelometric assays. Other methods that have been used to quantify apolipoproteins include radioimmunoassay (RIA) radioimmunodetection (RID), and enzyme labeled immunosorbent immunoassay (ELISA). [28] Either polyclonal or monoclonal antibodies may be employed in these assays.

Various molecular methods may be used to genotype apolipoprotein E, including genotyping of the apo E locus by isoelectric focusing, restriction digestion of a PCR fragment of the gene, and allele-specific oligonucleotide hybridization. Note: The isoelectric focusing method is long and cumbersome, while earlier restriction digestion methods using the enzyme HhaI produce too many small fragments to permit easy interpretation.

Reducing disease risk

It is well established that atherosclerosis is the cause of CHD and stroke--the number one and number three killers in the U.S., respectively. Lipids, lipoprotein, and apolipoproteins have been implicated in the pathogenesis of atherosclerosis. [52,53] Evidence also suggests that apo E might be implicated in late-onset AD, a significant finding considering that as the baby boomer generation continues to gray, AD cases are likely to increase.

Efforts to reduce the incidence of CHD, stroke, and AD in this country must include frequent checks of patients' cholesterol levels in addition to proactive initiatives to keep these levels under control. Measuring lipid, lipoprotein, and apolipoprotein concentrations to determine patient risk is key to these efforts, as is patient awareness of preventive measures designed to further decrease disease risk.

Drs. Henry O. Ogedegbe and David W. Brown are assistant professors in the Department of Environmental Health, Molecular, and Clinical Sciences, Florida Gulf Coast University, Fort Myers, Fla.


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Author:Ogedegbe, Henry O.; Brown, David W.
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Jul 1, 2001
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