asmi
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Can anybody tell me etilogy,sign and symptoms and treatment for abetalipoproteinemia .
thanks in advance :|
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| Medicine Guy
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Hi i found this for you from harrisons textbook of medicine.
Hope it helps you.
Lipoproteins are macromolecular complexes that carry hydrophobic plasma lipids, particularly cholesterol and triglyceride, in the plasma. More than half of the coronary heart disease (CHD) in the United States is attributable to abnormalities in the levels and metabolism of plasma lipids and lipoproteins. Some premature CHD is due to mutations in major genes involved in lipoprotein metabolism. However, elevated lipoprotein levels in most patients with CHD reflect the adverse impact of a sedentary lifestyle, excess body weight, and diets high in total and saturated fat superimposed on a genetic background that confers susceptibility to increased circulating lipids. A large body of evidence indicates that lifestyle changes and drug treatment strategies that correct hyperlipidemias reduce CHD risk . More than 70 clinical trials examining the effects of cholesterol reduction have been reported, including several large-scale studies using the potent cholesterol-lowering HMG-CoA reductase inhibitors (also known as statins). These studies unequivocally demonstrate that lowering low-density lipoprotein (LDL) cholesterol reduces fatal and nonfatal heart attacks .
This chapter focuses on the major lipid disorders, including both the dyslipoproteinemias caused by single-gene defects and the disorders that are likely to be multifactorial in origin. A practical approach is provided to assist in the identification, evaluation, and treatment of patients with increased risk of CHD.
LIPID AND LIPOPROTEIN TRANSPORT
LIPOPROTEIN STRUCTURE
Lipoproteins are spherical particles made up of hundreds of lipid and protein molecules. They are smaller than red blood cells and visible only by electron microscopy. However, when the larger, triglyceride-rich lipoproteins are present in high concentration, plasma can appear turbid or milky to the naked eye. The major lipids of the lipoproteins are cholesterol, triglycerides, and phospholipids. Triglycerides and the esterified form of cholesterol (cholesteryl esters) are nonpolar lipids that are insoluble in aqueous environments (hydrophobic) and comprise the core of the lipoproteins. Phospholipids and a small quantity of free (unesterified) cholesterol, which are soluble in both lipid and aqueous environments (amphipathic), cover the surface of the particles, where they act as the interface between the plasma and core components. A family of proteins, the apolipoproteins, also occupies the surface of the lipoproteins; the apolipoproteins play crucial roles in the regulation of lipid transport and lipoprotein metabolism.
Lipoproteins have been classified on the basis of their densities into five major classes 1) chylomicrons, (2) very low density lipoproteins (VLDL), (3) intermediate-density lipoproteins (IDL), (4) LDL, and (5) high-density lipoproteins (HDL).
APOLIPOPROTEINS
The apolipoproteins (apos) provide structural stability to the lipoproteins and determine the metabolic fate of the particles upon which they reside.
There are two forms of apo B¾apo B100 and apo B48. Apo B100 is the major apolipoprotein of VLDL, IDL, and LDL, comprising approximately 30, 60, and 95% of the protein in these lipoproteins, respectively. Apo B100 has a molecular mass of about 545 kDa and is synthesized in the liver. It is essential for the assembly and secretion of VLDL from the liver and is the ligand for the removal of LDL by the LDL receptor. The LDL receptor is a cell-surface protein that binds and internalizes lipoproteins that contain apo B100 or apo E. The LDL receptor binding domain of apo B100 is the sequence between amino acids 3200 and 3600, a region that is absent in apo B48.
Apo B48 is essential for the assembly and secretion of chylomicrons. Apo B48 is encoded by the same gene and messenger ribonucleic acid (mRNA) as Apo B100. However, the mRNA is edited in an unusual way: A cytidine deaminase in the intestine changes a cytidine to a uridine in base 6666 of the apo B100 mRNA to produce a stop codon so that apo B48 contains only the N-terminal 48% of the full-length apo B100. In contrast, the apo B100 mRNA in human liver is not edited. The role of apo B48 in the metabolism of chylomicrons in plasma is unclear. Individuals with mutations that interfere with the normal synthesis of apo B have absent or very low levels of chylomicrons, VLDL, IDL and LDL.
The apolipoproteins of the C series are synthesized in the liver and are present in all plasma lipoproteins (trace amounts in LDL). Individual apo Cs have different metabolic roles, but all inhibit the removal of plasma chylomicrons and VLDL remnants by the liver. Overexpression of apo CI in transgenic mice inhibits the uptake of chylomicron and VLDL remnants by the liver. Apo CI under- or overexpression has not been described in humans. Apo CII is an essential activator of the enzyme lipoprotein lipase (LPL), which hydrolyzes triglycerides in chylomicrons and VLDL; individuals lacking apo CII have severe hypertriglyceridemia. Apo CIII inhibits LPL, and apo CIII overexpression in transgenic mice causes severe hypertriglyceridemia. Humans who lack apo CIII have accelerated rates of VLDL triglyceride lipolysis.
Apo E is synthesized mainly in hepatocytes but is also made in other cells, including macrophages, neurons, and glial cells. It is found in chylomicrons, IDL, VLDL, and HDL and mediates the uptake of these lipoproteins in the liver by both the LDL receptor and the LDL receptor-related protein (LRP). Apo E also binds to heparin-like proteoglycan molecules on the surface of all cells. There are three major apo E alleles: E2, E3, and E4; these isoforms differ in sequence at two positions and have frequencies of about 0.12, 0.75, and 0.13, respectively, in the general population. Apo E2 binds to the LDL receptor with lower affinity than apo E3 or E4. Individuals who are homozygous for apo E2 may develop severe hyperlipidemia (type III dysbetalipoproteinemia); complete absence of apo E increases plasma levels of chylomicron and VLDL remnants and causes early atherosclerosis.
Apo AI, apo AII, and apo AIV are found primarily on HDL. Apo AI and apo AII are synthesized in the small intestine and the liver; apo AIV is made only in the intestine. Apo AI comprises about 70 to 80% of the protein of HDL and plays a critical structural role in HDL particles. Individuals with a profound deficiency of apo AI also lack HDL. Apo AI activates the enzyme lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol in plasma. Plasma levels of HDL cholesterol and apo AI are inversely related to risk for CHD, and some patients with apo AI deficiency develop early, severe atherosclerosis. Transgenic mice that overexpress human apo AI are resistant to atherosclerosis. Apo AII is the second most abundant apoprotein in HDL, but its function has not been determined; transgenic mice that overexpress apo AII have high plasma levels of both HDL cholesterol and triglycerides but may be susceptible to atherosclerosis. Apo AII knockout mice have low levels of HDL, indicating that apo AII is also necessary for the integrity of HDL particles. Apo AIV, a minor component of HDL and chylomicrons may play a role in the activation of LCAT.
Apoprotein(a), a large glycoprotein that shares a high degree of sequence homology with plasminogen, is made by hepatocytes and is secreted into plasma where it forms a covalent linkage with the apo B100 of LDL to form lipoprotein(a). The physiologic role of lipoprotein(a) is not known, but elevated levels are associated with an increased risk for atherosclerosis.
ENZYMES INVOLVED IN LIPOPROTEIN METABOLISM
LPL is synthesized in fat and muscle, secreted into the interstitial space, transported across endothelial cells, and bound to proteoglycans on the luminal surfaces in the adjacent capillary beds. LPL mediates the hydrolysis of the triglycerides of chylomicrons and VLDL to generate free fatty acids and glycerol. The free fatty acids diffuse into adjacent tissues to be burned for energy or stored as fat. Most circulating LPL is associated with LDL. Insulin stimulates the synthesis and secretion of LPL; reduced LPL activity in diabetes mellitus can lead to impaired triglyceride clearance. Homozygotes for mutations that impair LPL have severe hypertriglyceridemia that usually manifests in childhood (type I hyperlipidemia). Heterozygotes for LPL defects have mild to moderate fasting hypertriglyceridemia but may have marked hypertriglyceridemia after consuming a high-fat meal. LPL is also expressed in macrophages, including cholesteryl ester-laden macrophages (foam cells) in atherosclerotic lesions. In this setting, secreted LPL may associate with LDL, causing retention of the lipoprotein in the subendothelial space.
Hepatic triglyceride lipase (HTGL), a member of a family of enzymes that includes LPL and pancreatic lipase, is synthesized in the liver and interacts with lipoproteins in hepatic sinusoids. HTGL removes triglycerides from VLDL remnants (IDL), thus promoting the conversion of VLDL to LDL. It may also play a role in the clearance of chylomicron remnants and in the conversion of HDL2 to HDL3 in the liver by hydrolyzing the triglyceride and phospholipid in HDL (see below). Severe hypertriglyceridemia in individuals with genetic deficiency of HTGL is due to the accumulation of chylomicron and VLDL remnants in plasma. In contrast to most patients with hypertriglyceridemia, however, individuals with HTGL deficiency have normal levels of HDL.
LCAT is synthesized in the liver and secreted into plasma where it is bound predominantly to HDL. LCAT mediates the transfer of linoleate from lecithin to free cholesterol on the surface of HDL to form cholesteryl esters that are then transferred to VLDL and eventually LDL. Apo AI is a cofactor for esterification of free cholesterol by LCAT. Deficiency of LCAT can be caused by mutations in the enzyme or in Apo A1. LCAT deficiency causes low levels of cholesteryl esters and HDL, and it can lead to corneal clouding and renal insufficiency.
Cholesteryl ester transfer protein (CETP) is synthesized primarily in the liver and circulates in plasma in association with HDL. CETP mediates the exchange of cholesteryl esters from HDL with triglyceride from chylomicrons or VLDL. This exchange can explain much of the inverse relationship between plasma levels of triglycerides and HDL cholesterol. LDL cholesteryl ester can also be exchanged with triglyceride from chylomicrons and VLDL, leading to the generation of small, dense LDL. Individuals who are homozygotes for mutations in the CETP gene have marked elevations of HDL cholesterol and apo AI. Heterozygotes for these mutations have slight elevations of HDL, indicating that CETP plays an important role in the removal of cholesteryl esters from HDL.
Phospholipid transfer protein (PLTP) is synthesized in the liver and lung. The production of mature HDL particles depends on PLTP, which provides phospholipid to the enlarging particles.
TRANSPORT OF EXOGENOUS (DIETARY) LIPIDS
Exogenous lipid transport in chylomicrons and chylomicron remnants is depicted in Fig. 344-1A. In western societies, where individuals ordinarily consume 50 to 100 g of fat and 0.5 g of cholesterol during three or four meals, transport of dietary fats is essentially continual. Normolipidemic individuals dispose of most dietary fat in the bloodstream within 8 h of the last meal, but some individuals with dyslipidemia, particularly those with elevated fasting levels of VLDL triglyceride, have measurable levels of intestinally derived lipoproteins in the circulation as long as 24 h after the last meal.
In the intestinal mucosa dietary triglyceride and cholesterol are incorporated into the core of nascent chylomicrons. The surface coat of the chylomicron is composed of phospholipid, free cholesterol, apo B48, apo AI, apo AII, and apo AIV. The chylomicron, essentially a fat droplet containing 80 to 95% triglycerides, is secreted into lacteals and transported to the circulation via the thoracic duct. In the plasma, apo C proteins are transferred to the chylomicron from HDL. Apo CII mediates hydrolysis of triglycerides by activating LPL on capillary endothelial cells in fat and muscle. After the triglyceride core has been hydrolyzed, apo CII and apo CIII recirculate back to HDL. The addition of apo E allows the chylomicron remnant to bind first to heparan sulfate proteoglycans within the space of Disse and then to hepatic LDL receptors and/or LDL receptor-related protein. As a consequence, dietary triglyceride is delivered to adipocytes and muscle cells as fatty acids, and dietary cholesterol is taken up by the liver where it can be used for bile acid formation, incorporated into membranes, resecreted as lipoprotein cholesterol back into the circulation, or excreted as cholesterol into bile. Dietary cholesterol also regulates endogenous hepatic cholesterol synthesis.
Abnormal transport and metabolism of chylomicrons may predispose to atherosclerosis, and postprandial hyperlipidemia may be a risk factor for CHD. Chylomicrons and their remnants can be taken up by cells of the vessel wall, including monocyte-derived macrophages that migrate into the vessel wall from plasma. Cholesteryl ester accumulation by these macrophages transforms them into foam cells, the earliest cellular lesion of the atherosclerotic plaque (Chap. 241). If the postprandial levels of chylomicrons or their remnants are elevated, or if their removal from plasma is prolonged, cholesterol delivery to the artery wall may be increased.
TRANSPORT OF ENDOGENOUS LIPIDS
The endogenous lipid transport system, which conveys lipids from the liver to peripheral tissues and from peripheral tissues back to the liver, can be separated into two subsystems: the apo B100 lipoprotein system (VLDL, IDL, and LDL) and the apo AI lipoprotein system (HDL).
The Apo B100 Lipoprotein System. In the liver, triglycerides are made from fatty acids that are either taken up from plasma or synthesized de novo within the liver. Cholesterol can also be synthesized by the liver or delivered to the liver via lipoproteins, particularly chylomicron remnants. These core lipids are packaged together with apo B100 and phospholipids into VLDL and secreted into plasma where apos CI, CII, CIII, and E are added to the nascent VLDL particles. Triglycerides make up the bulk of the VLDL (55 to 80% by weight), and the size of the VLDL is determined by the amount of triglyceride available. Hence, very large triglyceride-rich VLDL are secreted in situations where excess triglycerides are synthesized, such as in states of caloric excess, in diabetes mellitus, and after alcohol consumption. Small VLDL are secreted when fewer triglycerides are available. Although VLDL are the principal hepatic lipoprotein secreted by most individuals, VLDL and cholesteryl ester-enriched IDL and/or LDL-like particles may be secreted by the liver in individuals with combined hyperlipidemia (see below).
In the plasma, triglycerides are hydrolyzed by LPL and VLDL particles are converted to VLDL remnants (IDL). In contrast to chylomicron remnants, VLDL remnants can either enter the liver or give rise to LDL. Larger VLDL particles carry more triglycerides and are likely to be removed directly from plasma without being converted to LDL; apo E in the VLDL remnants binds to the LDL receptor to mediate removal from the plasma. Smaller, more dense VLDL particles are more efficiently converted to LDL; apo E and HTGL play important roles in this process. Individuals with deficiency of either apo E2 or HTGL accumulate IDL in plasma. Apo B100 is the only protein that remains on the surface of the LDL particle.
The half-life of LDL in plasma is determined principally by the availability (or "activity") of LDL receptors. Most plasma LDL is taken up by the liver, and the remainder is delivered to peripheral tissues, including the adrenals and gonads, which utilize cholesterol as a precursor for steroid hormone synthesis. The adrenals have the highest concentration of LDL receptors per cell in the body. Overall, about 70 to 80% of LDL catabolism occurs via LDL receptors, and the remainder is removed by fluid endocytosis and possibly by other receptors.
The LDL receptor, a glycoprotein with a molecular mass of approximately 160 kDa, is present on the surfaces of nearly all cells in the body. Goldstein and Brown characterized the molecular genetics and cell biology of the LDL receptor and defined its role in cholesterol metabolism. They showed that cholesterol delivered to the cytoplasm by LDL regulates both the rate of cholesterol synthesis in the liver and the number of LDL receptors on the surface of hepatocytes. LDL receptor synthesis is mediated by sterol response element regulatory proteins (SREBPs). These transcription factors are activated in the absence of cholesterol, proteolytically cleaved, and transferred from the endoplasmic reticulum into the nucleus where they stimulate LDL receptor gene expression. Though the LDL receptor is a major factor in determining plasma LDL cholesterol levels, the rates of entry of VLDL into plasma and the efficiency with which VLDL is converted to LDL also influence steady-state LDL concentrations in plasma.
Increased levels of plasma LDL cholesterol and apo B100 are risk factors for atherosclerosis. Normal LDL does not cause foam cell formation when incubated with cultured macrophages or smooth-muscle cells. But, when LDL undergoes lipid peroxidation, it becomes a ligand for alternative, scavenger receptors that are present on endothelial cells and macrophages. Uptake of modified (oxidized) lipoproteins by these receptors in macrophages results in formation of cholesterol-laden foam cells. In addition to inducing foam cell formation, oxidized LDL acts in the vessel wall to stimulate the secretion of cytokines and growth factors by endothelial cells, smooth-muscle cells, and monocyte-derived macrophages . The consequence is recruitment of more monocytes to the lesion and proliferation of smooth-muscle cells, which synthesize and secrete increased amounts of extracellular matrix, such as collagen. The critical role of LDL in atherosclerosis has been confirmed in genetically altered mice. Although mice are normally resistant to atherosclerosis, increased plasma levels of remnant lipoproteins or LDL lead to atherosclerosis in this species.
The role of VLDL in atherogenesis is less certain. The major reason for this uncertainty derives from the inverse relationship between elevated levels of triglyceride-rich lipoproteins and reduced levels of the antiatherogenic HDL cholesterol. It is possible, for example, that hypertriglyceridemia may not be directly atherogenic but rather the surrogate of other lipoprotein abnormalities. If postprandial hyperlipidemia is a risk factor for CHD, individuals who have normal fasting plasma triglyceride levels but develop postprandial hypertriglyceridemia after consumption of a fat load would be misclassified as "normal" in studies in which only fasting blood samples are analyzed. It is clear that cholesteryl ester-enriched VLDL, isolated from cholesterol-fed animals, can be taken up by receptors on macrophages and smooth-muscle cells and cause foam cell formation. These cholesteryl ester-laden VLDLs are enriched in apo E and are probably representative of VLDL remnants. Thus, the risk of atherosclerosis from hypertriglyceridemia and elevated VLDL levels may be determined by the level of cholesteryl ester-enriched VLDL remnants. The atherogenic potential of IDL is probably similar to that of VLDL remnants.
Apo AI-Containing Lipoproteins. In contrast to atherogenic apo B lipoproteins, the apo AI-containing HDL appear to be antiatherogenic. In fact, in some studies, HDL cholesterol levels are as strong an indicator of protection from CHD as LDL cholesterol levels are an indicator of risk. Although a great deal is known about the HDL transport system, the mechanism by which these lipoproteins protect against atherosclerosis is poorly defined.
HDL particles are formed in plasma from the coalescence of individual phospholipid-apolipoprotein complexes. Apo AI appears to be the crucial, structural apoprotein for HDL, and apo AI/phospholipid complexes probably fuse with other phospholipid vesicles that contain apo AII and apo AIV to form the various types of HDL. The C apoproteins can be added to HDL after their secretion as phospholipid complexes or by their transfer from triglyceride-rich lipoproteins. This may involve the action of PLTP. These small, cholesterol-poor HDL particles are heterogeneous in size and content and are referred to as HDL3. Free cholesterol is transferred from cell membranes to HDL3; a cholesterol transporter called ABC1 mediates this important first step in reverse cholesterol transport. Free cholesterol in HDL3 is converted to cholesteryl ester by LCAT, and the cholesteryl ester moves into the core of the HDL. Formation of cholesteryl ester increases the capacity of the HDL3 to accept more free cholesterol and enlarge to form the more buoyant class of HDL particles termed HDL2. HDL2 can be metabolized by two pathways: (1) cholesteryl esters can be transferred from HDL2 to apo B lipoproteins or cells, or (2) the entire HDL2 particle can be removed from plasma. The transfer of cholesteryl ester from HDL to triglyceride-rich apo B lipoproteins (chylomicrons and VLDL in the fed and fasted states, respectively) is mediated by CETP. Triglyceride is transferred to HDL in this process and is a substrate for lipolysis by LPL and/or HTGL. As a result, HDL2 is converted back into HDL3. When the apo B lipoproteins are removed by the liver, reverse cholesterol transfer is complete. HDL cholesteryl ester may also be transferred selectively to cells via interaction of HDL with the scavenger receptor B-1, a receptor expressed by hepatocytes and steroid-producing cells. HDL-mediated reverse cholesterol transport (from peripheral tissues to the liver) is thought to be the primary mechanism by which HDL protects against atherosclerosis.
Rarely, low plasma HDL is due to a genetic deficiency of one of the structural components of HDL (such as apo AI). However, low HDL cholesterol levels are usually the secondary consequence of increased plasma levels of VLDL and IDL (or chylomicrons and their remnants). Mutations in the ABC1 gene (see above) are associated with Tangier's disease, a rare form of low HDL. Low levels of HDL cholesterol and apo AI may increase atherosclerosis risk by any of several mechanisms. HDL could remove cholesterol from foam cells in atherosclerotic lesions or protect LDL from oxidative modification. Alternatively, the atherosclerotic risk of low HDL may be due to the commonly associated elevations of apo B-containing lipoproteins, which accept HDL cholesteryl esters and deliver cholesteryl esters to the vessel wall.
THE HYPERLIPOPROTEINEMIAS
HYPERCHOLESTEROLEMIA
Elevated levels of fasting plasma total cholesterol in the presence of normal levels of triglycerides are almost always associated with increased concentrations of plasma LDL cholesterol (type IIa), as LDL carries about 65 to 75% of total plasma cholesterol. A rare individual with markedly elevated HDL cholesterol may also have increased plasma total cholesterol levels. Elevations of LDL cholesterol can result from single-gene defects, polygenic disorders, or from the secondary effects of other disease states.
Familial Hypercholesterolemia (FH) FH is a codominant genetic disorder that occurs in the heterozygous form in approximately 1 in 500 individuals. FH is due to mutations in the gene for the LDL receptor and is genetically heterogeneous, >200 different mutations in the gene having been described. Plasma levels of LDL cholesterol are elevated at birth and remain so throughout life. In untreated adults, total cholesterol levels range from 7 to 13 mmol/L (275 to 500 mg/dL). Plasma triglyceride levels are typically normal, and HDL cholesterol levels are normal or reduced. As would be expected of a disorder with decreased numbers of LDL receptors, the fractional clearance of LDL apo B is reduced. LDL production is increased because the liver secretes more VLDL and IDL and more IDL particles are converted to LDL rather than taken up by the hepatic LDL receptors. FH heterozygotes usually develop severe atherosclerosis in early or middle age. Tendon xanthomas, which are due to both intracellular and extracellular deposits of cholesterol, most commonly involve the Achilles tendons and the extensor tendons of the knuckles; they are found in about 75% of adults with FH (Fig. 344-CD1). Tuberous xanthomas, which are softer, painless nodules on the elbows and buttocks, and xanthelasmas, which are barely elevated deposits of cholesterol on the eyelids, are common in heterozygous FH (Figs. 344-CD2 and 344-CD3). CHD develops in men by the fourth decade of life or earlier.
The homozygous form of FH occurs in 1 out of 1 million individuals and is associated with a marked increase of plasma cholesterol levels (>13 mmol/L; >500 mg/dL), large xanthelesmas, and prominent tendon and planar xanthomas. These individuals have severe, premature CHD that can be manifested in childhood.
Familial Defective Apo B100 This autosomal dominant disorder is a phenocopy of FH and is due to a missense mutation at amino acid 3500 that reduces the affinity of LDL for the LDL receptor and, thus, impairs LDL catabolism. The prevalence and manifestations of both the heterozygous and homozygous forms are similar to those produced by mutations of the LDL receptor.
Polygenic Hypercholesterolemia Most moderate hypercholesterolemia [plasma cholesterol levels between 6.5 and 9 mmol/L (240 and 350 mg/dL)] is polygenic in origin. Multiple genes interact with environmental factors to contribute to the hypercholesterolemia, and both overproduction and reduced catabolism of LDL are thought to play roles in the pathophysiology. The severity is probably affected by the consumption of saturated fat and cholesterol, age, and the level of physical activity. Plasma triglyceride and HDL cholesterol levels are usually normal. These individuals are at increased risk of atherosclerosis. Tendon xanthomas are not present. Genes involved in cholesterol and bile acid metabolism may be involved in the pathogenesis.
HYPERTRIGLYCERIDEMIA
The diagnosis of hypertriglyceridemia is made by determining plasma lipids after an overnight fast. Because of the less certain association of triglycerides with CHD (compared to LDL cholesterol), plasma concentrations greater than the 90th or 95th percentile for age and sex have been used to define hypertriglyceridemia. Some studies show, however, that plasma triglyceride levels >130 to 150 mg/dL are associated with low HDL cholesterol levels and small, dense LDL particles. Furthermore, a meta-analysis of several prospective population studies confirms that triglyceride concentrations are independent predictors of CHD risk. Isolated elevations of plasma triglycerides can be due to increased levels of VLDL (type IV) or combinations of VLDL and chylomicrons (type V). Rarely, only chylomicron levels are elevated (type I). Plasma is usually clear when triglyceride levels are <4.5 mmol/L (<400 mg/dL) and cloudy when levels are higher and VLDL (and/or chylomicron) particles become large enough to scatter light. When chylomicrons are present, a creamy layer floats to the top of plasma after refrigeration for several hours. Tendon xanthomas and xanthelasmas do not occur with isolated hypertriglyceridemia, but eruptive xanthomas (small orange-red papules) (Fig. 344-CD4) can appear on the trunk and extremities when triglyceride levels are >11.5 mmol/L (>1000 mg/dL) (i.e., when chylomicronemia is present). At these high levels of triglycerides, the retinal vessels can appear to be orange-yellow in color (lipemia retinalis). Pancreatitis is the major risk associated with plasma triglyceride concentrations >11 mmol/L (>1000 mg/dL).
Elevations in plasma triglycerides are usually associated with increased synthesis and secretion of VLDL triglycerides by the liver. Hepatic triglyceride synthesis is regulated by substrate flow (the availability of free fatty acids), energy balance (the level of glycogen stores in the liver), and hormonal status (the balance between insulin and glucagon). Obesity, excessive consumption of simple sugars and saturated fats, inactivity, alcohol consumption, and insulin resistance are commonly associated with hypertriglyceridemia. In most of these situations, increased free fatty acid flux from adipose tissue to the liver stimulates the assembly and secretion of VLDL. When VLDL triglyceride levels are markedly elevated [>11.5 mmol/L (>1000 mg/dL)], LPL may be saturated so that an acquired LPL deficiency develops during the postprandial period even if there is no underlying genetic disorder. The addition of chylomicrons to the circulation may cause dramatic increases in plasma triglycerides.
Familial Hypertriglyceridemia Familial hypertriglyceridemia appears to be transmitted as an autosomal dominant disorder, though the underlying mutation(s) have not been identified. The pathophysiology is complex: both reduced catabolism of triglyceride-rich lipoproteins and overproduction of VLDL have been reported. Elevated levels of fasting plasma triglycerides in the range of 2.3 to 8.5 mmol/L (200 to 750 mg/dL) are usually associated with increased levels of VLDL triglycerides only. When VLDL triglyceride levels are markedly elevated (regardless of etiology), chylomicron triglycerides can also be present, even after a 14-h fast. A 20-year follow-up of individuals with familial hypertriglyceridemia demonstrated a moderate increase in CHD risk.
Familial Lipoprotein Lipase Deficiency This autosomal recessive disorder is due to the severe impairment or absence of LPL, leading to massive accumulation of chylomicrons in plasma. Manifestations begin in infancy and include pancreatitis, eruptive xanthomas, hepatomegaly, splenomegaly, foam cell infiltration of the bone marrow, and, when the level of triglycerides is >11 mmol/L (1000 mg/dL), lipemia retinalis. Atherosclerosis is not accelerated. The diagnosis is suspected by finding a creamy layer (chylomicrons) at the top of plasma that has incubated overnight at 4°C; it is confirmed by demonstrating that LPL levels in plasma do not increase after the administration of heparin (which normally releases LPL from endothelial surfaces). Manifestations recede dramatically when patients are placed on fat-free diets.
LPL levels are within the normal range in most patients with moderate hypertriglyceridemia [2.8 to 5.6 mmol/L (250 to 500 mg/dL)]. Heterozygous mutations in the LPL gene are present in 5 to 10% of hypertriglyceridemic individuals; LPL activity may be reduced by 20 to 50% in these individuals. Heterozygotes for LPL deficiency may also present with severe hypertriglyceridemia if they have poorly controlled diabetes, are pregnant, consume excessive quantities of alcohol, take exogenous estrogen, or are obese.
Familial Apoprotein CII Deficiency This rare autosomal recessive disorder causes a functional deficiency of LPL and clinical manifestations similar to those of familial LPL deficiency. Deficiency of apoprotein CII impairs hydrolysis of chylomicrons and VLDL so that either, or both, lipoproteins accumulate in blood. The diagnosis is suspected in children or adults with recurrent attacks of pancreatitis and confirmed by demonstrating the absence of apo CII on gel electrophoresis and that plasma transfusion (which contains abundant apo CII) causes a dramatic fall in plasma triglycerides. Heterozygotes have half-normal levels of apo CII, may have mild elevations of triglycerides, and are asymptomatic. Dietary fat restriction should be life-long.
Hepatic Lipase Deficiency Total deficiency of HTGL is a rare autosomal recessive disorder that impairs the final catabolism and/or remodeling of small VLDL and IDL. Subjects with HTGL deficiency often have elevated levels of VLDL remnants; HDL2 levels may be elevated because HTGL participates in the conversion of HDL2 to HDL3. HTGL activity is frequently increased in hypertriglyceridemic individuals, but the meaning of this association is unclear.
HYPERCHOLESTEROLEMIA WITH HYPERTRIGLYCERIDEMIA
Concomitant hypercholesterolemia and hypertriglyceridemia occurs in two disorders¾familial combined hyperlipidemia (FCHL) and dysbetalipoproteinemia.
Familial Combined Hyperlipidemia FCHL is transmitted as an autosomal dominant disorder. Probands (the initial case discovered within a family) typically have combined hyperlipidemia, isolated hypertriglyceridemia, or isolated elevated levels of LDL cholesterol. The diagnosis requires documentation at some time of combined hyperlipidemia in the proband or, if the proband has isolated hypercholesterolemia or hypertriglyceridemia, the various lipid phenotypes in first-degree relatives at risk. The lipoprotein phenotype in affected individuals may change over time. The underlying defect in this disorder is not known, though mutations or polymorphisms in the LPL gene and in the gene cluster for apo AI, apo CIII, and apo AIV may contribute to the disorder in some families. Insulin resistance is present in many individuals with FCHL; the link may result from increased free fatty acid flux driving assembly and secretion of apo B100 lipoproteins.
FCHL is associated with increased secretion of VLDL particles, as determined by the flux of VLDL apo B. The lipoprotein patterns associated with the disorder are most likely determined by genetic polymorphisms in genes that regulate the metabolism of VLDL. For example, if the affected individual also has a defect in LPL, hypertriglyceridemia will be present. Since the hydrolysis of VLDL triglycerides also regulates the generation of LDL in plasma, individuals with FCHL who have inefficient catabolism of VLDL may also have reduced levels of LDL cholesterol and high VLDL cholesterol. Finally, individuals with FCHL who synthesize normal quantities of triglycerides and secrete VLDL that carries normal amounts of triglyceride generate increased numbers of LDL particles and present with isolated elevations of plasma LDL cholesterol. These variations in VLDL catabolism, together with additional genetic heterogeneity and environmental variability, form the basis for the variable phenotype in this disorder. FCHL may occur in as many as 0.5 to 1.0% of Americans and is the most common familial lipid disorder in survivors of myocardial infarction. The increased risk for atherosclerosis is due to the presence of increased numbers of small, atherogenic VLDLs and the conversion of VLDL to the more atherogenic IDL and LDL. Persons with FCHL usually have clear plasma and do not have xanthomas or xanthelasma.
Dysbetalipoproteinemia This rare disorder affects 1 in 10,000 persons and is due to homozygosity for apo E2, the binding-defective form of apo E. Because apo E plays a crucial role in the catabolism of chylomicron and VLDL remnants, affected individuals have elevations in both VLDL triglyceride and VLDL cholesterol, and chylomicron remnants are present in fasting plasma. The ratio of total cholesterol to triglyceride approximates 1.0, and the ratio of VLDL cholesterol to triglyceride is greater than 0.25. LDL and HDL cholesterol levels are usually low. Although 1% of the population is homozygous for apo E2, most have normal plasma triglyceride and cholesterol levels. Thus, a second defect in lipid metabolism must be present in the 0.01% of individuals with dysbetalipoproteinemia. These individuals may have tuberous xanthomas and deposits of cholesterol in the palmar creases (striae palmaris); the latter, appearing as yellow-orange lines, are specific for dysbetalipoproteinemia. The risk for atherosclerosis and its complications is increased, with onset in the fourth and fifth decades. The incidence of peripheral vascular disease is higher than in FH.
REDUCED HDL CHOLESTEROL
Low levels of HDL cholesterol can be defined as <0.9 mmol/L (<35 mg/dL) in men and <1 to 1.2 mmol/L (<40 to 45 mg/dL) in women. Low concentrations of HDL cholesterol are usually associated with coexistent hypertriglyceridemia, though "primary hypoalphalipoproteinemia" has been identified in both individuals and families. The relationship between hypertriglyceridemia and low HDL levels probably derives from: (1) CETP-mediated transfer of cholesteryl ester from the core of HDL to VLDL; (2) shift of surface components, particularly phospholipids apo CII, and apo CIII, from HDL to VLDL; and (3) increased fractional catabolism of the cholesteryl ester-poor apoAI that results from the first two processes. The complexity of the relationship between HDL and triglyceride levels is highlighted by the fact that HDL levels do not return to normal when fasting plasma triglycerides are reduced in most persons with hypertriglyceridemia and low HDL cholesterol levels. Low HDL is clinically silent, and the plasma is usually clear (it can be cloudy or creamy if there is concomitant hypertriglyceridemia).
Primary hypoalphalipoproteinemia refers to the state where HDL cholesterol concentrations are markedly reduced but plasma triglyceride concentrations are normal. Many individuals with this phenotype have had hypertriglyceridemia in the past or have an older (or more obese) first-degree relative who has both low HDL and increased triglyceride levels. Hence, both family studies and long-term follow-up may be required to identify individuals with primary reductions in HDL cholesterol. Rare mutations have been described in the apo AI gene that lead to reductions in apo AI synthesis or increases in catabolism. One mutation that is common in Italy, apo AI-Milano, is associated with a high fractional clearance rate of apo AI but is not associated with increased risk for atherosclerosis.
SECONDARY CAUSES OF HYPERLIPOPROTEINEMIA
Diabetes Mellitus Diabetes can affect lipid and lipoprotein metabolism through several mechanisms. In type 1 diabetes mellitus (DM) (formerly called insulin-dependent diabetes mellitus), plasma lipids are usually normal when control of diabetes with insulin is adequate. In diabetic ketoacidosis, hypertriglyceridemia can be severe due to increases in both VLDL and chylomicrons. These abnormalities are associated with overproduction of VLDL and LPL deficiency secondary to insulinopenia. They usually improve with tight control of the diabetes. In type 2 DM (formerly called non-insulin-dependent diabetes mellitus), insulin resistance and obesity combine to cause mild to moderate hypertriglyceridemia and low HDL cholesterol levels. In general, this pattern of dyslipidemia is due to overproduction of VLDL. LDL cholesterol is usually normal in type 2 DM, though the LDLs are small, dense, and perhaps more atherogenic. Treatment of type 2 DM and weight reduction improve, but usually do not completely correct, the dyslipidemia (particularly the low HDL cholesterol levels). Therapy of hyperlipidemia should not be delayed in patients with type 2 DM, as they are at increased risk for CHD. It is recommended that patients with diabetes should be treated as if they already have CHD, i.e., the treatment goal is to reduce their LDL to <2.6 mmol/L (<100 mg/dL) .
Hypothyroidism Hypothyroidism accounts for about 2% of all cases of hyperlipidemia and is second only to DM as a cause of secondary hyperlipidemia. Levels of LDL cholesterol can be elevated, even in patients with subclinical disease in whom thyroid-stimulating hormone (TSH) levels are elevated but other thyroid function tests are normal. Hypertriglyceridemia can occur if obesity is present. Hypothyroidism is also associated with increased levels of HDL cholesterol, probably because of reduced HTGL activity. Correction of hypothyroidism reverses the lipid abnormalities.
Renal Disease Renal disease causes a wide range of lipid abnormalities. The nephrotic syndrome can be accompanied by elevations in LDL, VLDL, or both. The severity of the hyperlipidemia correlates with the degree of hypoproteinemia. Renal failure is associated with hypertriglyceridemia and low HDL cholesterol concentrations.
Ethanol The metabolism of ethanol enhances the level of NADH in the liver which, in turn, stimulates the synthesis of fatty acids and their incorporation into triglycerides. Moderate ethanol consumption raises plasma VLDL levels, with the degree of elevation dependent on the baseline level. Severe hypertriglyceridemia and pancreatitis usually develop on the background of a genetic hyperlipidemia and heavy alcohol intake. Because ethanol also stimulates the synthesis of apo AI and inhibits CETP, ethanol-associated hypertriglyceridemia is usually accompanied by normal or elevated levels of HDL cholesterol.
Liver Disease Primary biliary cirrhosis and extrahepatic biliary obstruction can cause hypercholesterolemia and elevated levels of plasma phospholipids associated with increased levels of an abnormal lipoprotein (lipoprotein X; Chap. 299) and LDL. Severe liver injury often leads to a decrease in levels of both cholesterol and triglyceride. Acute hepatitis can cause elevated levels of VLDL and impairment of LCAT formation.
AIDS Use of protease inhibitor therapies has been associated with a generalized metabolic syndrome that includes hypertriglyceridemia, alterations in fat distribution, and occasionally type 2 DM .
DIAGNOSIS
Although the initial indication of an abnormality in lipoprotein metabolism is via blood measurements of triglyceride and cholesterol, the disorders are due to abnormalities of specific lipoproteins. Thus, lipoprotein analysis should assess VLDL, LDL, and HDL levels. Direct measurements of plasma LDL require laborious centrifugation techniques. However, LDL cholesterol concentrations can be estimated indirectly in individuals with triglyceride levels <4.5 mmol/L (<400 mg/dL) by subtracting the HDL and VLDL cholesterol from the total plasma cholesterol. HDL cholesterol is determined after chemical precipitation of VLDL and LDL. VLDL cholesterol is estimated to be the plasma triglyceride level divided by five. Therefore
^
where all values are measured in milligrams per deciliter.
In persons with triglyceride levels >4.5 mmol/L (>400 mg/dL), the ratio of triglyceride to cholesterol in VLDL is >5, and this equation cannot be used to calculate the plasma LDL cholesterol level. The other disorder that is not detected with this method is dysbetalipoproteinemia because the ratio of triglyceride to cholesterol in the VLDL is <<5. In these two situations, direct measurement of LDL cholesterol must be performed in ultracentrifuged plasma. Commercial methods for the measurement of "direct LDL" are available. Although these methods appear to be precise and accurate, the measured values for LDL cholesterol are 0.06 to 0.17 mmol/L (5 to 15 mg/dL) less than estimated LDL because the estimated value is actually the combination of IDL and LDL. If a "direct LDL" measurement is used, the National Cholesterol Education Program (NCEP) guidelines (based on estimated LDL) must be adjusted before therapeutic decisions are made.
Because plasma triglyceride levels rise and both HDL and LDL cholesterol levels fall modestly after a fat-containing meal (due to the action of CETP), it is preferable to measure plasma lipids after a 12-h fast. Measuring cholesterol levels alone will not detect individuals with isolated low HDL; screening for CHD should therefore include measurement of HDL. Because serum lipid levels vary from day to day, at least two to three measurements should be made days or weeks apart before initiating therapy. Some experts advocate the use of total cholesterol/HDL ratios as a better assessment of individual risk. This is a reasonable approach provided both the patient and physician are aware that the treatment goal is to reduce LDL. In addition, rare patients with very high or very low levels of both LDL and HDL have ratios that are not interpretable on the basis of population studies. Although some laboratories offer measurements of individual apoproteins (e.g., apo B100 and apo AI), or size estimates of LDL, this information is not generally helpful in decision-making. Measurement of lipoprotein (a) levels can provide an indication of risk that cannot be gleaned from lipid measurements. Lipoprotein electrophoresis is not useful except for the diagnosis of dysbetalipoproteinemia, a diagnosis that otherwise requires ultracentrifugation methods. Apo E genotyping is also helpful in the diagnosis of dysbetalipoproteinemia (although rarely the disorder can be due to other defects in the apo E gene).
Both LDL and HDL cholesterol levels are temporarily decreased for several weeks after myocardial infarction or acute inflammatory states but can be accurately measured if blood is obtained within 8 h of the event.
^Approach to the Patient
Elevated LDL Cholesterol Treatment of elevated LDL cholesterol can have either of two aims¾primary prevention of the complications of atherosclerosis or secondary treatment after complications have occurred. The rationale for primary prevention is based on the large body of data linking elevated levels of LDL cholesterol with increased CHD risk and an impressive body of clinical and experimental data demonstrating that reducing LDL cholesterol slows progression and may actually induce regression of atherosclerotic lesions. Both primary and secondary intervention trials indicate that total mortality can be reduced when the LDL cholesterol is lowered. A meta-analysis of four randomized trials (4S, CARE, AFCAPS/TexCAPS, LIPID) comparing HMG-CoA reductase inhibitors to control included 30,817 participants and found that HMG-CoA reductase inhibitor treatment was associated with: (1) a 20% decrease in total cholesterol, a 28% decrease in LDL cholesterol, a 13% decrease in triglycerides, and a 5% increase in HDL cholesterol; (2) a 31% decrease in major coronary events and a 21% decrease in all-cause mortality; (3) similar risk reduction in women and men; and (4) no effect on noncardiovascular mortality. Unexpectedly, the risk of stroke was also reduced 19 to 32% by HMG-CoA reductase inhibitor treatment, even though previous observational studies show a relatively weak association between cholesterol level and stroke risk.
Dietary Alterations A fundamental starting point for both primary prevention and secondary treatment involves counseling to modify diet, exercise, smoking, and other life-style factors that increase the risk of CHD. The typical American diet derives about 35% of its calories from fat (14 to 15% from saturated fat) and contains 400 to 500 mg/d of cholesterol. Individuals with hyperlipidemia should be encouraged to eat a diet lower in cholesterol and saturated fat. The NCEP Step 1 diet, which is recommended for all Americans above age 2, provides 30% of calories from fat, <10% of calories from saturated fat, and <300 mg/d of cholesterol (Table 344-7). Carbohydrate is the typical nutrient used to replace fat in patients with isolated hypercholesterolemia. In general, whole-milk dairy products, egg yolks, meats, palm oil, and coconut oil should be replaced with fresh fruits and vegetables, complex carbohydrates (especially whole-grain products), and low-fat dairy products. Shellfish are low in fat content and, except for shrimp, also have low cholesterol levels; shrimp, in moderation, is acceptable. Portion size needs to be stressed; the protein and fat-rich portion of meat in a given meal should be <115 g (4 oz), the size of a deck of cards. Substitutions with any food low in saturated fat such as bran, nuts, and olive oil will have positive effects on LDL. Hydrogenation of vegetable oils increases the saturation of the fatty acids. In particular, trans-fatty acids, mainly found in commercially hydrogenated vegetable oils, raise LDL and can lower HDL cholesterol levels. Use of stanol-containing margarines has, by contrast, lowered LDL cholesterol about 5 to 10% by blocking cholesterol absorption in the small intestine. When further diet therapy is indicated, the NCEP Step 2 diet provides 30% of calories as fat but <7% of calories from saturated fat, and <200 mg/d of cholesterol. After changing from the average American diet to the Step 1 diet, the LDL cholesterol usually drops 8 to 10%; an additional reduction of 5 to 7% can be achieved by advancing to the Step 2 diet. There is, however, great individual variability in diet responsiveness, and several values should be obtained before judging the efficacy of any diet treatment.
Primary Prevention The NCEP Adult Treatment Panel recommends measuring plasma cholesterol in all adults older than age 20 at least every 5 years. Ideally, this testing involves a lipoprotein profile to allow better risk stratification. Primary prevention goals include LDL cholesterol <3.36 mmol/L (<130 mg/dL), triglycerides <1.7 mmol/L (<150 mg/dL), and HDL cholesterol >1.03 mmol/L (>40 mg/dL) for men and >1.29 mmol/L (>50 mg/dL) for women. In individuals without DM or known CHD, treatment recommendations for primary prevention are outlined in Fig. 344-2. Assessment of risk factors in addition to LDL cholesterol is an essential part of this decision-making process. Risk factors include: (1) family history of premature CHD (<55 years in a male parent or sibling or <65 in female relatives), (2) hypertension (even if it is controlled with medications), (3) cigarette smoking (>10 cigarettes per day), (4) DM, and (5) low HDL [<0.9 mmol/L (<35 mg/dL)]. In addition, because CHD is more prevalent in older individuals, age (men >45 years, women >55 years, or younger women with premature menopause without estrogen replacement) is also an important risk factor. HDL cholesterol >1.6 mmol/L (>60 mg/dL) is a negative risk factor, i.e., one other risk factor can be negated by a high HDL cholesterol level.
In individuals with fewer than two risk factors, life-style modifications alone and follow-up testing may be used if LDL is <4.14 mmol/L (<160 mg/dL). For those with LDL >4.91 mmol/L (>190 mg/dL), drug treatment is indicated. If two or more risk factors are present, drug treatment in addition to life-style modifications should be instituted if LDL cholesterol is >3.36 mmol/L (>130 mg/dL). HMG-CoA reductase inhibitors are first-line medications for most patients; niacin and resins are second-line treatments (see below).
Secondary Prevention The NCEP guidelines are stringent for the secondary treatment of patients with CHD. Patients with CHD should be screened for lipid abnormalities during and after their initial diagnoses. A goal of lowering plasma LDL concentrations to <2.6 mmol/L (<100 mg/dL) is advocated for such individuals as well as for patients with DM (Fig. 344-2). As described below, this requires modifications of diet in addition to the use of one or more medications.
If a patient with CHD has only a modestly elevated LDL cholesterol level [e.g., <3.36 mol/L (<130 mg/dL)], a 4- to 6-week period of Step 1 diet therapy can precede the addition of drugs. In such a patient, moving to the Step 2 diet, which provides the same total fat but <7% of calories from saturated fat, can be useful. If, however, the LDL cholesterol is >3.36 mmol/L (>130 mg/dL), drug therapy should be instituted along with diet therapy (Fig. 344-2).
High Triglycerides and Low HDL The evidence that treatment to reduce plasma triglyceride levels or increase levels of HDL cholesterol leads to long-term health benefits is less compelling than that for treatment of high LDL levels. Two recent clinical trials have shown, however, that lowering triglycerides (using fibric acids) or lowering LDL (HMG-CoA reductase inhibitors) decreases CHD events in these patients. There have been no intervention trials in which only increases in HDL cholesterol concentrations have been achieved. Beneficial effects of niacin have been attributed, in part, to its HDL-raising effect and its action to reduce triglycerides and LDL. Even with drugs that primarily affect LDL cholesterol levels, such as bile acid-binding resins and HMG-CoA reductase inhibitors, some of the benefits achieved may be related to increases in HDL cholesterol levels.
In patients with isolated elevations of triglyceride levels or with hypertriglyceridemia and high LDL cholesterol, life-style modifications should be introduced as described above, and weight reduction should be strongly encouraged if obesity is present. Fat intake should be decreased, but the concomitant increase in carbohydrate intake may raise triglyceride and lower HDL cholesterol levels. If this occurs, replacing some of the saturated fat with monounsaturated fat, which will not raise LDL cholesterol, may be valuable. Severe hypertriglyceridemia and hyperchylomicronemia require very low fat diets, avoidance of free sugars, and decreased alcohol intake. Patients with genetic LPL deficiency are instructed to prepare their food using medium-chain triglycerides, which are not incorporated into chylomicrons. Fish oils decrease triglyceride synthesis, and high doses may be used for severe hypertriglyceridemia.
The management of hypertriglyceridemia focuses on the associated LDL and HDL concentrations as guidelines for therapy. Thus, the overall risk profile can be used to set goals for LDL cholesterol, using a low HDL level (commonly associated with hypertriglyceridemia) as a concomitant major risk factor for atherosclerosis. However, when triglyceride levels are >5.6 mmol/L (>500 mg/dL), the risk of developing pancreatitis increases, and a direct focus on lowering triglycerides is recommended. Thus, triglyceride levels >5.6 mmol/L (>500 mg/dL) are generally treated with drugs, whereas lower levels [2.2 to 5.6 mmol/L (200 to 500 mg/dL)] are not treated unless other CHD risk factors are present .^
^TREATMENT
Three classes of lipid-lowering agents are recommended as first-line therapy against hypercholesterolemia: (1) the HMG-CoA reductase inhibitors; (2) niacin; and (3) the bile acid-binding resins . Fibric acid derivatives are second-line agents for hypercholesterolemia and are most effective for lowering triglycerides.
HMG-CoA Reductase Inhibitors This class of drugs, which include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin, inhibits the rate-limiting step in hepatic cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate), causing an increase in LDL receptor levels in hepatocytes and enhanced receptor-mediated clearance of LDL cholesterol from the circulation. At usual doses, the HMG-CoA reductase inhibitors decrease total cholesterol by 20 to 30% and LDL cholesterol by 25 to 40%. Larger reductions may be achieved with higher doses. Treatment with reductase inhibitors often reduces triglycerides by 10 to 20%, possibly due to reduced secretion of VLDL by the liver. Higher doses of more potent reductase inhibitors, which can lower LDL cholesterol by 45 to 60%, can lower triglycerides by 30 to 45%. HDL cholesterol levels rise about 5 to 10%. In comparison with other lipid-lowering agents, HMG-CoA reductase inhibitors are relatively free of side effects. Mild, transient elevations in liver enzymes occur with all of the agents at the highest doses, but elevations in serum aminotransferases to more than three times the upper limits of normal occur in <2% of patients. Therapy should be discontinued when elevations of this magnitude occur. A rare but potentially serious adverse effect of HMG-CoA reductase inhibitors is myopathy, manifest by muscle pain with elevation of serum creatine phosphokinase (CPK). This occurs in <1% of patients treated with reductase inhibitors alone but is more common (about 2 to 3%) when used in combination with gemfibrozil, niacin, or cyclosporine.
Niacin The mechanism of action of niacin is not fully understood, but it appears to inhibit the secretion of lipoproteins containing apo B100 from the liver. Niacin decreases both total and LDL cholesterol approximately 15 to 25%, reduces VLDL levels by 25 to 35%, and raises HDL cholesterol levels by as much as 15 to 25%. Thus, niacin exerts favorable changes on the three major lipoproteins (VLDL, LDL, and HDL). Efficacy of monotherapy was confirmed in a long-term secondary prevention trial in which niacin significantly reduced the incidence of myocardial infarction. An even longer-term follow-up of that study (15 years total) showed an 11% decrease in all-cause mortality among patients randomized to niacin. Because of its ability to reduce VLDL synthesis, niacin is also a first-line drug for treatment of hypertriglyceridemia.
Niacin is safe, having been in use for almost 30 years, but unpleasant side effects, including cutaneous flushing with or without pruritus, may limit patient acceptability. The cutaneous symptoms tend to subside after several weeks and may be minimized by initiating therapy at low doses or by administering aspirin 30 min before the niacin dose. Less common adverse effects include elevations of liver enzymes, gastrointestinal distress, impaired glucose tolerance, and elevated serum uric acid levels with or without gouty arthritis. Liver enzymes may be elevated in 3 to 5% of patients on full doses of niacin (>2 g/d). Because of its propensity to worsen the control of blood sugar, niacin should be used with caution in patients with DM. Niaspan, an intermediate-release form of niacin, appears to exhibit lipid-altering activity similar to regular niacin.
Bile Acid-Binding Resins Cholestyramine and colestipol have been in use as lipid-lowering agents for almost three decades. These drugs interfere with reabsorption of bile acids in the intestine, resulting in a compensatory increase in bile acid synthesis and upregulation of LDL receptors in hepatocytes. The bile acid sequestrants are useful in the treatment of patients with elevated levels of LDL cholesterol and normal triglycerides. Sequestrants produce dose-dependent decreases on the order of 15 to 25% in total cholesterol and of 20 to 35% in LDL cholesterol. The agents cause modest increases in HDL cholesterol. A limitation of the sequestrants is their tendency to raise triglyceride levels through compensatory increases in hepatic synthesis of VLDL; they should not be given to hypertriglyceridemic individuals. Bile acid-binding resins are efficacious and safe and are recommended for young adult men and premenopausal women with moderate cholesterol elevations. Patient compliance is low, in part because of the need to dissolve these powdered agents in fluid; the availability of colestipol as a tablet may alleviate this problem. Gastrointestinal side effects include constipation, bloating, and gas.
Combination Therapy Combinations of bile acid-binding resins and reductase inhibitors are effective for the treatment of severe, isolated elevations of LDL cholesterol. Combinations of reductase inhibitors and niacin, or resins and niacin, are useful for the treatment of high LDL and low HDL cholesterol levels, though the former combination carries an increased risk of myositis (2 to 3%). If triglyceride and LDL levels are both elevated (HDL is usually reduced as well), resins and niacin are an excellent combination, with resins and gemfibrozil (see below) as an alternative. The combination of a reductase inhibitor and gemfibrozil can be useful when LDL cholesterol is very high in the face of concomitant hypertriglyceridemia, but the risk of myositis (about 2 to 3%) must be considered. Combinations of reductase inhibitors with either niacin or gemfibrozil might best be reserved for patients with CHD and combined hyperlipidemia.
LDL Apheresis In patients with homozygous FH and in ordinary FH patients who respond poorly to diet and drug therapy or who cannot tolerate drugs, apheresis at 7- to 14-day intervals can cause profound lowering of LDL cholesterol levels. Diet and drug regimens are continued during treatment. This approach should be considered for patients with few therapeutic options.
Fibric Acids Gemfibrozil and fenofibrate stimulate the activity of a liver transcription factor termed PPARa that increases LPL activity and production of apo AI. Moreover, these drugs reduce VLDL triglyceride entry into plasma and reduce synthesis of apo CIII, which might improve LPL-induced lipolysis or reduce VLDL secretion. Stimulation of peroxisomal fatty acid oxidation by fibrates may also contribute to the triglyceride-lowering actions. Gemfibrozil and fenofibrate treatment is associated with 25 to 40% reductions in plasma triglyceride levels. Postprandial triglyceride levels, which are linked to fasting concentrations, are also reduced. HDL cholesterol levels increase 5 to 15% with fibrate treatment. Fibric acids and a low-fat diet are particularly useful in the treatment of dysbetalipoproteinemia and are first-line therapy for this disorder except in postmenopausal women, who should initially be given estrogen replacement (if not contraindicated).
Significant increases in LDL cholesterol can accompany otherwise potentially beneficial falls in triglycerides and increases in HDL cholesterol during fibrate therapy. Such rises may require a change to another drug or addition of a second agent.
In the short term, these drugs are well tolerated; mild gastrointestinal distress in the form of epigastric pain is the major side effect. Elevations of liver enzymes occur in 2 to 3% of patients but do not usually require cessation of treatment. Rarely, hepatitis can occur. Fibrates appear to make the bile more lithogenic, and long-term use is probably associated with a twofold increase in gallstone formation. Myopathy with myositis is a rare occurrence with the fibrates, either alone or in combination with HMG CoA reductase inhibitors.
Fish Oils Large doses of omega-3 fatty acids reduce triglyceride levels by diminishing their production. In the United States, omega-3 fatty acid capsules contain 40 to 60% omega-3 fatty acids; the rest of the fatty acids are omega-6. Therefore, to consume 2 to 4 g of omega-3 fatty acids, an individual must take 5 to 10 capsules per day.^
HYPOCHOLESTEROLEMIA
A low total cholesterol concentration [<2.6 mmol/L (<100 mg/dL)] in an adult can be due to rare hereditary traits or secondary to a number of diseases. As described earlier, mutations in the gene for apo B100 that disrupt synthesis or produce truncated forms of apo B100 are associated with hypobetalipoproteinemia. These mutations are inherited as codominant traits; heterozygotes have plasma cholesterol levels in the range of 1.3 to 2.6 mmol/L (50 to 100 mg/dL), with reduced LDL cholesterol levels but normal plasma HDL cholesterol levels. Heterozygotes are asymptomatic, whereas hypolipoproteinemia homozygotes (or compound heterozygotes) have even lower total and LDL cholesterol concentrations and may have malabsorption of fats and fat-soluble vitamins similar to that in abetalipoproteinemia.
Abetalipoproteinemia (Table 344-5) is a rare, autosomal recessive disorder in which there are mutations in the microsomal triglyceride transfer protein (MTP) gene. Individuals who are homozygous for this disorder have total cholesterol levels <1.3 mmol/L (<50 mg/dL) and essentially no VLDL, IDL, LDL, or chylomicrons. Because dietary fat and vitamins A and E are transported from the intestine in chylomicrons, these patients may have malabsorption of fat and fat-soluble vitamins. Vitamin E deficiency in infancy and early childhood can result in neurologic problems (Chap. 75). If vitamin replacement is adequate, individuals with abetalipoproteinemia can live normal, healthy lives.
Moderately low levels of total cholesterol may also be associated with extreme reductions in HDL cholesterol. As noted above, these are almost always secondary to mutations in the gene for apo AI and a lack of apo AI in plasma.
A number of systemic diseases can cause low cholesterol concentrations. Malnutrition, often associated with alcoholism or gastrointestinal disease, can cause low levels of total and LDL cholesterol. Hyperthyroidism, particularly when severe, can reduce cholesterol levels. Patients with uncontrolled AIDS may have total cholesterol levels <2.1 mmol/L (<80 mg/dL), usually associated with severe wasting, diarrhea, and a poor prognosis. Several neoplasms, particularly those involving the hematopoietic system, are associated with hypocholesterolemia. Patients with acute and chronic myelogenous leukemia and myeloid metaplasia with splenomegaly can have severe reductions in both LDL and HDL levels. Other d
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Hi i found this for you from harrisons textbook of medicine.
Hope it helps you.
Lipoproteins are macromolecular complexes that carry hydrophobic plasma lipids, particularly cholesterol and triglyceride, in the plasma. More than half of the coronary heart disease (CHD) in the United States is attributable to abnormalities in the levels and metabolism of plasma lipids and lipoproteins. Some premature CHD is due to mutations in major genes involved in lipoprotein metabolism. However, elevated lipoprotein levels in most patients with CHD reflect the adverse impact of a sedentary lifestyle, excess body weight, and diets high in total and saturated fat superimposed on a genetic background that confers susceptibility to increased circulating lipids. A large body of evidence indicates that lifestyle changes and drug treatment strategies that correct hyperlipidemias reduce CHD risk . More than 70 clinical trials examining the effects of cholesterol reduction have been reported, including several large-scale studies using the potent cholesterol-lowering HMG-CoA reductase inhibitors (also known as statins). These studies unequivocally demonstrate that lowering low-density lipoprotein (LDL) cholesterol reduces fatal and nonfatal heart attacks .
This chapter focuses on the major lipid disorders, including both the dyslipoproteinemias caused by single-gene defects and the disorders that are likely to be multifactorial in origin. A practical approach is provided to assist in the identification, evaluation, and treatment of patients with increased risk of CHD.
LIPID AND LIPOPROTEIN TRANSPORT
LIPOPROTEIN STRUCTURE
Lipoproteins are spherical particles made up of hundreds of lipid and protein molecules. They are smaller than red blood cells and visible only by electron microscopy. However, when the larger, triglyceride-rich lipoproteins are present in high concentration, plasma can appear turbid or milky to the naked eye. The major lipids of the lipoproteins are cholesterol, triglycerides, and phospholipids. Triglycerides and the esterified form of cholesterol (cholesteryl esters) are nonpolar lipids that are insoluble in aqueous environments (hydrophobic) and comprise the core of the lipoproteins. Phospholipids and a small quantity of free (unesterified) cholesterol, which are soluble in both lipid and aqueous environments (amphipathic), cover the surface of the particles, where they act as the interface between the plasma and core components. A family of proteins, the apolipoproteins, also occupies the surface of the lipoproteins; the apolipoproteins play crucial roles in the regulation of lipid transport and lipoprotein metabolism.
Lipoproteins have been classified on the basis of their densities into five major classes1) chylomicrons, (2) very low density lipoproteins (VLDL), (3) intermediate-density lipoproteins (IDL), (4) LDL, and (5) high-density lipoproteins (HDL).
APOLIPOPROTEINS
The apolipoproteins (apos) provide structural stability to the lipoproteins and determine the metabolic fate of the particles upon which they reside.
There are two forms of apo B¾apo B100 and apo B48. Apo B100 is the major apolipoprotein of VLDL, IDL, and LDL, comprising approximately 30, 60, and 95% of the protein in these lipoproteins, respectively. Apo B100 has a molecular mass of about 545 kDa and is synthesized in the liver. It is essential for the assembly and secretion of VLDL from the liver and is the ligand for the removal of LDL by the LDL receptor. The LDL receptor is a cell-surface protein that binds and internalizes lipoproteins that contain apo B100 or apo E. The LDL receptor binding domain of apo B100 is the sequence between amino acids 3200 and 3600, a region that is absent in apo B48.
Apo B48 is essential for the assembly and secretion of chylomicrons. Apo B48 is encoded by the same gene and messenger ribonucleic acid (mRNA) as Apo B100. However, the mRNA is edited in an unusual way: A cytidine deaminase in the intestine changes a cytidine to a uridine in base 6666 of the apo B100 mRNA to produce a stop codon so that apo B48 contains only the N-terminal 48% of the full-length apo B100. In contrast, the apo B100 mRNA in human liver is not edited. The role of apo B48 in the metabolism of chylomicrons in plasma is unclear. Individuals with mutations that interfere with the normal synthesis of apo B have absent or very low levels of chylomicrons, VLDL, IDL and LDL.
The apolipoproteins of the C series are synthesized in the liver and are present in all plasma lipoproteins (trace amounts in LDL). Individual apo Cs have different metabolic roles, but all inhibit the removal of plasma chylomicrons and VLDL remnants by the liver. Overexpression of apo CI in transgenic mice inhibits the uptake of chylomicron and VLDL remnants by the liver. Apo CI under- or overexpression has not been described in humans. Apo CII is an essential activator of the enzyme lipoprotein lipase (LPL), which hydrolyzes triglycerides in chylomicrons and VLDL; individuals lacking apo CII have severe hypertriglyceridemia. Apo CIII inhibits LPL, and apo CIII overexpression in transgenic mice causes severe hypertriglyceridemia. Humans who lack apo CIII have accelerated rates of VLDL triglyceride lipolysis.
Apo E is synthesized mainly in hepatocytes but is also made in other cells, including macrophages, neurons, and glial cells. It is found in chylomicrons, IDL, VLDL, and HDL and mediates the uptake of these lipoproteins in the liver by both the LDL receptor and the LDL receptor-related protein (LRP). Apo E also binds to heparin-like proteoglycan molecules on the surface of all cells. There are three major apo E alleles: E2, E3, and E4; these isoforms differ in sequence at two positions and have frequencies of about 0.12, 0.75, and 0.13, respectively, in the general population. Apo E2 binds to the LDL receptor with lower affinity than apo E3 or E4. Individuals who are homozygous for apo E2 may develop severe hyperlipidemia (type III dysbetalipoproteinemia); complete absence of apo E increases plasma levels of chylomicron and VLDL remnants and causes early atherosclerosis.
Apo AI, apo AII, and apo AIV are found primarily on HDL. Apo AI and apo AII are synthesized in the small intestine and the liver; apo AIV is made only in the intestine. Apo AI comprises about 70 to 80% of the protein of HDL and plays a critical structural role in HDL particles. Individuals with a profound deficiency of apo AI also lack HDL. Apo AI activates the enzyme lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol in plasma. Plasma levels of HDL cholesterol and apo AI are inversely related to risk for CHD, and some patients with apo AI deficiency develop early, severe atherosclerosis. Transgenic mice that overexpress human apo AI are resistant to atherosclerosis. Apo AII is the second most abundant apoprotein in HDL, but its function has not been determined; transgenic mice that overexpress apo AII have high plasma levels of both HDL cholesterol and triglycerides but may be susceptible to atherosclerosis. Apo AII knockout mice have low levels of HDL, indicating that apo AII is also necessary for the integrity of HDL particles. Apo AIV, a minor component of HDL and chylomicrons may play a role in the activation of LCAT.
Apoprotein(a), a large glycoprotein that shares a high degree of sequence homology with plasminogen, is made by hepatocytes and is secreted into plasma where it forms a covalent linkage with the apo B100 of LDL to form lipoprotein(a). The physiologic role of lipoprotein(a) is not known, but elevated levels are associated with an increased risk for atherosclerosis.
ENZYMES INVOLVED IN LIPOPROTEIN METABOLISM
LPL is synthesized in fat and muscle, secreted into the interstitial space, transported across endothelial cells, and bound to proteoglycans on the luminal surfaces in the adjacent capillary beds. LPL mediates the hydrolysis of the triglycerides of chylomicrons and VLDL to generate free fatty acids and glycerol. The free fatty acids diffuse into adjacent tissues to be burned for energy or stored as fat. Most circulating LPL is associated with LDL. Insulin stimulates the synthesis and secretion of LPL; reduced LPL activity in diabetes mellitus can lead to impaired triglyceride clearance. Homozygotes for mutations that impair LPL have severe hypertriglyceridemia that usually manifests in childhood (type I hyperlipidemia). Heterozygotes for LPL defects have mild to moderate fasting hypertriglyceridemia but may have marked hypertriglyceridemia after consuming a high-fat meal. LPL is also expressed in macrophages, including cholesteryl ester-laden macrophages (foam cells) in atherosclerotic lesions. In this setting, secreted LPL may associate with LDL, causing retention of the lipoprotein in the subendothelial space.
Hepatic triglyceride lipase (HTGL), a member of a family of enzymes that includes LPL and pancreatic lipase, is synthesized in the liver and interacts with lipoproteins in hepatic sinusoids. HTGL removes triglycerides from VLDL remnants (IDL), thus promoting the conversion of VLDL to LDL. It may also play a role in the clearance of chylomicron remnants and in the conversion of HDL2 to HDL3 in the liver by hydrolyzing the triglyceride and phospholipid in HDL (see below). Severe hypertriglyceridemia in individuals with genetic deficiency of HTGL is due to the accumulation of chylomicron and VLDL remnants in plasma. In contrast to most patients with hypertriglyceridemia, however, individuals with HTGL deficiency have normal levels of HDL.
LCAT is synthesized in the liver and secreted into plasma where it is bound predominantly to HDL. LCAT mediates the transfer of linoleate from lecithin to free cholesterol on the surface of HDL to form cholesteryl esters that are then transferred to VLDL and eventually LDL. Apo AI is a cofactor for esterification of free cholesterol by LCAT. Deficiency of LCAT can be caused by mutations in the enzyme or in Apo A1. LCAT deficiency causes low levels of cholesteryl esters and HDL, and it can lead to corneal clouding and renal insufficiency.
Cholesteryl ester transfer protein (CETP) is synthesized primarily in the liver and circulates in plasma in association with HDL. CETP mediates the exchange of cholesteryl esters from HDL with triglyceride from chylomicrons or VLDL. This exchange can explain much of the inverse relationship between plasma levels of triglycerides and HDL cholesterol. LDL cholesteryl ester can also be exchanged with triglyceride from chylomicrons and VLDL, leading to the generation of small, dense LDL. Individuals who are homozygotes for mutations in the CETP gene have marked elevations of HDL cholesterol and apo AI. Heterozygotes for these mutations have slight elevations of HDL, indicating that CETP plays an important role in the removal of cholesteryl esters from HDL.
Phospholipid transfer protein (PLTP) is synthesized in the liver and lung. The production of mature HDL particles depends on PLTP, which provides phospholipid to the enlarging particles.
TRANSPORT OF EXOGENOUS (DIETARY) LIPIDS
Exogenous lipid transport in chylomicrons and chylomicron remnants is depicted in Fig. 344-1A. In western societies, where individuals ordinarily consume 50 to 100 g of fat and 0.5 g of cholesterol during three or four meals, transport of dietary fats is essentially continual. Normolipidemic individuals dispose of most dietary fat in the bloodstream within 8 h of the last meal, but some individuals with dyslipidemia, particularly those with elevated fasting levels of VLDL triglyceride, have measurable levels of intestinally derived lipoproteins in the circulation as long as 24 h after the last meal.
In the intestinal mucosa dietary triglyceride and cholesterol are incorporated into the core of nascent chylomicrons. The surface coat of the chylomicron is composed of phospholipid, free cholesterol, apo B48, apo AI, apo AII, and apo AIV. The chylomicron, essentially a fat droplet containing 80 to 95% triglycerides, is secreted into lacteals and transported to the circulation via the thoracic duct. In the plasma, apo C proteins are transferred to the chylomicron from HDL. Apo CII mediates hydrolysis of triglycerides by activating LPL on capillary endothelial cells in fat and muscle. After the triglyceride core has been hydrolyzed, apo CII and apo CIII recirculate back to HDL. The addition of apo E allows the chylomicron remnant to bind first to heparan sulfate proteoglycans within the space of Disse and then to hepatic LDL receptors and/or LDL receptor-related protein. As a consequence, dietary triglyceride is delivered to adipocytes and muscle cells as fatty acids, and dietary cholesterol is taken up by the liver where it can be used for bile acid formation, incorporated into membranes, resecreted as lipoprotein cholesterol back into the circulation, or excreted as cholesterol into bile. Dietary cholesterol also regulates endogenous hepatic cholesterol synthesis.
Abnormal transport and metabolism of chylomicrons may predispose to atherosclerosis, and postprandial hyperlipidemia may be a risk factor for CHD. Chylomicrons and their remnants can be taken up by cells of the vessel wall, including monocyte-derived macrophages that migrate into the vessel wall from plasma. Cholesteryl ester accumulation by these macrophages transforms them into foam cells, the earliest cellular lesion of the atherosclerotic plaque (Chap. 241). If the postprandial levels of chylomicrons or their remnants are elevated, or if their removal from plasma is prolonged, cholesterol delivery to the artery wall may be increased.
TRANSPORT OF ENDOGENOUS LIPIDS
The endogenous lipid transport system, which conveys lipids from the liver to peripheral tissues and from peripheral tissues back to the liver, can be separated into two subsystems: the apo B100 lipoprotein system (VLDL, IDL, and LDL) and the apo AI lipoprotein system (HDL).
The Apo B100 Lipoprotein System. In the liver, triglycerides are made from fatty acids that are either taken up from plasma or synthesized de novo within the liver. Cholesterol can also be synthesized by the liver or delivered to the liver via lipoproteins, particularly chylomicron remnants. These core lipids are packaged together with apo B100 and phospholipids into VLDL and secreted into plasma where apos CI, CII, CIII, and E are added to the nascent VLDL particles. Triglycerides make up the bulk of the VLDL (55 to 80% by weight), and the size of the VLDL is determined by the amount of triglyceride available. Hence, very large triglyceride-rich VLDL are secreted in situations where excess triglycerides are synthesized, such as in states of caloric excess, in diabetes mellitus, and after alcohol consumption. Small VLDL are secreted when fewer triglycerides are available. Although VLDL are the principal hepatic lipoprotein secreted by most individuals, VLDL and cholesteryl ester-enriched IDL and/or LDL-like particles may be secreted by the liver in individuals with combined hyperlipidemia (see below).
In the plasma, triglycerides are hydrolyzed by LPL and VLDL particles are converted to VLDL remnants (IDL). In contrast to chylomicron remnants, VLDL remnants can either enter the liver or give rise to LDL. Larger VLDL particles carry more triglycerides and are likely to be removed directly from plasma without being converted to LDL; apo E in the VLDL remnants binds to the LDL receptor to mediate removal from the plasma. Smaller, more dense VLDL particles are more efficiently converted to LDL; apo E and HTGL play important roles in this process. Individuals with deficiency of either apo E2 or HTGL accumulate IDL in plasma. Apo B100 is the only protein that remains on the surface of the LDL particle.
The half-life of LDL in plasma is determined principally by the availability (or "activity") of LDL receptors. Most plasma LDL is taken up by the liver, and the remainder is delivered to peripheral tissues, including the adrenals and gonads, which utilize cholesterol as a precursor for steroid hormone synthesis. The adrenals have the highest concentration of LDL receptors per cell in the body. Overall, about 70 to 80% of LDL catabolism occurs via LDL receptors, and the remainder is removed by fluid endocytosis and possibly by other receptors.
The LDL receptor, a glycoprotein with a molecular mass of approximately 160 kDa, is present on the surfaces of nearly all cells in the body. Goldstein and Brown characterized the molecular genetics and cell biology of the LDL receptor and defined its role in cholesterol metabolism. They showed that cholesterol delivered to the cytoplasm by LDL regulates both the rate of cholesterol synthesis in the liver and the number of LDL receptors on the surface of hepatocytes. LDL receptor synthesis is mediated by sterol response element regulatory proteins (SREBPs). These transcription factors are activated in the absence of cholesterol, proteolytically cleaved, and transferred from the endoplasmic reticulum into the nucleus where they stimulate LDL receptor gene expression. Though the LDL receptor is a major factor in determining plasma LDL cholesterol levels, the rates of entry of VLDL into plasma and the efficiency with which VLDL is converted to LDL also influence steady-state LDL concentrations in plasma.
Increased levels of plasma LDL cholesterol and apo B100 are risk factors for atherosclerosis. Normal LDL does not cause foam cell formation when incubated with cultured macrophages or smooth-muscle cells. But, when LDL undergoes lipid peroxidation, it becomes a ligand for alternative, scavenger receptors that are present on endothelial cells and macrophages. Uptake of modified (oxidized) lipoproteins by these receptors in macrophages results in formation of cholesterol-laden foam cells. In addition to inducing foam cell formation, oxidized LDL acts in the vessel wall to stimulate the secretion of cytokines and growth factors by endothelial cells, smooth-muscle cells, and monocyte-derived macrophages . The consequence is recruitment of more monocytes to the lesion and proliferation of smooth-muscle cells, which synthesize and secrete increased amounts of extracellular matrix, such as collagen. The critical role of LDL in atherosclerosis has been confirmed in genetically altered mice. Although mice are normally resistant to atherosclerosis, increased plasma levels of remnant lipoproteins or LDL lead to atherosclerosis in this species.
The role of VLDL in atherogenesis is less certain. The major reason for this uncertainty derives from the inverse relationship between elevated levels of triglyceride-rich lipoproteins and reduced levels of the antiatherogenic HDL cholesterol. It is possible, for example, that hypertriglyceridemia may not be directly atherogenic but rather the surrogate of other lipoprotein abnormalities. If postprandial hyperlipidemia is a risk factor for CHD, individuals who have normal fasting plasma triglyceride levels but develop postprandial hypertriglyceridemia after consumption of a fat load would be misclassified as "normal" in studies in which only fasting blood samples are analyzed. It is clear that cholesteryl ester-enriched VLDL, isolated from cholesterol-fed animals, can be taken up by receptors on macrophages and smooth-muscle cells and cause foam cell formation. These cholesteryl ester-laden VLDLs are enriched in apo E and are probably representative of VLDL remnants. Thus, the risk of atherosclerosis from hypertriglyceridemia and elevated VLDL levels may be determined by the level of cholesteryl ester-enriched VLDL remnants. The atherogenic potential of IDL is probably similar to that of VLDL remnants.
Apo AI-Containing Lipoproteins. In contrast to atherogenic apo B lipoproteins, the apo AI-containing HDL appear to be antiatherogenic. In fact, in some studies, HDL cholesterol levels are as strong an indicator of protection from CHD as LDL cholesterol levels are an indicator of risk. Although a great deal is known about the HDL transport system, the mechanism by which these lipoproteins protect against atherosclerosis is poorly defined.
HDL particles are formed in plasma from the coalescence of individual phospholipid-apolipoprotein complexes. Apo AI appears to be the crucial, structural apoprotein for HDL, and apo AI/phospholipid complexes probably fuse with other phospholipid vesicles that contain apo AII and apo AIV to form the various types of HDL. The C apoproteins can be added to HDL after their secretion as phospholipid complexes or by their transfer from triglyceride-rich lipoproteins. This may involve the action of PLTP. These small, cholesterol-poor HDL particles are heterogeneous in size and content and are referred to as HDL3. Free cholesterol is transferred from cell membranes to HDL3; a cholesterol transporter called ABC1 mediates this important first step in reverse cholesterol transport. Free cholesterol in HDL3 is converted to cholesteryl ester by LCAT, and the cholesteryl ester moves into the core of the HDL. Formation of cholesteryl ester increases the capacity of the HDL3 to accept more free cholesterol and enlarge to form the more buoyant class of HDL particles termed HDL2. HDL2 can be metabolized by two pathways: (1) cholesteryl esters can be transferred from HDL2 to apo B lipoproteins or cells, or (2) the entire HDL2 particle can be removed from plasma. The transfer of cholesteryl ester from HDL to triglyceride-rich apo B lipoproteins (chylomicrons and VLDL in the fed and fasted states, respectively) is mediated by CETP. Triglyceride is transferred to HDL in this process and is a substrate for lipolysis by LPL and/or HTGL. As a result, HDL2 is converted back into HDL3. When the apo B lipoproteins are removed by the liver, reverse cholesterol transfer is complete. HDL cholesteryl ester may also be transferred selectively to cells via interaction of HDL with the scavenger receptor B-1, a receptor expressed by hepatocytes and steroid-producing cells. HDL-mediated reverse cholesterol transport (from peripheral tissues to the liver) is thought to be the primary mechanism by which HDL protects against atherosclerosis.
Rarely, low plasma HDL is due to a genetic deficiency of one of the structural components of HDL (such as apo AI). However, low HDL cholesterol levels are usually the secondary consequence of increased plasma levels of VLDL and IDL (or chylomicrons and their remnants). Mutations in the ABC1 gene (see above) are associated with Tangier's disease, a rare form of low HDL. Low levels of HDL cholesterol and apo AI may increase atherosclerosis risk by any of several mechanisms. HDL could remove cholesterol from foam cells in atherosclerotic lesions or protect LDL from oxidative modification. Alternatively, the atherosclerotic risk of low HDL may be due to the commonly associated elevations of apo B-containing lipoproteins, which accept HDL cholesteryl esters and deliver cholesteryl esters to the vessel wall.
THE HYPERLIPOPROTEINEMIAS
HYPERCHOLESTEROLEMIA
Elevated levels of fasting plasma total cholesterol in the presence of normal levels of triglycerides are almost always associated with increased concentrations of plasma LDL cholesterol (type IIa), as LDL carries about 65 to 75% of total plasma cholesterol. A rare individual with markedly elevated HDL cholesterol may also have increased plasma total cholesterol levels. Elevations of LDL cholesterol can result from single-gene defects, polygenic disorders, or from the secondary effects of other disease states.
Familial Hypercholesterolemia (FH) FH is a codominant genetic disorder that occurs in the heterozygous form in approximately 1 in 500 individuals. FH is due to mutations in the gene for the LDL receptor and is genetically heterogeneous, >200 different mutations in the gene having been described. Plasma levels of LDL cholesterol are elevated at birth and remain so throughout life. In untreated adults, total cholesterol levels range from 7 to 13 mmol/L (275 to 500 mg/dL). Plasma triglyceride levels are typically normal, and HDL cholesterol levels are normal or reduced. As would be expected of a disorder with decreased numbers of LDL receptors, the fractional clearance of LDL apo B is reduced. LDL production is increased because the liver secretes more VLDL and IDL and more IDL particles are converted to LDL rather than taken up by the hepatic LDL receptors. FH heterozygotes usually develop severe atherosclerosis in early or middle age. Tendon xanthomas, which are due to both intracellular and extracellular deposits of cholesterol, most commonly involve the Achilles tendons and the extensor tendons of the knuckles; they are found in about 75% of adults with FH (Fig. 344-CD1). Tuberous xanthomas, which are softer, painless nodules on the elbows and buttocks, and xanthelasmas, which are barely elevated deposits of cholesterol on the eyelids, are common in heterozygous FH (Figs. 344-CD2 and 344-CD3). CHD develops in men by the fourth decade of life or earlier.
The homozygous form of FH occurs in 1 out of 1 million individuals and is associated with a marked increase of plasma cholesterol levels (>13 mmol/L; >500 mg/dL), large xanthelesmas, and prominent tendon and planar xanthomas. These individuals have severe, premature CHD that can be manifested in childhood.
Familial Defective Apo B100 This autosomal dominant disorder is a phenocopy of FH and is due to a missense mutation at amino acid 3500 that reduces the affinity of LDL for the LDL receptor and, thus, impairs LDL catabolism. The prevalence and manifestations of both the heterozygous and homozygous forms are similar to those produced by mutations of the LDL receptor.
Polygenic Hypercholesterolemia Most moderate hypercholesterolemia [plasma cholesterol levels between 6.5 and 9 mmol/L (240 and 350 mg/dL)] is polygenic in origin. Multiple genes interact with environmental factors to contribute to the hypercholesterolemia, and both overproduction and reduced catabolism of LDL are thought to play roles in the pathophysiology. The severity is probably affected by the consumption of saturated fat and cholesterol, age, and the level of physical activity. Plasma triglyceride and HDL cholesterol levels are usually normal. These individuals are at increased risk of atherosclerosis. Tendon xanthomas are not present. Genes involved in cholesterol and bile acid metabolism may be involved in the pathogenesis.
HYPERTRIGLYCERIDEMIA
The diagnosis of hypertriglyceridemia is made by determining plasma lipids after an overnight fast. Because of the less certain association of triglycerides with CHD (compared to LDL cholesterol), plasma concentrations greater than the 90th or 95th percentile for age and sex have been used to define hypertriglyceridemia. Some studies show, however, that plasma triglyceride levels >130 to 150 mg/dL are associated with low HDL cholesterol levels and small, dense LDL particles. Furthermore, a meta-analysis of several prospective population studies confirms that triglyceride concentrations are independent predictors of CHD risk. Isolated elevations of plasma triglycerides can be due to increased levels of VLDL (type IV) or combinations of VLDL and chylomicrons (type V). Rarely, only chylomicron levels are elevated (type I). Plasma is usually clear when triglyceride levels are <4.5 mmol/L (<400 mg/dL) and cloudy when levels are higher and VLDL (and/or chylomicron) particles become large enough to scatter light. When chylomicrons are present, a creamy layer floats to the top of plasma after refrigeration for several hours. Tendon xanthomas and xanthelasmas do not occur with isolated hypertriglyceridemia, but eruptive xanthomas (small orange-red papules) (Fig. 344-CD4) can appear on the trunk and extremities when triglyceride levels are >11.5 mmol/L (>1000 mg/dL) (i.e., when chylomicronemia is present). At these high levels of triglycerides, the retinal vessels can appear to be orange-yellow in color (lipemia retinalis). Pancreatitis is the major risk associated with plasma triglyceride concentrations >11 mmol/L (>1000 mg/dL).
Elevations in plasma triglycerides are usually associated with increased synthesis and secretion of VLDL triglycerides by the liver. Hepatic triglyceride synthesis is regulated by substrate flow (the availability of free fatty acids), energy balance (the level of glycogen stores in the liver), and hormonal status (the balance between insulin and glucagon). Obesity, excessive consumption of simple sugars and saturated fats, inactivity, alcohol consumption, and insulin resistance are commonly associated with hypertriglyceridemia. In most of these situations, increased free fatty acid flux from adipose tissue to the liver stimulates the assembly and secretion of VLDL. When VLDL triglyceride levels are markedly elevated [>11.5 mmol/L (>1000 mg/dL)], LPL may be saturated so that an acquired LPL deficiency develops during the postprandial period even if there is no underlying genetic disorder. The addition of chylomicrons to the circulation may cause dramatic increases in plasma triglycerides.
Familial Hypertriglyceridemia Familial hypertriglyceridemia appears to be transmitted as an autosomal dominant disorder, though the underlying mutation(s) have not been identified. The pathophysiology is complex: both reduced catabolism of triglyceride-rich lipoproteins and overproduction of VLDL have been reported. Elevated levels of fasting plasma triglycerides in the range of 2.3 to 8.5 mmol/L (200 to 750 mg/dL) are usually associated with increased levels of VLDL triglycerides only. When VLDL triglyceride levels are markedly elevated (regardless of etiology), chylomicron triglycerides can also be present, even after a 14-h fast. A 20-year follow-up of individuals with familial hypertriglyceridemia demonstrated a moderate increase in CHD risk.
Familial Lipoprotein Lipase Deficiency This autosomal recessive disorder is due to the severe impairment or absence of LPL, leading to massive accumulation of chylomicrons in plasma. Manifestations begin in infancy and include pancreatitis, eruptive xanthomas, hepatomegaly, splenomegaly, foam cell infiltration of the bone marrow, and, when the level of triglycerides is >11 mmol/L (1000 mg/dL), lipemia retinalis. Atherosclerosis is not accelerated. The diagnosis is suspected by finding a creamy layer (chylomicrons) at the top of plasma that has incubated overnight at 4°C; it is confirmed by demonstrating that LPL levels in plasma do not increase after the administration of heparin (which normally releases LPL from endothelial surfaces). Manifestations recede dramatically when patients are placed on fat-free diets.
LPL levels are within the normal range in most patients with moderate hypertriglyceridemia [2.8 to 5.6 mmol/L (250 to 500 mg/dL)]. Heterozygous mutations in the LPL gene are present in 5 to 10% of hypertriglyceridemic individuals; LPL activity may be reduced by 20 to 50% in these individuals. Heterozygotes for LPL deficiency may also present with severe hypertriglyceridemia if they have poorly controlled diabetes, are pregnant, consume excessive quantities of alcohol, take exogenous estrogen, or are obese.
Familial Apoprotein CII Deficiency This rare autosomal recessive disorder causes a functional deficiency of LPL and clinical manifestations similar to those of familial LPL deficiency. Deficiency of apoprotein CII impairs hydrolysis of chylomicrons and VLDL so that either, or both, lipoproteins accumulate in blood. The diagnosis is suspected in children or adults with recurrent attacks of pancreatitis and confirmed by demonstrating the absence of apo CII on gel electrophoresis and that plasma transfusion (which contains abundant apo CII) causes a dramatic fall in plasma triglycerides. Heterozygotes have half-normal levels of apo CII, may have mild elevations of triglycerides, and are asymptomatic. Dietary fat restriction should be life-long.
Hepatic Lipase Deficiency Total deficiency of HTGL is a rare autosomal recessive disorder that impairs the final catabolism and/or remodeling of small VLDL and IDL. Subjects with HTGL deficiency often have elevated levels of VLDL remnants; HDL2 levels may be elevated because HTGL participates in the conversion of HDL2 to HDL3. HTGL activity is frequently increased in hypertriglyceridemic individuals, but the meaning of this association is unclear.
HYPERCHOLESTEROLEMIA WITH HYPERTRIGLYCERIDEMIA
Concomitant hypercholesterolemia and hypertriglyceridemia occurs in two disorders¾familial combined hyperlipidemia (FCHL) and dysbetalipoproteinemia.
Familial Combined Hyperlipidemia FCHL is transmitted as an autosomal dominant disorder. Probands (the initial case discovered within a family) typically have combined hyperlipidemia, isolated hypertriglyceridemia, or isolated elevated levels of LDL cholesterol. The diagnosis requires documentation at some time of combined hyperlipidemia in the proband or, if the proband has isolated hypercholesterolemia or hypertriglyceridemia, the various lipid phenotypes in first-degree relatives at risk. The lipoprotein phenotype in affected individuals may change over time. The underlying defect in this disorder is not known, though mutations or polymorphisms in the LPL gene and in the gene cluster for apo AI, apo CIII, and apo AIV may contribute to the disorder in some families. Insulin resistance is present in many individuals with FCHL; the link may result from increased free fatty acid flux driving assembly and secretion of apo B100 lipoproteins.
FCHL is associated with increased secretion of VLDL particles, as determined by the flux of VLDL apo B. The lipoprotein patterns associated with the disorder are most likely determined by genetic polymorphisms in genes that regulate the metabolism of VLDL. For example, if the affected individual also has a defect in LPL, hypertriglyceridemia will be present. Since the hydrolysis of VLDL triglycerides also regulates the generation of LDL in plasma, individuals with FCHL who have inefficient catabolism of VLDL may also have reduced levels of LDL cholesterol and high VLDL cholesterol. Finally, individuals with FCHL who synthesize normal quantities of triglycerides and secrete VLDL that carries normal amounts of triglyceride generate increased numbers of LDL particles and present with isolated elevations of plasma LDL cholesterol. These variations in VLDL catabolism, together with additional genetic heterogeneity and environmental variability, form the basis for the variable phenotype in this disorder. FCHL may occur in as many as 0.5 to 1.0% of Americans and is the most common familial lipid disorder in survivors of myocardial infarction. The increased risk for atherosclerosis is due to the presence of increased numbers of small, atherogenic VLDLs and the conversion of VLDL to the more atherogenic IDL and LDL. Persons with FCHL usually have clear plasma and do not have xanthomas or xanthelasma.
Dysbetalipoproteinemia This rare disorder affects 1 in 10,000 persons and is due to homozygosity for apo E2, the binding-defective form of apo E. Because apo E plays a crucial role in the catabolism of chylomicron and VLDL remnants, affected individuals have elevations in both VLDL triglyceride and VLDL cholesterol, and chylomicron remnants are present in fasting plasma. The ratio of total cholesterol to triglyceride approximates 1.0, and the ratio of VLDL cholesterol to triglyceride is greater than 0.25. LDL and HDL cholesterol levels are usually low. Although 1% of the population is homozygous for apo E2, most have normal plasma triglyceride and cholesterol levels. Thus, a second defect in lipid metabolism must be present in the 0.01% of individuals with dysbetalipoproteinemia. These individuals may have tuberous xanthomas and deposits of cholesterol in the palmar creases (striae palmaris); the latter, appearing as yellow-orange lines, are specific for dysbetalipoproteinemia. The risk for atherosclerosis and its complications is increased, with onset in the fourth and fifth decades. The incidence of peripheral vascular disease is higher than in FH.
REDUCED HDL CHOLESTEROL
Low levels of HDL cholesterol can be defined as <0.9 mmol/L (<35 mg/dL) in men and <1 to 1.2 mmol/L (<40 to 45 mg/dL) in women. Low concentrations of HDL cholesterol are usually associated with coexistent hypertriglyceridemia, though "primary hypoalphalipoproteinemia" has been identified in both individuals and families. The relationship between hypertriglyceridemia and low HDL levels probably derives from: (1) CETP-mediated transfer of cholesteryl ester from the core of HDL to VLDL; (2) shift of surface components, particularly phospholipids apo CII, and apo CIII, from HDL to VLDL; and (3) increased fractional catabolism of the cholesteryl ester-poor apoAI that results from the first two processes. The complexity of the relationship between HDL and triglyceride levels is highlighted by the fact that HDL levels do not return to normal when fasting plasma triglycerides are reduced in most persons with hypertriglyceridemia and low HDL cholesterol levels. Low HDL is clinically silent, and the plasma is usually clear (it can be cloudy or creamy if there is concomitant hypertriglyceridemia).
Primary hypoalphalipoproteinemia refers to the state where HDL cholesterol concentrations are markedly reduced but plasma triglyceride concentrations are normal. Many individuals with this phenotype have had hypertriglyceridemia in the past or have an older (or more obese) first-degree relative who has both low HDL and increased triglyceride levels. Hence, both family studies and long-term follow-up may be required to identify individuals with primary reductions in HDL cholesterol. Rare mutations have been described in the apo AI gene that lead to reductions in apo AI synthesis or increases in catabolism. One mutation that is common in Italy, apo AI-Milano, is associated with a high fractional clearance rate of apo AI but is not associated with increased risk for atherosclerosis.
SECONDARY CAUSES OF HYPERLIPOPROTEINEMIA
Diabetes Mellitus Diabetes can affect lipid and lipoprotein metabolism through several mechanisms. In type 1 diabetes mellitus (DM) (formerly called insulin-dependent diabetes mellitus), plasma lipids are usually normal when control of diabetes with insulin is adequate. In diabetic ketoacidosis, hypertriglyceridemia can be severe due to increases in both VLDL and chylomicrons. These abnormalities are associated with overproduction of VLDL and LPL deficiency secondary to insulinopenia. They usually improve with tight control of the diabetes. In type 2 DM (formerly called non-insulin-dependent diabetes mellitus), insulin resistance and obesity combine to cause mild to moderate hypertriglyceridemia and low HDL cholesterol levels. In general, this pattern of dyslipidemia is due to overproduction of VLDL. LDL cholesterol is usually normal in type 2 DM, though the LDLs are small, dense, and perhaps more atherogenic. Treatment of type 2 DM and weight reduction improve, but usually do not completely correct, the dyslipidemia (particularly the low HDL cholesterol levels). Therapy of hyperlipidemia should not be delayed in patients with type 2 DM, as they are at increased risk for CHD. It is recommended that patients with diabetes should be treated as if they already have CHD, i.e., the treatment goal is to reduce their LDL to <2.6 mmol/L (<100 mg/dL) .
Hypothyroidism Hypothyroidism accounts for about 2% of all cases of hyperlipidemia and is second only to DM as a cause of secondary hyperlipidemia. Levels of LDL cholesterol can be elevated, even in patients with subclinical disease in whom thyroid-stimulating hormone (TSH) levels are elevated but other thyroid function tests are normal. Hypertriglyceridemia can occur if obesity is present. Hypothyroidism is also associated with increased levels of HDL cholesterol, probably because of reduced HTGL activity. Correction of hypothyroidism reverses the lipid abnormalities.
Renal Disease Renal disease causes a wide range of lipid abnormalities. The nephrotic syndrome can be accompanied by elevations in LDL, VLDL, or both. The severity of the hyperlipidemia correlates with the degree of hypoproteinemia. Renal failure is associated with hypertriglyceridemia and low HDL cholesterol concentrations.
Ethanol The metabolism of ethanol enhances the level of NADH in the liver which, in turn, stimulates the synthesis of fatty acids and their incorporation into triglycerides. Moderate ethanol consumption raises plasma VLDL levels, with the degree of elevation dependent on the baseline level. Severe hypertriglyceridemia and pancreatitis usually develop on the background of a genetic hyperlipidemia and heavy alcohol intake. Because ethanol also stimulates the synthesis of apo AI and inhibits CETP, ethanol-associated hypertriglyceridemia is usually accompanied by normal or elevated levels of HDL cholesterol.
Liver Disease Primary biliary cirrhosis and extrahepatic biliary obstruction can cause hypercholesterolemia and elevated levels of plasma phospholipids associated with increased levels of an abnormal lipoprotein (lipoprotein X; Chap. 299) and LDL. Severe liver injury often leads to a decrease in levels of both cholesterol and triglyceride. Acute hepatitis can cause elevated levels of VLDL and impairment of LCAT formation.
AIDS Use of protease inhibitor therapies has been associated with a generalized metabolic syndrome that includes hypertriglyceridemia, alterations in fat distribution, and occasionally type 2 DM .
DIAGNOSIS
Although the initial indication of an abnormality in lipoprotein metabolism is via blood measurements of triglyceride and cholesterol, the disorders are due to abnormalities of specific lipoproteins. Thus, lipoprotein analysis should assess VLDL, LDL, and HDL levels. Direct measurements of plasma LDL require laborious centrifugation techniques. However, LDL cholesterol concentrations can be estimated indirectly in individuals with triglyceride levels <4.5 mmol/L (<400 mg/dL) by subtracting the HDL and VLDL cholesterol from the total plasma cholesterol. HDL cholesterol is determined after chemical precipitation of VLDL and LDL. VLDL cholesterol is estimated to be the plasma triglyceride level divided by five. Therefore
^
where all values are measured in milligrams per deciliter.
In persons with triglyceride levels >4.5 mmol/L (>400 mg/dL), the ratio of triglyceride to cholesterol in VLDL is >5, and this equation cannot be used to calculate the plasma LDL cholesterol level. The other disorder that is not detected with this method is dysbetalipoproteinemia because the ratio of triglyceride to cholesterol in the VLDL is <<5. In these two situations, direct measurement of LDL cholesterol must be performed in ultracentrifuged plasma. Commercial methods for the measurement of "direct LDL" are available. Although these methods appear to be precise and accurate, the measured values for LDL cholesterol are 0.06 to 0.17 mmol/L (5 to 15 mg/dL) less than estimated LDL because the estimated value is actually the combination of IDL and LDL. If a "direct LDL" measurement is used, the National Cholesterol Education Program (NCEP) guidelines (based on estimated LDL) must be adjusted before therapeutic decisions are made.
Because plasma triglyceride levels rise and both HDL and LDL cholesterol levels fall modestly after a fat-containing meal (due to the action of CETP), it is preferable to measure plasma lipids after a 12-h fast. Measuring cholesterol levels alone will not detect individuals with isolated low HDL; screening for CHD should therefore include measurement of HDL. Because serum lipid levels vary from day to day, at least two to three measurements should be made days or weeks apart before initiating therapy. Some experts advocate the use of total cholesterol/HDL ratios as a better assessment of individual risk. This is a reasonable approach provided both the patient and physician are aware that the treatment goal is to reduce LDL. In addition, rare patients with very high or very low levels of both LDL and HDL have ratios that are not interpretable on the basis of population studies. Although some laboratories offer measurements of individual apoproteins (e.g., apo B100 and apo AI), or size estimates of LDL, this information is not generally helpful in decision-making. Measurement of lipoprotein (a) levels can provide an indication of risk that cannot be gleaned from lipid measurements. Lipoprotein electrophoresis is not useful except for the diagnosis of dysbetalipoproteinemia, a diagnosis that otherwise requires ultracentrifugation methods. Apo E genotyping is also helpful in the diagnosis of dysbetalipoproteinemia (although rarely the disorder can be due to other defects in the apo E gene).
Both LDL and HDL cholesterol levels are temporarily decreased for several weeks after myocardial infarction or acute inflammatory states but can be accurately measured if blood is obtained within 8 h of the event.
^Approach to the Patient
Elevated LDL Cholesterol Treatment of elevated LDL cholesterol can have either of two aims¾primary prevention of the complications of atherosclerosis or secondary treatment after complications have occurred. The rationale for primary prevention is based on the large body of data linking elevated levels of LDL cholesterol with increased CHD risk and an impressive body of clinical and experimental data demonstrating that reducing LDL cholesterol slows progression and may actually induce regression of atherosclerotic lesions. Both primary and secondary intervention trials indicate that total mortality can be reduced when the LDL cholesterol is lowered. A meta-analysis of four randomized trials (4S, CARE, AFCAPS/TexCAPS, LIPID) comparing HMG-CoA reductase inhibitors to control included 30,817 participants and found that HMG-CoA reductase inhibitor treatment was associated with: (1) a 20% decrease in total cholesterol, a 28% decrease in LDL cholesterol, a 13% decrease in triglycerides, and a 5% increase in HDL cholesterol; (2) a 31% decrease in major coronary events and a 21% decrease in all-cause mortality; (3) similar risk reduction in women and men; and (4) no effect on noncardiovascular mortality. Unexpectedly, the risk of stroke was also reduced 19 to 32% by HMG-CoA reductase inhibitor treatment, even though previous observational studies show a relatively weak association between cholesterol level and stroke risk.
Dietary Alterations A fundamental starting point for both primary prevention and secondary treatment involves counseling to modify diet, exercise, smoking, and other life-style factors that increase the risk of CHD. The typical American diet derives about 35% of its calories from fat (14 to 15% from saturated fat) and contains 400 to 500 mg/d of cholesterol. Individuals with hyperlipidemia should be encouraged to eat a diet lower in cholesterol and saturated fat. The NCEP Step 1 diet, which is recommended for all Americans above age 2, provides 30% of calories from fat, <10% of calories from saturated fat, and <300 mg/d of cholesterol (Table 344-7). Carbohydrate is the typical nutrient used to replace fat in patients with isolated hypercholesterolemia. In general, whole-milk dairy products, egg yolks, meats, palm oil, and coconut oil should be replaced with fresh fruits and vegetables, complex carbohydrates (especially whole-grain products), and low-fat dairy products. Shellfish are low in fat content and, except for shrimp, also have low cholesterol levels; shrimp, in moderation, is acceptable. Portion size needs to be stressed; the protein and fat-rich portion of meat in a given meal should be <115 g (4 oz), the size of a deck of cards. Substitutions with any food low in saturated fat such as bran, nuts, and olive oil will have positive effects on LDL. Hydrogenation of vegetable oils increases the saturation of the fatty acids. In particular, trans-fatty acids, mainly found in commercially hydrogenated vegetable oils, raise LDL and can lower HDL cholesterol levels. Use of stanol-containing margarines has, by contrast, lowered LDL cholesterol about 5 to 10% by blocking cholesterol absorption in the small intestine. When further diet therapy is indicated, the NCEP Step 2 diet provides 30% of calories as fat but <7% of calories from saturated fat, and <200 mg/d of cholesterol. After changing from the average American diet to the Step 1 diet, the LDL cholesterol usually drops 8 to 10%; an additional reduction of 5 to 7% can be achieved by advancing to the Step 2 diet. There is, however, great individual variability in diet responsiveness, and several values should be obtained before judging the efficacy of any diet treatment.
Primary Prevention The NCEP Adult Treatment Panel recommends measuring plasma cholesterol in all adults older than age 20 at least every 5 years. Ideally, this testing involves a lipoprotein profile to allow better risk stratification. Primary prevention goals include LDL cholesterol <3.36 mmol/L (<130 mg/dL), triglycerides <1.7 mmol/L (<150 mg/dL), and HDL cholesterol >1.03 mmol/L (>40 mg/dL) for men and >1.29 mmol/L (>50 mg/dL) for women. In individuals without DM or known CHD, treatment recommendations for primary prevention are outlined in Fig. 344-2. Assessment of risk factors in addition to LDL cholesterol is an essential part of this decision-making process. Risk factors include: (1) family history of premature CHD (<55 years in a male parent or sibling or <65 in female relatives), (2) hypertension (even if it is controlled with medications), (3) cigarette smoking (>10 cigarettes per day), (4) DM, and (5) low HDL [<0.9 mmol/L (<35 mg/dL)]. In addition, because CHD is more prevalent in older individuals, age (men >45 years, women >55 years, or younger women with premature menopause without estrogen replacement) is also an important risk factor. HDL cholesterol >1.6 mmol/L (>60 mg/dL) is a negative risk factor, i.e., one other risk factor can be negated by a high HDL cholesterol level.
In individuals with fewer than two risk factors, life-style modifications alone and follow-up testing may be used if LDL is <4.14 mmol/L (<160 mg/dL). For those with LDL >4.91 mmol/L (>190 mg/dL), drug treatment is indicated. If two or more risk factors are present, drug treatment in addition to life-style modifications should be instituted if LDL cholesterol is >3.36 mmol/L (>130 mg/dL). HMG-CoA reductase inhibitors are first-line medications for most patients; niacin and resins are second-line treatments (see below).
Secondary Prevention The NCEP guidelines are stringent for the secondary treatment of patients with CHD. Patients with CHD should be screened for lipid abnormalities during and after their initial diagnoses. A goal of lowering plasma LDL concentrations to <2.6 mmol/L (<100 mg/dL) is advocated for such individuals as well as for patients with DM (Fig. 344-2). As described below, this requires modifications of diet in addition to the use of one or more medications.
If a patient with CHD has only a modestly elevated LDL cholesterol level [e.g., <3.36 mol/L (<130 mg/dL)], a 4- to 6-week period of Step 1 diet therapy can precede the addition of drugs. In such a patient, moving to the Step 2 diet, which provides the same total fat but <7% of calories from saturated fat, can be useful. If, however, the LDL cholesterol is >3.36 mmol/L (>130 mg/dL), drug therapy should be instituted along with diet therapy (Fig. 344-2).
High Triglycerides and Low HDL The evidence that treatment to reduce plasma triglyceride levels or increase levels of HDL cholesterol leads to long-term health benefits is less compelling than that for treatment of high LDL levels. Two recent clinical trials have shown, however, that lowering triglycerides (using fibric acids) or lowering LDL (HMG-CoA reductase inhibitors) decreases CHD events in these patients. There have been no intervention trials in which only increases in HDL cholesterol concentrations have been achieved. Beneficial effects of niacin have been attributed, in part, to its HDL-raising effect and its action to reduce triglycerides and LDL. Even with drugs that primarily affect LDL cholesterol levels, such as bile acid-binding resins and HMG-CoA reductase inhibitors, some of the benefits achieved may be related to increases in HDL cholesterol levels.
In patients with isolated elevations of triglyceride levels or with hypertriglyceridemia and high LDL cholesterol, life-style modifications should be introduced as described above, and weight reduction should be strongly encouraged if obesity is present. Fat intake should be decreased, but the concomitant increase in carbohydrate intake may raise triglyceride and lower HDL cholesterol levels. If this occurs, replacing some of the saturated fat with monounsaturated fat, which will not raise LDL cholesterol, may be valuable. Severe hypertriglyceridemia and hyperchylomicronemia require very low fat diets, avoidance of free sugars, and decreased alcohol intake. Patients with genetic LPL deficiency are instructed to prepare their food using medium-chain triglycerides, which are not incorporated into chylomicrons. Fish oils decrease triglyceride synthesis, and high doses may be used for severe hypertriglyceridemia.
The management of hypertriglyceridemia focuses on the associated LDL and HDL concentrations as guidelines for therapy. Thus, the overall risk profile can be used to set goals for LDL cholesterol, using a low HDL level (commonly associated with hypertriglyceridemia) as a concomitant major risk factor for atherosclerosis. However, when triglyceride levels are >5.6 mmol/L (>500 mg/dL), the risk of developing pancreatitis increases, and a direct focus on lowering triglycerides is recommended. Thus, triglyceride levels >5.6 mmol/L (>500 mg/dL) are generally treated with drugs, whereas lower levels [2.2 to 5.6 mmol/L (200 to 500 mg/dL)] are not treated unless other CHD risk factors are present .^
^TREATMENT
Three classes of lipid-lowering agents are recommended as first-line therapy against hypercholesterolemia: (1) the HMG-CoA reductase inhibitors; (2) niacin; and (3) the bile acid-binding resins . Fibric acid derivatives are second-line agents for hypercholesterolemia and are most effective for lowering triglycerides.
HMG-CoA Reductase Inhibitors This class of drugs, which include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin, inhibits the rate-limiting step in hepatic cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate), causing an increase in LDL receptor levels in hepatocytes and enhanced receptor-mediated clearance of LDL cholesterol from the circulation. At usual doses, the HMG-CoA reductase inhibitors decrease total cholesterol by 20 to 30% and LDL cholesterol by 25 to 40%. Larger reductions may be achieved with higher doses. Treatment with reductase inhibitors often reduces triglycerides by 10 to 20%, possibly due to reduced secretion of VLDL by the liver. Higher doses of more potent reductase inhibitors, which can lower LDL cholesterol by 45 to 60%, can lower triglycerides by 30 to 45%. HDL cholesterol levels rise about 5 to 10%. In comparison with other lipid-lowering agents, HMG-CoA reductase inhibitors are relatively free of side effects. Mild, transient elevations in liver enzymes occur with all of the a | | |
