Annabelle Rodriguez-Oquendo, Peter O. Kwiterovich, Jr.
32.1 Overview of Plasma Lipid and Lipoprotein Metabolism – 391 32.1.1 Exogenous Lipoprotein Metabolism – 391 32.1.2 Endogenous Lipoprotein Metabolism – 392 32.1.3 Reverse Cholesterol Transport and High Density Lipoproteins – 393 32.1.4 Lipid Lowering Drugs – 394
32.2 Disorders of Exogenous Lipoprotein Metabolism – 394 32.2.1 Lipoprotein Lipase Deficiency – 394 32.2.2 Apo C-II Deficiency – 395
32.3 Disorders of Endogenous Lipoprotein Metabolism – 395 32.3.1 Disorders of VLDL Overproduction – 396 32.3.2 Disorders of LDL Removal – 397
32.4 Disorders of Endogenous and Exogenous Lipoprotein Transport – 399 32.4.1 Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) – 399 32.4.2 Hepatic Lipase Deficiency – 400
32.5 Disorders of Reduced LDL Cholesterol Levels – 400 32.5.1 Abetalipoproteinemia – 400 32.5.2 Hypobetalipoproteinemia – 401 32.5.3 Homozygous Hypobetalipoproteinemia – 401
32.6 Disorders of Reverse Cholesterol Transport – 401 32.6.1 Familial Hypoalphalipoproteinemia – 401 32.6.2 Apolipoprotein A-I Mutations – 401 32.6.3 Tangier Disease – 402 32.6.4 Lecithin-Cholesterol Acyltransferase Deficiency – 402 32.6.5 Cholesteryl Ester Transfer Protein Deficiency – 402 32.6.6 Elevated Lipoprotein (a) – 403
32.7 Guidelines for the Clinical Evaluation and Treatment of Dyslipidemia – 403 32.7.1 Clinical Evaluation – 403 32.7.2 Dietary Treatment, Weight Reduction and Exercise – 404 32.7.3 Goals for Dietary and Hygienic Therapy – 405 32.7.4 Low Density Lipoprotein-Lowering Drugs – 406 32.7.5 Triglyceride Lowering Drugs – 407 32.7.6 Combination Pharmacotherapy – 408
Abbreviations – 408
References – 408 390 Chapter 32 · Dyslipidemias
Lipoprotein Metabolism Lipids are transported in plasma on lipoproteins, spher- for lipoprotein biosynthesis, or to downregulate LDL ical particles that consist of a hydrophobic core of trig- receptors and cholesterol biosynthesis. lycerides and cholesteryl esters, surrounded by an am- (2) The endogenous (hepatic) pathway transports phiphilic coating of apolipoproteins, phospholipids and triglycerides and cholesterol from the liver as VLDL unesterified cholesterol. The human plasma lipopro- (. Fig. 32.1). In the capillaries of muscle and fat, VLDL teins are classified according to their density and elec- are also hydrolyzed by lipoprotein lipase, yielding free trophoretic mobility (. Table 32.1), and a number of fatty acids for uptake. Their remnants, IDL, are in part species of apolipoproteins are known (. Table 32.2). Li- cleared from the circulation by the liver LDL receptor, poprotein metabolism involves three major pathways, and in part converted into LDL. LDL are taken up via which are briefly summarized here and reviewed in LDL receptors by a variety of extrahepatic tissues, where more detail in the first section of the chapter. they supply cholesterol mainly for membrane synthesis. (1) The exogenous (intestinal) pathway transports Liver also takes up LDL via LDL receptors and uses their mainly triglycerides from the diet, but also cholesterol cholesterol for the synthesis of bile acids or lipopro- of both dietary and biliary origin, as chylomicrons teins. (. Fig. 32.1). Lipoprotein lipase, an enzyme on the sur- (3) Reverse cholesterol transport involves release face of capillary endothelial cells that requires apo C-II of unesterified cholesterol from cells into plasma, fol- VII as cofactor, hydrolyzes chylomicron triglycerides into lowed by binding to HDL, conversion by LCAT of un- free fatty acids for uptake by muscle and fat. The result- esterified into esterified cholesterol, and transfer of the ant chylomicron remnants are taken up by the LDL re- latter via cholesteryl ester transfer protein to VLDL and ceptor-related protein (LRP) in liver, where they deliver ultimately IDL and LDL. HDL can also deliver choles- cholesterol that can be converted into bile acids, used teryl esters directly to the liver (. Fig. 32.2).
Major Nonhepatic Lipoprotein apolipoproteins capillary Uptake of Chylomicron B-48, E, C endothelium cholesterol
ase Chylomicron B-48, E lip remnant Endogenous in te ro 6 pathway p o p Free i IDL VLDL B-100, C, E fatty acids L IDL B-100 E Peripheral LDL tissues HTGL LDL B-100 (adipose VLDL 5 VLDL and muscle) remnant 4 Acetyl-CoA e MVA as 1 p Cholesterol li HMG- in 2 e Chyclomicron t CoA o r remnant p Liver o
p Bile acids
i 6 L Free Chyclomicron fatty acids
Bile Portal Exogenous duct vein pathway 3 Cholesterol Triglycerides 2
Bile acids Dietary Intestines fat
. Fig. 32.1. Pathways of exogenous and endogenous lipopro- inhibitor (3) all induce LDL receptors (4). Niacin (5), inhibits VLDL, tein metabolism. The metabolism of the apoB containing lipo- IDL and LDL production. The fibric acid derivatives (6) enhance li- proteins from the intestine and the liver are depicted. The site of poprotein lipase activity. See text for abbreviations. Modified and action of the lipid-lowering drugs are also shown. The statins (1), reproduced with permission from Braunwald E (ed) Essential atlas the bile acid sequestrants (2) and the cholesterol absorption of heart diseases, Appleton and Lange, Philadelphia, 1997, p 1.28 391 32 32.1 · Overview of Plasma Lipid and Lipoprotein Metabolism
32.1.1 Exogenous Lipoprotein Metabolism Conversion Factors The exogenous pathway of lipoprotein metabolism trans- mg/dl o mmol/l o mg/dl ports dietary fats from intestine to muscle, adipose tissue Cholesterol x 0.0259 x 38.6 and liver. After a meal is consumed, dietary lipids, mainly Triglycerides x 0.0114 x 87.7 triglycerides (TG), cholesteryl esters, and phospholipids, are Phospholipids x 0.323 x 77.5 emulsified by bile acids and hydrolyzed by pancreatic lipases into their component parts, monoglyceride and free fatty acids (FFA), and unesterified cholesterol and FFA, respec- tively. After absorption into the intestinal cells, the mono- 32.1 Overview of Plasma Lipid glycerides are reconverted into TG, and incorporated to- and Lipoprotein Metabolism gether with cholesterol into chylomicrons, which contain apolipoproteins A-I, A-II, A-IV, and B-48. The assembled Lipoproteins play an essential role in the delivery of free chylomicrons are secreted into the thoracic duct, a process fatty acids to muscle and adipose tissue where they, respec- that requires apo B-48. Thereafter, they enter the peripheral tively, serve as a fuel and are stored as triglycerides. Lipo- circulation, where they acquire apo E and apo C-I, apo C-II proteins also intervene in the transfer of cholesterol from and apo C-III by transfer from HDL. When they enter the intestine to liver, from liver to other tissues, and from the capillaries of skeletal muscle and adipose tissue, the chylo- latter back to the liver. The lipoprotein structure resembles microns are exposed to the enzyme lipoprotein lipase (LPL), a plasma membrane bilayer with hydrophilic phospholipids, located on the surface of the endothelial cells (. Table 32.3). apolipoproteins and some cholesterol on the outer surface, Apo C-II is necessary for activation of LPL, provoking hy- and hydrophobic triglycerides and cholesteryl esters in the drolysis of the TG into FFA which enter muscle and adipose core. The physical-chemical properties and composition of tissue. the major human plasma proteins are given in . Table 32.1. The resulting chylomicron remnants, still containing The plasma apolipoproteins are amphipathic proteins cholesterol, apo B-48 and apo E, the latter acting as a ligand that interact with both the polar aqueous environment of for the hepatic chylomicron remnant receptor, are taken blood, and the nonpolar core lipids. They serve various up into the liver, where they deliver dietary and biliary chol- functions such as ligands for receptors, cofactors for en- esterol (. Fig. 32.1). zymes, and structural proteins for packaging. The main characteristics of human plasma apolipoproteins are given in . Table 32.2.
. Table 32.1. Physical-chemical properties of human plasma lipoproteins
Class Density (g/ml) Electrophoretic Surface components Core lipids mobility Cholesterol Phospho- Apolipo- Triglycerides Cholesteryl lipids protein esters
Chylomicrons <0.95 Remains at origin 2 7 2 86 3
VLDL 0.950–1.006 Pre-β lipoproteins 7 18 8 55 12
IDL 1.006–1.019Slow pre-β lipo- 9 19 19 23 29 proteins
LDL 1.019–1.063 β-Lipoproteins 8 22 22 6 42
HDL-2 1.063–1.125 α-Lipoproteins 5 33 40 5 17
HDL-3 1.125–1.210 α-Lipoproteins 4 35 55 3 13
Lp(a) 1.040–1.090 Slow pre-β-lipo- proteins
VLDL, very low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. HDL- 2 and HDL-3 are the two major subclasses of HDL. Lp(a) consists of a molecule of LDL covalently attached to a molecule of apo(a), a protein homologous to plasminogen. Its lipid composition is similar to that of LDL. Compositions are given in % (by weight). 392 Chapter 32 · Dyslipidemias
. Table 32.2. Characteristics of human plasma apolipoproteins
Apolipoproteins Major tissue sources Functions Molecular weight
Apo A-I Co-factor LCAT 29,016 Apo A-II · Liver and intestine Not known 17,414 Apo A-IV Activates LCAT 44,465
Apo B-48 Intestine Secretion TG from intestine 240,800
Apo B-100 Liver Secretion TG from liver; binding ligand to LDL receptor 512,723
Apo C-I Activates LCAT; inhibits CETP 6,630 Apo C-II · Liver Cofactor LPL 8,900 Apo C-III Inhibits LPL 8,800
Apo D Many sources Reverse cholesterol transport 19,000
Apo E Liver Ligand for uptake of chylomicron remnants and IDL 34,145
LCAT, lecithin cholesterol acyl transferase; TG, triglyceride; LDL, low density lipoprotein; CETP, cholesteryl ester transfer protein; LPL, lipo- protein lipase; IDL, intermediate density lipoprotein VII
. Table 32.3. Key enzymes and transfer proteins of plasma lipid transport
Enzyme Major tissue source Functions Molecular weight
Lipoprotein lipase (LPL) Adipose tissue Hydrolyzes triglycerides and phospholipids of chylo- 50,394 Striated muscle microns and large VLDL
Hepatic lipase (HL) Liver Hydrolyzes triglycerides and phospholipids of small 53,222 VLDL, IDL, and HDL-2
Lecithin:cholesterol Liver Converts free cholesterol from cell membranes to 47,090 acyltransferase (LCAT) esterified cholesterol using a free fatty acid from phos- phatidylcholine on nascent (prebeta) HDL
Cholesterol ester trans- Liver, spleen and Transfers cholesteryl esters from HDL to apo B- contain- 74,000 port protein (CETP) adipose tissue ing triglyceride-rich lipoproteins Converts α HDL to pre-β HDL
Phospholipid transfer Placenta, pancreas, Transfers the majority of phospholipids in plasma 81,000 protein (PTP) adipose tissue, lung Converts α HDL to pre-β HDL
32.1.2 Endogenous Lipoprotein Liver LDL receptors are clustered on the surface of the Metabolism hepatocytes. They remove LDL particles by endocytosis. The cholesteryl esters are hydrolyzed to unesterified chol- The endogenous pathway of lipoprotein metabolism trans- esterol. Overaccumulation of intrahepatic cholesterol is ports TG and cholesteryl esters, synthesized in the liver, to prevented by cholesterol-induced down-regulation of the the peripheral tissues. Transport occurs under the form of transcription of the genes for the LDL receptor and the rate- VLDL with their major apolipoproteins, B-100, E, and C (I, limiting enzyme of cholesterol synthesis, hydroxymethyl- II, III). The VLDL triglycerides are transported to tissue glutaryl coenzyme A (HMG-CoA) reductase, by inhibiting capillaries, where they are hydrolyzed by LPL (that also the release of transcription factors, i.e. sterol regulatory hydrolyzes chylomicrons) and its co-factor apo C-II, and element binding proteins (SREBPs), from the cytoplasm thereby release FFA. The resulting VLDL remnants are into the nucleus [2]. Conversely, when the cholesterol pool further hydrolyzed, generating IDL. A portion of the IDL in the liver is low, there is an increased release of SREBPs is cleared from the circulation via direct uptake by the liver and an upregulation of LDL receptors and HMG CoA re- by the binding of IDL apoE to the LDL receptor (. Fig. 32.1). ductase. The remaining IDL can undergo further hydrolysis by LDL also supplies cholesterol to a variety of extrahe- hepatic lipase (. Table 32.3) to yield LDL. Most of LDL are patic parenchymal tissues, where it is used mainly for mem- removed from the peripheral circulation by binding of brane synthesis, and to adrenal cortical cells, where it serves apo B-100 to the liver LDL receptors. as a precursor for steroid synthesis. Like the liver, extra- 393 32 32.1 · Overview of Plasma Lipid and Lipoprotein Metabolism
hepatic tissues also have abundant LDL receptors. LDL ance in one often produces an abnormal effect in the other. cholesterol can also be removed via non-LDL receptor Thus, reduced LPL activity or decreased apo C-II, as well mechanisms. One class of cell surface receptors, termed as elevated apo C-III or apo C-I, can promote hypertrigly- scavenger receptors, takes up chemically modified LDL ceridemia and accumulation of remnant particles from such as oxidized LDL (. Fig. 32.1), which has been gener- both chylomicrons and VLDL. When the remnant particles ated by release of oxygen radicals from endothelial cells. are sufficiently small (Svedberg flotation units 20 to 60), Scavenger receptors are not regulated by intracellular chol- they can enter the vascular wall and promote atherogenesis. esterol levels. In peripheral tissues such as macrophages and The greater the cholesterol content of the remnants, the smooth muscle cells of the arterial wall, excess cholesterol more atherogenic they are. This scenario can be further accumulates within the plasma membrane, and then is complicated by VLDL overproduction or by reduced LDL transported to the endoplasmic reticulum where it is esteri- receptor activity. fied to cholesteryl esters by the enzyme, acyl-CoA choles- terol acyltransferase. It is at this stage that cytoplasmic droplets are formed and that the cells are converted into 32.1.3 Reverse Cholesterol Transport foam cells (an early stage of atherogenesis). Later on, choles- and High Density Lipoproteins teryl esters accumulate as insoluble residues in athero- sclerotic plaques. Reverse cholesterol transport (. Fig. 32.2) refers to the The optimal level of plasma LDL to prevent athero- process by which unesterified or free cholesterol is removed sclerosis and to maintain normal cholesterol homeostasis in from extrahepatic tissues, probably by extraction from humans is not known. At birth, the average LDL choles- cell membranes via the ATP binding cassette transporter terol level is 30 mg/dL. After birth, if the LDL cholesterol ABCA1, and transported on HDL [3]. HDL particles are level is <100 mg/dl, LDL is primarily removed through the heterogeneous and differ in their percentage of apolipopro- high affinity LDL receptor pathway. In Western societies, teins (A-I, A-II, and A-IV). HDL can be formed by remod- the LDL cholesterol is usually >100 mg/dl; the higher the eling of apolipoproteins cleaved during the hydrolysis of LDL-cholesterol the greater the amount that is removed by tri glyceride-rich lipoproteins (chylomicrons, VLDL and the scavenger pathway. IDL). They can also be synthesized by intestine, liver and While the exogenous and endogenous pathways are macrophages as nascent or pre-E HDL particles that are conceptually considered as separate pathways, an imbal- relatively lipid-poor and disc-like in appearance. Pre-E-1
. Fig. 32.2. The pathway for HDL metabolism and reverse cholesterol transport. See text for abbreviations. Modified and reproduced with permission from Braunwald E (ed) Essential atlas of heart diseases, Appleton & Lange, Philadelphia, 1997, p 1.29 394 Chapter 32 · Dyslipidemias
HDL is a molecular species of plasma HDL of approximate- 32.1.4 Lipid Lowering Drugs ly 67 kDa that contains apoA-I, phospholipids and unester- ified chol esterol, and plays a major role in the retrieval of In recent years, pharmacologic manipulation of the meta- cholesterol from peripheral tissues. HDL particles possess a bolic and cellular processes of lipid and lipoprotein me- number of enzymes on their cell surface [4]. One enzyme, tabolism (. Figs. 32.1 and 32.2) has greatly improved the lecithin-cholesterol acyltransferase (LCAT), plays a signifi- treatment of dyslipidemias. Inhibitors of the rate-limiting cant role by catalyzing the conversion of unesterified to es- enzyme of cholesterol synthesis, HMG-CoA reductase, terified cholesterol (. Fig. 32.2, Table 32.3). Esterified cho- called statins, effectively decrease the intrahepatic choles- lesterol is nonpolar and will localize in the center core of the terol pool (. Fig. 32.1) This effect, in turn, leads to the pro- HDL particle, allowing it to remove more unesterified cho- teolytic release of SREBPs from the cytoplasm into the lesterol from cells. Esterified cholesterol can be transferred, nucleus where they stimulate the transcription of the LDL via the action of cholesteryl ester transfer protein (CETP), receptor gene, resulting in an increased uptake of plasma to VLDL and IDL particles (. Fig. 32.2). These TG-rich li- LDL by the liver. Resins, which sequester bile acids, prevent poproteins can be hydrolyzed to LDL, which can then be entero-hepatic recycling and reuptake of bile acids through cleared by hepatic LDL receptor. Another enzyme that plays the ileal bile acid transporter. More hepatic cholesterol is a critical role in the metabolic fate of HDL is hepatic lipase converted into bile acids, lowering the cholesterol pool, and (HL), which hydrolyzes the triglycerides and phospho- thus also inducing LDL receptors (. Fig. 32.1). A choles- lipids on larger HDL particles (HDL-2), producing smaller terol absorption inhibitor interferes with the uptake of cho- VII HDL particles (HDL-3). Nascent HDL particles are re- lesterol from the diet and bile by a cholesterol transporter generated by the action of HL and phospholipid transfer (CT) (. Fig. 32.1). This decreases the amount of cholesterol protein (PTP) (. Table 32.3). HDL may also deliver choles- delivered by the chylomicron remnants to the liver, pro- teryl esters to the liver directly via the scavenger receptor ducing a fall in the hepatic cholesterol pool and induction SRB-1 (. Fig. 32.2) [3, 5]. of LDL receptors. Niacin, or vitamin B3, when given at high A number of epidemiological studies has shown an doses, inhibits the release of FFA from adipose tissue, de- inverse relationship between coronary artery disease (CAD) creases the hepatic production of apoB-100, leading to and HDL cholesterol. HDL are thought to be cardioprotec- decreased production of VLDL, and subsequently, IDL and tive due to their participation in reverse cholesterol trans- LDL (. Fig 32.1). Fibrates are agonists for peroxisome pro- port, and perhaps also by their role as an antioxidant [3]. liferator activator receptors (PPAR), which upregulate the HDL impedes LDL oxidation by metal ions, an effect that LPL gene and repress the apo C-III gene; both of these effects may be due to the influence of several molecules on HDL, enhance lipolysis of triglycerides in VLDL (. Fig. 32.1). including apoA-I, platelet-activating factor acetylhydrolase, Fibrates also increase apo A-I production, while niacin and paraoxonase [4]. Accumulation of HDL-2, thought to be decreases HDL catabolism, both leading to increased HDL the most cardioprotective of the HDL subclasses, is favored levels. by estrogens, which negatively regulate hepatic lipase. In contrast, progesterone and androgens, which positively reg- ulate this enzyme, lead to increased production of HDL-3. 32.2 Disorders of Exogenous Clinical studies have begun to address the effect of Lipoprotein Metabolism HDL cholesterol on cardiovascular endpoints. Men in the Veterans Administration High-density Lipoprotein Inter- Two disorders of exogenous lipoprotein metabolism are vention Trial, with known CAD and treated with gem- known. Both involve chylomicron removal. fibrozil for approximately 5 years, had a 24% reduction in death from CAD, nonfatal myocardial infarction and stroke, compared to men treated with placebo. This risk reduction 32.2.1 Lipoprotein Lipase Deficiency was associated with a 6% increase in HDL cholesterol, 31% decrease in triglyceride levels and no significant change in Patients with classic lipoprotein lipase (LPL) deficiency LDL cholesterol levels [6]. Further analysis using nuclear present in the first several months of life with very marked magnetic resonance spectroscopy indicated that the shift hypertriglyceridemia, often ranging between 5,000 to from small, dense LDL particles to larger LDL particles and 10,000 mg/dl (. Table 32.4). The plasma cholesterol level is an increase in HDL-3 with gemfibrozil explained a further usually 1/10 of the triglyceride level. This disorder is often amount of the percent reduction in CAD. In the Bezafibrate suspected because of colic, creamy plasma on the top of a Infarction Prevention Study, bezafibrate significantly raised hematocrit tube, hepatosplenomegaly, or eruptive xan- HDL cholesterol by 18% and reduced relative risk for thomas. Usually only the chylomicrons are elevated (type I nonfatal myocardial infarction and sudden death by 40% phenotype) (. Table 32.5), but occasionally the VLDL are in a subpopulation of study participants with triglycerides also elevated (type V phenotype). The disorder can present >200 mg/dl [7]. later in childhood with abdominal pain and pancreatitis, a 395 32 32.3 · Disorders of Endogenous Lipoprotein Metabolism
fants can be given Portagen, a soybean-based formula . Table 32.4. Guidelines for plasma triglyceride levels in containing medium-chain triglycerides (MCT). MCT do adults not require the formation of chylomicrons for absorption, Triglyceride levels Category since they are directly transported from the intestine to the liver by the portal vein. A subset of LPL-deficient patients mg/dl mmol/l with unique, possibly posttranscriptional genetic defects, <150 <1.71 Desirable respond to therapy with MCT oil or omega-3 fatty acids by normalizing fasting plasma triglycerides; a therapeutic trial 150–199 1.71–2.67 Borderline with MCT oil should, therefore, be considered in all patients 200–399 2.28–4.55 Elevated presenting with the familial chylomicronemia syndrome [8]. Older children may also utilize MCT oil to improve the 400–999 4.56–11.39 High palatability and caloric content of their diet. Care must be >1,000 >11.40 Very High taken that affected infants and children get at least 1% of their calories from the essential fatty acid, linoleic acid.
. Table 32.5. Lipoprotein phenotypes of hyperlipidemia 32.2.2 Apo C-II Deficiency
Lipoprotein phenotype Elevated lipoprotein Marked hypertriglyceridemia (TG >1,000 mg/dl) can also Type I Chylomicrons present in patients with a rare autosomal recessive disorder affecting apo C-II, the co-factor for LPL. Affected homo- Type IIa LDL zygotes have been reported to have triglycerides ranging Type IIb LDL, VLDL from 500 to 10,000 mg/dl (. Table 32.4). Apo C-II deficiency can be expressed in childhood but is often delayed into Type III Cholesterol-enriched IDL adulthood. The disorder is suspected by milky serum or Type IV VLDL plasma or by unexplained recurrent bouts of pancreatitis. A type V lipoprotein phenotype (. Table 32.5) is often Type VChylomicrons, VLDL found, but a type I pattern may also be present. Eruptive xanthomas and lipemia retinalis may also be found. As with the LPL defect, those with apo C-II deficiency do not get life-threatening complication of the massive elevation in premature atherosclerosis. chylomicrons. Lipemia retinalis is usually present, prema- The diagnosis can be confirmed by a PHLA test, and ture atherosclerosis is uncommon. measuring apo C-II levels in plasma, using an ELISA assay. Familial LPL deficiency is a rare, autosomal recessive Apo C-II levels are very low to undetectable. The deficiency condition that affects about one in one million children. can be corrected by the addition of normal plasma to the in Parents are often consanguineous. The large amounts of vitro assay for PHLA. chylomicrons result from a variety of mutations in the Apo C-II deficiency is even rarer than LPL deficiency LPL gene. and caused by a variety of mutations. Obligate heterozygous When chylomicrons are markedly increased, they can carriers of apo C-II mutants usually have normal plasma replace water (volume) in plasma, producing artifactual lipid levels, despite a 50% reduction in apo C-II levels. decreases in concentrations of plasma constituents; for ex- The treatment of patients with apo C-II deficiency is the ample, for each 1,000 mg/dl increase of plasma triglyceride, same as that discussed above for LPL deficiency. Infusion of serum sodium levels decrease between 2 and 4 meq/liter. normal plasma in vivo into an affected patient will decrease The diagnosis is first made by a test for post-heparin plasma triglycerides levels. lipolytic activity (PHLA). LPL is attached to the surface of endothelial cells through a heparin-binding site. After the intravenous injection of heparin (60 units/kg), LPL is re- leased and the activity of the enzyme is assessed in plasma 32.3 Disorders of Endogenous drawn 45 min after the injection. The mass of LPL released Lipoprotein Metabolism can also be assessed, using an ELISA assay. Parents of LPL deficient patients often have LPL activity halfway between These diseases comprise disorders of VLDL overproduc- normal controls and the LPL deficient child. The parents tion and of LDL removal. may or may not be hypertriglyceridemic. Treatment is a diet very low in fat (10–15% of calories) [8]. Lipid lowering medication is ineffective. Affected in- 396 Chapter 32 · Dyslipidemias
32.3.1 Disorders of VLDL Overproduction (hyperapoB), LDL subclass pattern B, and familial dyslipid- emic hypertension [9]. In addition to hypertension, patients Familial Hypertriglyceridemia with the small-dense LDL syndromes can also manifest Patients with familial hypertriglyceridemia (FHT) most of- hyperinsulinism, glucose intolerance, low HDL cholesterol ten present with elevated triglyceride levels with normal levels, and increased visceral obesity (syndrome X). LDL cholesterol levels (type IV lipoprotein phenotype) From a clinical prospective, FCHL and other small, (. Table 32.5). The diagnosis is confirmed by finding at dense LDL syndromes clearly aggregate in families with least one (and preferably two or more) first degree relatives premature CAD, and as a group, these disorders are the with a similar type IV lipoprotein phenotype. The VLDL most commonly recognized dyslipidemias associated with levels may increase to a considerable degree, leading to hyper- premature CAD, and may account for one-third, or more, cholesterolemia as well as marked hypertriglyceridemia of the families with early CAD. (>1,000 mg/dl) and occasionally to hyperchylomicronemia (type V lipoprotein phenotype) (. Table 32.5). This extreme Metabolic Derangement presentation of FHT is usually due to the presence of obesity There are three metabolic defects that have been described and type II diabetes. Throughout this spectrum of hyper- both in FCHL patients and in those with hyperapoB: triglyceridemia and hypercholesterolemia, the LDL choles- (1) overproduction of VLDL and apo B-100 in liver; (2) terol levels remain normal, or low normal. The LDL par- slower removal of chylomicrons and chylomicron remnants; ticles may be small and dense, secondary to the hypertri- and, (3) abnormally increased free-fatty acids (FFA) levels VII glyceridemia, but the number of these particles is not [9, 10]. increased (see also below). The abnormal FFA metabolism in FCHL and hyper- Patients with FHT often manifest hyperuricemia, in apo B subjects may reflect the primary defect in these pa- addition to hyperglycemia. There is a greater propensity to tients. The elevated FFA levels indicate an impaired meta- peripheral vascular disease than CAD in FHT. A family his- bolism of intestinally derived triglyceride-rich lipoproteins tory of premature CAD is not usually present. The unusual in the post-prandial state and, as well, impaired insulin- rarer patient with FHT who has a type V lipoprotein phe- mediated suppression of serum FFA levels. Fatty acids and notype may develop pancreatitis. glucose compete as oxidative fuel sources in muscle, such The metabolic defect in FHT appears to be due to the that increased concentrations of FFA inhibit glucose uptake increased hepatic production of triglycerides but the pro- in muscle and result in insulin resistance. Finally, elevated duction of apo B-100 is not increased. This results in the FFA may drive hepatic overproduction of triglycerides enhanced secretion of very large VLDL particles that are not and apo B. hydrolyzed at a normal rate by LPL and apoC-II. Thus, in It has been hypothesized that a cellular defect in the FHT there is not an enhanced conversion of VLDL into IDL adipocytes of hyperapoB patients prevents the normal sti- and subsequently, into LDL (. Fig. 32.1). mulation of FFA incorporation into TG by a small mole- Diet, particularly reduction to ideal body weight, is the cular weight basic protein, called the acylation stimulatory cornerstone of therapy in FHT. For patients with persistent protein (ASP) [11]. The active component in chylomicrons hypertriglyceridemia above 400 mg/dl, treatment with responsible for enhancement of ASP in human adipocytes fibric acid derivatives, niacin or the statins may reduce the does not appear to be an apolipoprotein, but may be trans- elevated triglycerides by up to 50%. Management of type II thyretin, a protein that binds retinol-binding protein and diabetes, if present, is also an important part of the manage- complexes thyroxin and retinol [11]. ASP also appears to be ment of patients with FHT (7 Sect. 32.7). generated in vivo by human adipocytes, a process that is accentuated postprandially, supporting the hypothesis that Familial Combined Hyperlipidemia ASP plays an important role in clearance of triglycerides and the Small Dense LDL Syndromes from plasma and fatty acid storage in adipose tissue [11]. Clinical Presentation Recently, Cianflone and co-workers [12] reported that an Patients with familial combined hyperlipidemia (FCHL) orphan G protein coupled receptor (GPCR), called C5L2, may present with elevated cholesterol alone (type IIa lipo- bound ASP with high affinity and promoted triglyceride protein phenotype), elevated triglycerides alone (type IV synthesis and glucose uptake. The functionality of C5L2 is lipoprotein phenotype), or both the cholesterol and tri- not known, nor is it known if there might be a defect in glycerides are elevated (type IIb lipoprotein phenotype) C5L2 in some patients with hyperapoB. (. Table 32.5). The diagnosis of FCHL is confirmed by the A defect in the adipocytes of hyperapoB patients might finding of a first degree family member, who has a different explain both metabolic abnormalities of TG-rich particles lipoprotein phenotype from the proband. Other charac- in hyperapoB. Following ingestion of dietary fat, chylomi- teristics of FCHL include the presence of an increased cron TG is hydrolyzed by LPL, producing FFA. The defect number of small, dense LDL particles, which link FCHL to in the normal stimulation of the incorporation of FFA into other disorders, including hyperapobetalipoproteinemia TG by ASP in adipocytes from hyperapoB patients leads to 397 32 32.3 · Disorders of Endogenous Lipoprotein Metabolism
increased levels of FFA that: (1) flux back to the liver in- exercise also appears important. Two classes of drugs, fibric creasing VLDL apo B production; and, (2) feedback inhibit acids and nicotinic acid, lower triglycerides and increase further hydrolysis of chylomicron triglyceride by LPL [9]. HDL and may also convert small, dense LDL to normal Alternatively, there could be a defect in stimulation of re- sized LDL. The HMG-CoA reductase inhibitors do not lease of ASP by adipocytes, perhaps due to an abnormal appear as effective as the fibrates or nicotinic acid in con- transthyretin/retinol binding system [11]. In that regard, verting small, dense LDL into large, buoyant LDL. However, plasma retinol levels have been found to be significantly the statins are very effective in lowering LDL cholesterol lower in FCHL patients. This may possibly also affect the and the total number of atherogenic, small, dense LDL par- peroxisome proliferator activator receptors which are ticles. In many patients with FCHL, combination therapy retinoic acid dependent. of a statin with either a fibrate or nicotinic acid will be Kwiterovich and colleagues isolated and characterized required to obtain the most optimal lipoprotein profile [9] three basic proteins (BP) from normal human serum [13]. (7 also Sect. 32.7). Patients with the small, dense LDL syn- BP I stimulates the mass of cellular triacylglycerols in cul- dromes appear to have a greater improvement in coronary tured fibroblasts from normals about two fold, while there stenosis severity on combined treatment. This appears to is a 50% deficiency in such activity in cultured fibroblasts be associated with drug-induced improvement in LDL from hyperapoB patients. In contrast, BP II abnormally buoyancy. stimulates the formation of unesterified and esterified cho- lesterol in hyperapoB cells [13]. Such an effect might further Lysosomal Acid Lipase Deficiency: Wolman accentuate the overproduction of apolipoprotein B and Disease and Cholesteryl Ester Storage Disease VLDL in hyperapoB patients [9]. Pilot data in hyperapoB Wolman disease is a fatal disease that occurs in infancy [18]. fibroblasts indicate a deficiency in the high-affinity binding Clinical manifestations include hepatosplenomegaly, steator- of BP I, but an enhanced high-affinity binding of BP II [13]. rhea, and failure to thrive. Patients have a lifespan that is HyperapoB fibroblasts have a baseline deficiency in protein generally under one year, while those with cholesteryl ester tyrosine phosphorylation that is not reversed with BP I, storage disease (CESD) can survive for longer periods of but is with BP II. These observations together suggest the time [19]. In some cases, patients with CESD have devel- existence of a receptor-mediated process for BP I and BP II oped premature atherosclerosis. that involves signal transduction [13]. We postulate that a Lysosomal acid lipase (LAL) is an important lysosomal defect in a BP receptor might exist in a significant number enzyme that hydrolyzes LDL-derived cholesteryl esters into of patients with hyperapoB and premature CAD. unesterified cholesterol. Intracellular levels of unesterified cholesterol are important in regulating cholesterol synthesis Genetics and LDL receptor activity. In LAL deficiency, cholesteryl The basic genetic defect(s) in FCHL and the other small, esters are not hydrolyzed in lysosomes and do not generate dense LDL syndromes are not known. FCHL and these unesterified cholesterol. In response to low levels of intrac- other syndromes are clearly genetically heterogeneous, and ellular unesterified cholesterol, cells continue to synthesize a number of genes (oligogenic effect) may influence the cholesterol and apo B-containing lipoproteins. In CESD, expression of FCHL and the small dense LDL syndromes [9, the inability to release free cholesterol from lysosomal 14, 15]. In a Finnish study, Pajukantaand coworkers mapped cholesteryl esters results in elevated synthesis of endog- the first major locus of FCHL to chromosome1q21–23, and enous cholesterol and increased production of apo B-con- recently provided strong evidence that the gene underlying taining lipoproteins. Wolman disease and CESD are auto- the linkage is the upstream transcription factor-1 (USF-1) somal recessive disorders due to mutations in the LAL gene gene [16]. USF-1 regulates many importantgenes in plasma on chromosome 10. lipid metabolism, including certain apolipoproteins and Lovastatin reduced both the rate of cholesterol synthesis HL. Linkage of type 2 diabetes mellitus as well as FCHL to and the secretion of apo B-containing lipoproteins, leading the region harboring the USF-1 gene has been observed in to significant reductions in total –197 mg/dl) and LDL several different populations worldwide [17], raising the (–102 mg/dl) cholesterol and triglycerides (–101 mg/dl) possibility that USF-1 may also contribute to the metabolic [20]. syndrome and type 2 diabetes.
Treatment and Prognosis 32.3.2 Disorders of LDL Removal The treatment of FCHL and hyperapoB starts with a diet reduced in total fat, saturated fat and cholesterol. This will These disorders, characterized by marked elevations of reduce the burden of post-prandial chylomicrons and plasma total and LDL cholesterol, provided the initial in- chylomicron remnants (which may also be atherogenic). sights into the role of LDL in human atherosclerosis. The Reduction to ideal body weight may improve insulin sensi- elucidation of the molecular defects in such patients, with tivity and decrease VLDL overproduction. Regular aerobic monogenic forms of marked hypercholesterolemia, has 398 Chapter 32 · Dyslipidemias
provided unique and paramount insights into the mecha- otic fluid cells, direct DNA analysis of the molecular nisms underlying cholesterol and LDL metabolism and the defect(s), or by linkage analysis using tetranucleotide DNA biochemical rationale for their treatment. Here we will polymorphisms. discuss six monogenic diseases that cause marked hyper- cholesterolemia: familial hypercholesterolemia (FH); fa- Treatment milial ligand defective apo B-100 (FDB); heterozygous FH3; Treatment of FH includes a diet low in cholesterol and sa- autosomal recessive hypercholesterolemia (ARH); sito- turated fat that can be supplemented with plant sterols or sterolemia, and cholesterol 7-α-hydroxylase deficiency. stanols to decrease cholesterol absorption. FH heterozy- gotes usually respond to higher doses of HMG-CoA reduc- Familial Hypercholesterolemia (LDL Receptor tase inhibitors. However, the addition of bile acid binding Defect) sequestrants or a cholesterol absorption inhibitor (see also Clinical Presentation below) is often necessary to also achieve LDL goals. Espe- Familial hypercholesterolemia (FH) is an autosomal domi- cially in those FH heterozygotes that may be producing nant disorder that presents in the heterozygous state with a increased amounts of VLDL, leading to borderline hyper- two- to three-fold elevation in the plasma levels of total and triglyceridemia and low HDL cholesterol levels, niacin LDL cholesterol [1]. Since FH is completely expressed at (nicotinic acid) may be a very useful adjunct to treatement. birth and early in childhood, it is often associated with pre- Nicotinic acid can also be used to lower an elevated Lp (a) mature CAD; by age 50, about half the heterozygous FH lipoprotein. FH homozygotes may respond somewhat to VII males and 25 percent of affected females will develop CAD. high doses of HMG-CoA reductase inhibitors and nico- Heterozygotes develop tendon xanthomas in adulthood, tinic acid, both of which decrease production of hepatic often in the Achilles tendons and the extensor tendons of VLDL, leading to decreased production of LDL. Choles- the hands. Homozygotes usually develop CAD in the sec- terol absorption inhibitors also lower LDL in FH homo- ond decade; atherosclerosis often affects the aortic valve, zygotes. In the end, however, FH homozygotes will re- leading to life-threatening supravalvular aortic stenosis. FH quire LDL apheresis every two weeks to effect a further homozygotes virtually all have planar xanthomas by the age lowering of LDL into a range that is less atherogenic. If of 5 years, notably in the webbing of fingers and toes and LDL apheresis is not sufficient, then heroic hepatic trans- over the buttocks. plantation may be considered. In the future, ex vivo gene therapy for FH homozygotes may become the treatment of Metabolic Derangement and Genetics choice [22]. FH is one of the most common inborn errors of metabolism and affects 1 in 500 worldwide (. Table 32.6). FH has a Familial Ligand-Defective Apo B higher incidence in certain populations, such as Afrikaners, Heterozygotes with familial ligand-defective apo B (FDB) Christian Lebanese, Finns and French-Canadians, due to may present with normal, moderately elevated, or mark- founder effects [21]. FH is due to one of more than 900 dif- edly increased LDL cholesterol levels [21] (. Table 32.6). ferent mutations in the LDL receptor gene [21]. About one Hypercholesterolemia is usually not as markedly elevated in in a million children inherit two mutant alleles for the LDL FDB as in patients with heterozygous FH, a difference at- receptor, presenting with a four- to eight-fold increase in tributed to effective removal of VLDL and IDL particles LDL cholesterol levels (FH homozygous phenotype). Based through the interaction of apo E with the normal LDL re- on their LDL receptor activity in cultured fibroblasts, ceptor in FDB. About 1/20 affected patients present with FH homozygotes are classified into LDL receptor-negative tendon xanthomas and more extreme hypercholesterolemia. (<2% of normal activity) or LDL receptor-defective (2–25% This disorder represents a small fraction of patients with of normal activity) homozygotes [1]. Most FH homozygotes premature CAD, i.e. no more than 1%. inherit two different mutant alleles (genetic compounds) In FDB patients, there is delayed removal of LDL from but some have two identical LDL receptor mutations (true blood despite normal LDL receptor activity. A mutant allele homozygotes). Mutant alleles may fail to produce LDL produces a defective ligand binding region in apo B-100, receptor proteins (null alleles), encode re ceptors blocked in leading to decreased binding of LDL to the LDL receptor. intracellular transport between endoplasmic reticulum and The most commonly recognized mutation in FDB is a mis- Golgi (transport-defective alleles), produce proteins that sense mutation (R3500Q) in the LDL receptor-binding do- cannot bind LDL normally (binding defective), those that main of apo B-100 [21]. The frequency of FDB heterozy- bind LDL normally, but do not internalize LDL (internali- gotes is about 1 in 1,000 in Central Europe but appears less zation defects), and those that disrupt the normal recycling common in other populations (. Table 32.6). Since the of the LDL receptor back to the cell surface (recycling clearance of VLDL remnants and IDL occurs through the d efects) [1]. binding of apo E, and not apo B, to the LDL (B, E) receptor, Prenatal diagnosis of FH homozygotes can be per- the clearance of these triglyceride enriched particles in this formed by assays of LDL receptor activity in cultured amni- disorder is not affected. 399 32 32.4 · Disorders of Endogenous and Exogenous Lipoprotein Transport
Dietary and drug treatment of FDB is similar to that 7–16% of the total plasma sterols. Patients often present in used for FH heterozygotes. Induction of LDL receptors will childhood with striking tuberous and tendon xanthomas enhance the removal of the LDL particles that contain the despite normal or FH heterozygote-like LDL cholesterol normal apo B-100 molecules, as well as increase the remov- levels. The clinical diagnosis is made by documenting the al of VLDL remnant and IDL that utilize apo E and not elevated plant sterol levels. The parents are normocholes- apo B-100 as a ligand for the LDL receptor. terolmic and have normal plant sterol levels. Two ABC half transporters, ABCG5 and ABCG 8 [21], Heterozygous FH3 together normally limit the intestinal absorption of plant Another form of autosomal dominant hypercholesterol- sterols and cholesterol and promote the elimination of these emia, termed heterozygous FH3 has been described [21]. dietary sterols in the liver. Sitosterolemia is caused by two While the clinical phenotype is indistinguishable from FH mutations in either of the two adjacent genes that encode heterozygotes, the disorder does not segregate with LDLR. these half-transporters (. Table 32.6), thereby enhancing The disorder results from a mutation in PCSK9, a gene that absorption of dietary sterols, and decreasing elimination of codes for neural apoptosis-regulated convertase 1, a mem- these sterols from liver into bile. This leads to suppression ber of the proteinase K family of subtilases. Further research of the LDL receptor gene, inhibition of LDL receptor syn- about the function of PCSK9, and its relation to LDL meta- thesis and elevated LDL levels. bolism, promises to provide new insights into the genetic Dietary treatment is very important in sitosterolemia and molecular control of marked hypercholesteromia and and primarily consists of diet very low in cholesterol and in very high LDL levels. plant sterols. Thus, in contrast to a standard low cholesterol, low saturated fat diet, plant foods with high fat, high Autosomal Recessive Hypercholesterolemia plant sterol content such as oils and margarines, must be Autosomal recessive hypercholesterolemia (ARH) is a rare avoided. Bile acid binding resins, such as cholestyramine, autosomal recessive disorder characterized clinically by LDL are particularly effective in lowering plant sterol and LDL cholesterol levels intermediate between FH heterozygotes sterol concentrations. The cholesterol absorption inhibitor, and FH homozygotes. ARH patients often have large tuber- ezetimibe, is also quite effective [23]. These patients re- ous xanthomas but their onset of CAD is on average later spond poorly to statins. than that in FH homozygotes. To date, most of the families reported have been Lebanese or Sardinian. The cholesterol Cholesterol 7α - Hydroxylase Deficiency levels in the parents are often normal, but can be elevated. Only a few patients have been described with a deficiency The ARH protein functions as an adapter linking the in the rate limiting enzyme of bile acid synthesis, choles- LDL receptor to the endocytic machinery [21]. A defect in terol 7α-hydroxylase that converts cholesterol into 7α-hy- ARH prevents internalization of the LDL receptor. Strik- droxy- cholesterol (7 Chap. 34 and . Fig. 34.1). Both hyper- ingly, in ARH there is normal LDL receptor activity in cholesterolemia and hypertriglyceridemia were reported fibroblasts but it is defective in lymphocytes. To date at least [21]. It is postulated that this defect increases the hepatic ten mutations have been described in ARH, all involving cholesterol pool, and decreases LDL receptors. As with the the interruption of the reading frame, producing truncated sitosterolemics, these subjects were relatively resistent to ARH [21]. statin therapy. Fortunately, patients with ARH respond quite drama- tically to treatment with statins, but some will also require LDL apheresis. A bile acid sequestrants or a cholesterol ab- 32.4 Disorders of Endogenous sorption inhibitor may be added to the statin to effect a and Exogenous Lipoprotein further reduction in LDL cholesterol. Transport
Sitosterolemia 32.4.1 Dysbetalipoproteinemia This is a rare, autosomal, recessive trait in which patients (Type III Hyperlipo proteinemia) present with normal to moderately to markedly elevated total and LDL cholesterol levels, tendon and tuberous This disorder is often associated with premature athero- xanthomas, and premature CAD [21]. Homozygotes mani- sclerosis of the coronary, cerebral and peripheral arteries. fest abnormal intestinal hyperabsorption of plant or shell Xanthomas are often present and usually are tuberoeruptive fish sterols (sitosterol, campesterol, and stigmasterol) and or planar, especially in the creases of the palms. O ccasionally, of cholesterol. In normal individuals, plant sterols are tuberous and tendon xanthomas are found. Patients with not absorbed and plasma sitosterol levels are low (0.3 to dysbetalipoproteinemia present with elevations in both 1.7 mg/dl) and are less than 1% of the total plasma sterol, plasma cholesterol and triglycerides, usually but not always, while in homozygotes with sitosterolemia, levels of total above 300 mg/dl. The hallmark of the disorder is the pre- plant sterols are elevated (13 to 37 mg/dl) and represent sence of VLDL that migrate as beta lipoproteins (E-VLDL), 400 Chapter 32 · Dyslipidemias
rather than prebeta lipoproteins (type III lipoprotein phe- the metabolism of both remnant lipoproteins and HDL notype) (. Table 32.5). E-VLDL reflect the accumulation (. Figs. 32.1 and 32.2). HL shares a high degree of homology of cholesterol-enriched remnants of both hepatic VLDL to LPL and pancreatic lipase. and intestinal chylomicrons (. Fig. 32.1) [24]. These rem- HL deficiency is a rare genetic disorder, which is in- nants accumulate because of the presence of a dysfunction- herited as an autosomal recessive trait. The frequency of al apoE, the ligand for the receptor-mediated removal of this disorder is not known, and it has been identified in only both chylomicron and VLDL remnants by the liver. a small number of kindreds. Obligate heterozygotes are There are two genetic forms of dysbetalipoproteinemia normal. The molecular defects described in HL deficiency [24]. The most common form is inherited as a recessive include a single A o G substitution in intron I of the HL trait. Such patients have an E2E2 genotype. The E2E2 geno- gene [26]. type is necessary but not sufficient for dysbetalipoprotein- HL deficiency can be distinguished from dysbeta- emia. Other genetic and metabolic factors, such as over- lipoproteinemia in two ways: first, the elevated triglyceride- production of VLDL in the liver seen in FCHL, or hormonal rich lipoproteins have a normal VLDL cholesterol/trigly- and environmental conditions, such as hypothyroidism, ceride ratio <0.3, because the triglyceride is not being low estrogen state, obesity, or diabetes are necessary for hydrolyzed by HL; and second, the HDL cholesterol often the full blown expression of dysbetalipoproteinemia. The exceeds the 95th percentile in HL deficiency but is low in recessive form has a delayed penetrance until adulthood dysbetalipoproteinemia. The diagnosis is made by a PHLA and a prevalence of about 1:2000. In the rarer form of the test (see above). Absent HL activity is documented by VII disorder, inherited as a dominant and expressed as hyper- measuring total PHLA activity, and HL and LPL activity lipidemia even in childhood, there is a single copy of an- separately. other defective apo E allele [24]. Treatment includes a low total fat diet. In one report, the The diagnosis of dysbetalipoproteinemia includes: dyslipidemia in HL deficiency improved on treatment with (1) demonstration of E2E2 genotype; (2) performing pre- lovastatin but not gemfibrozil. parative ultracentrifugation and finding the presence of E-VLDL on agarose gel electrophoresis (floating E lipopro- teins); and, (3) a cholesterol enriched VLDL (VLDL choles- 32.5 Disorders of Reduced LDL terol/triglyceride ratio > 0.30; normal ratio 0.30). LDL and Cholesterol Levels HDL cholesterol levels are low or normal. Patients with this disorder are very responsive to 32.5.1 Abetalipoproteinemia therapy . A low-fat diet is important to reduce the accumula- tion of chylomicron remnants, and reduction to ideal Abetalipoproteinemia is a rare, autosomal recessive dis- body weight may decrease the hepatic overproduction of order in patients with undetectable plasma apo B levels [27]. VLDL particles. The drug of choice is a fibric acid deriva- Patients present with symptoms of fat malabsorption and tive, but nicotinic acid and HMG-CoA reductase inhibitors neurological problems. Fat malabsorption occurs in infancy may also be effective. Treatment of the combined hyper- with symptoms of failure to thrive (poor weight gain and lipidemia in dysbetalipoproteinemia with a fibrate will steatorrhea). Fat malabsorption is secondary to the inability correct both the hypercholesterolemia and hypertrigly- to assemble and secrete chylomicrons from enterocytes. ceridemia; this effect is in contrast to treatment of FCHL Neurological problems begin during adolescence and in- with fibrates alone, which usually reduces the triglyceride clude dysmetria, cerebellar ataxia, and spastic gait. Other level, but increases the LDL cholesterol level. manifestations include atypical retinitis pigmentosa, anemia (acanthocytosis) and arrhythmias. Total cholesterol levels are exceedingly low (20 to 32.4.2 Hepatic Lipase Deficiency 50 mg/dl) and no detectable levels of chylomicrons, VLDL, or LDL are present. HDL levels are measurable but low. Patients with hepatic lipase (HL) deficiency can present Parents have normal lipid levels. with features similar to dyslipoproteinemia (type III hyper- It was initially thought that the lack of plasma apo B lipoproteinemia) (see above), including hypercholesterol- levels were due to defects in the APOB gene. Subsequent emia, hypertriglyceridemia, accumulation of triglyceride- studies have demonstrated no defects in the APOB gene. rich remnants, planar xanthomas and premature cardio- Immunoreactive apo B-100 is present in liver and intestinal vascular disease [25]. Recurrent bouts of pancreatitis have cells. Wetterau and colleagues [28] found that the defect in been described. The LDL cholesterol is usually low or synthesis and secretion of apo B is secondary to the absence normal in both disorders. of microsomal triglyceride transfer protein (MTP), a mole- HL hydrolyzes both triglycerides and phospholipids in cule that permits the transfer of lipid to apo B. MTP is a plasma lipoproteins. As a result, HL converts IDL to LDL heterodimer composed of the ubiquitous multifunctional and HDL-2 to HDL-3, thus playing an important role in protein, protein disulfide isomerase, and a unique 97-kDa 401 32 32.6 · Disorders of Reverse Cholesterol Transport
subunit. Mutations that lead to the absence of a functional 32.5.3 Homozygous Hypobetalipo- 97-kDa subunit cause abetalipoproteinemia. Over a dozen proteinemia mutant 97-kDa subunit alleles have been described. Treatment of patients with abetalipoproteinemia is dif- The clinical presentation of children with this disorder ficult. Steatorrhea can be controlled by reducing the intake depends upon whether they are homozygous for null alleles of fat to 5 to 20 g/day. This measure alone can result in in the APOB gene (i.e., make no detectable apo B) or homo- marked clinical improvement and growth acceleration. In zygous (or compound heterozygotes) for other alleles who addition, the diet should be supplemented with linoleic acid produce lipoproteins containing small amounts of apo B or (e.g., 5 g corn oil or safflower oil/day). MCT as a caloric a truncated apo B [29]. Null-allele homozygotes are similar sub stitute for long-chain fatty acids may produce hepatic phenotypically to those with abetalipoproteinemia (see fibrosis, and thus MCT should be used with caution, if at all. above) and may have fat malabsorption, neurologic disease, Fat-soluble vitamins should be added to the diet. Rickets and hematologic abnormalities as their prominent clinical can be prevented by normal quantities of vitamin D, but presentation and will require similar treatment (7 above). 200–400 IU/kg/day of vitamin A may be required to raise However, the parents of these children are heterozygous the level of vitamin A in plasma to normal. Enough vitamin for hypobetalipoproteinemia. Patients with homozygous K (5–10 mg/day) should be given to maintain a normal hypobetalipoproteinemia may develop less marked ocular prothrombin time. Neurologic and retinal complications and neuromuscular manifestations, and at a later age, than may be prevented, or ameliorated, through oral supplemen- those with abetalipoproteinemia. The concentrations of tation with vitamin E (150-200 mg/kg/day). Adipose tissue fat-soluble vitamins are low. rather than plasma may be used to assess the delivery of vitamin E. 32.6 Disorders of Reverse Cholesterol Transport 32.5.2 Hypobetalipoproteinemia 32.6.1 Familial Hypoalphalipoproteinemia Patients with hypobetalipoproteinemia often have a re- duced risk for premature atherosclerosis and an increased Hypoalphalipoproteinemia is defined as a low level of life span. These patients do not have any physical stigmata HDL cholesterol (<5th percentile, age and sex specific) in of dyslipidemia. The concentrations of fat-soluble vitamins the presence of normal lipid levels [30]. Patients with this in plasma are low to normal. Most patients have low levels syndrome have a significantly increased prevalence of CAD, of LDL cholesterol below the 5th percentile (approximately but do not manifest the clinical findings typical of other 40 to 60 mg/dl), owing to the inheritance of one normal forms of HDL deficiency (see below). Low HDL cholesterol allele and one autosomal dominant mutant allele for a levels of this degree are most often secondary to disorders truncated apolipoprotein B. Hypobetalipoproteinemia oc- of triglyceride metabolism (7 above). Consequently, pri- curs in about 1 in 2,000 people. mary hypoalphalipoproteinemia, although more prevalent Over several dozen gene mutations (nonsense and than the rare recessive disorders including deficiencies in frame shift mutations) have been shown to affect the full HDL, is relatively uncommon. In some families, hy- transcription of apolipoprotein B and cause familial hypo- poalphalipoproteinemia behaves as an autosomal dominant betalipoproteinemia. The various gene mutations lead to trait but the basic defect is unknown. Since it is likely that the production of truncated apolipoprotein B. the etiology of low HDL cholesterol levels is oligogenic Occasionally, hypobetalipoproteinemia is secondary (significant effect of several genes), Cohen, Hobbs and to anemia, dysproteinemias, hyperthyroidism, intestinal colleagues [31] tested whether rare DNA sequence variants lymphangiectasia with malabsorption, myocardial infarc- in three candidate genes, ABCA1, APOA1 and LCAT, tion, severe infections, and trauma. contributed to the hypoalpha phenotype. Nonsynonymous Plasma levels of truncated apo B are generally low and sequence variants were significantly more common (16% are thought to be secondary to low synthesis and secretion versus 2%) in individuals with hypoalpha (HDL cholesterol rates of the truncated forms of apo B from hepatocytes and <5th %) than in those with hyperalpha (HDL cholesterol enterocytes. The catabolism of LDL in hypobetalipo- >95th %). The variants were most prevalent in the ABCA1 proteinemia also appears to be increased. The diagnosis is gene. confirmed by demonstrating the presence of a truncated apoB in plasma. No treatment is required. Neurologic signs and symp- 32.6.2 Apolipoprotein A-I Mutations toms of a spinocerebellar degeneration similar to those of Friedreich ataxia and peripheral neuropathy have been The HDL cholesterol levels are very low (0–4 mg/dl), and found in several affected members. the apolipoprotein A-I levels are usually <5 mg/dl. Corneal 402 Chapter 32 · Dyslipidemias
clouding is usually present in these patients. Planar xantho- of Tangier disease can be confirmed by determining the mas are not infrequently described; the majority, but not all, reduced efflux of cholesterol from Tangier fibroblasts onto of these patients develop premature CAD [30, 32, 33]. an acceptor in the culture medium [36]. The APOA1 gene exists on chromosome 11 as part of a In general, patients with Tangier disease have an in- gene cluster with the APOC3 and APOA4 genes. A variety creased incidence of atherosclerosis in adulthood [30]. of molecular defects have been described in APOA1, in- Treatment with a low fat diet diminishes the abnormal cluding gene inversions, gene deletions, and nonsense and lipoprotein species that are believed to be remnants of ab- missense mutations. In contrast, APOA1 structural vari- normal chylomicron metabolism. ants, usually due to a single amino acid substitution, do not have, in most instances, any clinical consequences [33]. Despite lower HDL cholesterol levels (decreased by about 32.6.4 Lecithin-Cholesterol one half), premature CAD is not ordinarily present. In fact, Acyltransferase Deficiency in one Italian variant, APOA-IMilano, the opposite has been observed (i.e., increased longevity in affected subjects). In a Lecithin-cholesterol acyltransferase (LCAT) is an enzyme recent study by Nissen et al. [34], these investigators tested located on the surface of HDL particles and is important in proof of concept of apoA-IMilano by infusing recombinant transferring fatty acids from the sn-2 position of phospha- apoA-IMilano/phospholipid complexes (ETC-216) in a small tidylcholine (lecithin) to the 3-E-OH group on cholesterol group of adults between the ages of 30–75 years with acute (. Table 32.3). In this process, lysolecithin and esterified VII coronary syndrome. The study participants underwent cholesterol are generated (D-LCAT). Esterification can also five weekly infusions of placebo, low (15 mg/kg) or high occur on VLDL/LDL particles (E-LCAT). (45 mg/kg) dose of ETC-216. The primary outpoint, change In patients with classic LCAT deficiency, both D- and of percent atheroma volume as quantified by intravascular E-LCAT activity are missing [37]. LCAT deficiency is a rare, ultrasonography, decreased 3.2% (p<0.02) in subjects treat- autosomal, recessively inherited disorder. More than several ed with ETC-216, while the percent atheroma volume in- dozen mutations in this gene, located on chromosome 16, creased in the placebo group. have been described. The diagnosis should be suspected in patients presenting with low HDL cholesterol levels, corneal opacifications and renal disease (proteinuria, hematuria) . 32.6.3 Tangier Disease Laboratory tests include the measurement of plasma free cholesterol to total cholesterol ratio. Levels above 0.7 are Its name is derived from the island of Tangier in the diagnostic for LCAT deficiency. Chesapeake Bay in Virginia, USA, where Dr Donald In Fish Eye disease, only D-LCAT activity is absent. Pa- Fredrickson described the first kindred. HDL cholesterol tients present with corneal opacifications, but do not have levels are extremely low and of an abnormal composition renal disease [37]. It has been hypothesized that the va- (HDL Tangier or T). HDLT are chylomicron-like particles riability in clinical manifestations from patients with Fish on a high fat diet, which disappear when a patient consumes Eye disease, compared to LCAT deficiency, may reside in a low-fat diet [30]. the amount of total plasma LCAT activity. The characteristic clinical findings in Tangier patients To date, no therapies exist to treat the underlying include the presence of enlarged orange yellow tonsils, defects. Patients succumb primarily from renal disease, splenomegaly and a relapsing peripheral neuropathy. The and atherosclerosis may be accelerated by the underlying finding of orange tonsils is due to the deposition of beta nephrosis. Thus, patients with LCAT deficiency, and other carotene-rich cholesteryl esters (foam cells) in the lymph- lipid metabolic disorders associated with renal disease, atic tissue. Other sites of foam cell deposition include the should be aggressively treated including a low fat diet. This skin, peripheral nerves, bone marrow, and the rectum. Mild includes the secondary dyslipidemia associated with the hepatomegaly, lymphadenopathy and corneal infiltration nephrotic syndrome which responds to statin therapy. (in adulthood) may also occur. The APOA1 gene in Tangier patients is normal. The underlying defect has now been determined to be a defi- 32.6.5 Cholesteryl Ester Transfer Protein ciency in ABCA1, an ATP binding cassette transporter Deficiency [35]. Under normal circumstances, this plasma membrane protein has been shown to mediate cholesterol efflux to nas- The role of the cholesteryl ester transfer protein (CETP) in cent, apo A-I rich HDL particles (. Figs. 32.1 and 32.2). The atherosclerosis has not been well defined. The CETP gene presence of low HDL cholesterol in subjects with Tangier is upregulated in peripheral tissues and liver in response to disease is due to the lack of cholesterol efflux by the defi- dietary or endogenous hypercholesterolemia. HDL particles cient ABCA1 to nascent HDL and then increased catabo- isolated from patients with CETP deficiency may be less lism of this lipid-poor HDL particle. The clinical diagnosis effective in promoting cholesterol efflux from cultured cells. 403 32 32.7 · Guidelines for the Clinical Evaluation and Treatment of Dyslipidemia
This may be due to the increased concentration of choles- Lp(a). Plasma levels of Lp(a) in whites tend to be lower terol within the HDL particles and its inability to adsorb than in blacks (median values, 1 vs 10 mg/ml, respectively). additional cholesterol from peripheral tissues. Some inves- However, elevated plasma levels of Lp(a) do not correlate tigators have termed this type of HDL as being »dysfunc- directly with the extent of cardiovascular disease in African- tional«. Americans. It should be emphasized that Lp(a) is often not Elevated HDL cholesterol levels due to deficiency of measured accurately [43]. CETP were first described in Japanese families and several Niacin and estrogen can effectively lower Lp(a) levels, mutations have been found. Increased CAD in Japanese while the statins and fibrates do not. To date, clinical trial families with CETP deficiency was primarily observed evidence is lacking regarding the benefit of lowering Lp(a) for HDL cholesterol 41–60 mg/dl; for HDL cholesterol on the prevalence of cardiovascular disease. >60 mg/dl, men with and without mutations had low CAD prevalence [38]. Thus, genetic CETP deficiency may or may not be an independent risk factor for CAD. These effects oc- 32.7 Guidelines for the Clinical cur in spite of lower levels of apo B in CETP deficiency [39]. Evaluation and Treatment Due to its important role in modulating HDL levels, of Dyslipidemia CETP inhibitors have been developed to raise plasma HDL cholesterol levels. De Grooth et al [40] examined the safety 32.7.1 Clinical Evaluation and efficacy of the CETP inhibitor, JTT-705, in a ran- domized, double-blind, placebo controlled study of 198 The patient who is being evaluated for dyslipidemia re- subjects. Study subjects entered the active treatment phase quires a thorough family history and an evaluation of cur- and were randomized to placebo, JTT-705 300 mg once rent intake of dietary fat and cholesterol. The family history daily, 600 mg once daily, or 900 mg once daily for 4 weeks. is reviewed for premature (before 60 years of age) cardio- The activity of CETP decreased 37% in subjects taking the vascular disease (heart attacks, coronary artery bypasses, 900 mg dose, while HDL cholesterol levels increased in a coronary angioplasties, angina) cerebrovascular (strokes, dose-dependent manner, with a maximum rise of 34% in transient ischemic attacks) and peripheral vascular disease; subjects taking the 900 mg dose. LDL cholesterol levels dyslipidemia; diabetes mellitus; obesity; and, hypertension decreased 7% in the high dose group and triglyceride levels in grandparents, parents, siblings, children, and aunts and were unchanged. The effects of the CETP inhibitor CP- uncles. A dietary assessment is best performed by a regis- 529,414 (torcetrapib) on elevating HDL cholesterol were tered dietician. also examined by treating adults between the ages of 18 and The medical history is focused on the two major com- 55 years with placebo or torcetrapib 10, 30, 60, and 120 mg plications of dyslipidemias, atherosclerotic cardiovascular daily and 120 mg twice daily for 14 days [41]. The HDL disease and pancreatitis. The patient is asked about chest cholesterol levels increased from 16–91% with increasing pain, arrhythmias, palpitations, myocardial infarction, doses of this CETP inhibitor. Total cholesterol levels re- stroke (including transient ischemic attacks), coronary mained the same due to significant lowering of non-HDL artery bypass graft surgery, and balloon angioplasty. The cholesterol levels. In a separate study with torcetrapib, in- results of past resting and stress electrocardiograms and vestigators found that this inhibitor effectively increased coronary arteriography are assessed. Any history of recur- HDL cholesterol levels when given as monotherapy or in rent abdominal pain, fatty food intolerance and pancreatitis combination with atorvastatin [42]. is reviewed. The past and current use of lipid-lowering drugs is determined, as well as a history of an untoward reactions or side effects. The review of systems includes di- 32.6.6 Elevated Lipoprotein (a) seases of the liver, thyroid, and kidney, the presence of diabetes mellitus, and operations including transplantation. Lipoprotein (a) [Lp(a)] consists of one molecule of LDL For women, a menstrual history, including current use of whose apo B-100 is covalently linked to one molecule of oral contraceptives and post-menopausal estrogen replace- apolipoprotein (a) [apo(a)] by a disulfide bond [43]. The ment therapy, is obtained. physiol ogical function(s) of Lp(a) are unknown. Apo(a) is The presence of other risk factors for CAD [44, 45] are highly homologous to plasminogen, and when the Lp(a) systematically assessed: cigarette smoking, hypertension, level is elevated (>30 mg/dl for total Lp(a), >10 mg/dl for low HDL cholesterol (<40 mg/dl), age (>45 years in men, Lp(a) cholesterol), apo(a) interferes with the thrombolytic >55 years in women), diabetes (CAD risk equivalent), action of plasmin, promoting thrombosis. Lp(a) also ap- obesity, physical inactivity and atherogenic diet. An electro- pears to promote atherosclerosis, particularly in some fam- cardiogram is obtained. ilies, due to its similarity to LDL. Height and weight are determined to assess obesity Apo(a) exists in a number of size isoforms, with the using the Quetelet (body mass) index: weight (kg)/height smaller isoforms correlating with higher plasma levels of (m2). An index of 30 or higher is defined as obesity and 404 Chapter 32 · Dyslipidemias
between 25 and 30 is considered overweight. Waist circum- 32.7.2 Dietary Treatment, Weight ference can be measured (abnormal >40 inches in men, >35 Reduction and Exercise inches in women). The physical examination includes an assessment of tendon, tuberous and planar xanthomas. The The cornerstone of treatment of dyslipidemia is a diet eyes are examined for the presence of xanthelasmas, corneal reduced in total fat, saturated fat and cholesterol [44, 45] arcus, corneal clouding, lipemia retinalis, and atheroscle- (. Table 32.7). This is important to reduce the burden of rotic changes in the retinal blood vessels. The cardiovascu- post-prandial lipemia as well as to induce LDL receptors. lar exam includes an examination for bruits in the carotid, A Step I and Step II dietary approach is often used [44] abdominal, and femoral arteries, auscultation of the heart, (. Table 32.7), but most dyslipidemic patients will require a assessment of peripheral pulses and measurement of blood Step II Diet. The use of a registered dietician or nutritionist pressure. The rest of the exam includes palpation of the is usually essential to achieving dietary goals. The addition thyroid, assessment of hepatosplenomegaly and deep ten- of 400 I.U. or more of vitamin E and 500 mg or more of don reflexes (which are decreased in hypothyroidism). vitamin C is not currently recommended as an adjunct to The clinical chemistry examination includes (at the diet. There is no clear evidence that such supplementations minimum) a measurement of total cholesterol, total triglyce- decrease risk for CAD, and in fact may impair the treatment rides, LDL cholesterol and HDL cholesterol, a chemistry of dyslipidemia [46]. panel to assess fasting blood sugar, uric acid, tests of liver If a patient is obese (Quetelet index >30), or overweight and kidney function and thyroid stimulating hormone (Quetelet index 25–30), weight reduction will be an im- VII (TSH). We also assess the plasma levels of apo B and apo portant part of the dietary management. This is particu- A-I; apo B provides an assessment of the total number of larly true if hypertriglyceridemia or diabetes mellitus are atherogenic, apolipoprotein B-containing particles, while present. the ratio of apo B to apo A-I when > 1.0 often indicates high Regular aerobic exercise is essential in most patients risk of CAD and usually reflects an elevation in the apo B- to help control their weight and dyslipidemia. The dura- containing particles and a depression of the apo A-I-con- tion, intensity and frequency of exercise are critical. For taining particles. Other tests may be ordered when clini- an adult, a minimum of 1,000 calories per week of aerobic cally indicated, such as »non-traditional« risk factors for exercise is required. This usually translates into three or cardio vascular disease, i.e., Lp (a) lipoprotein, homo- four sessions a week of 30 min or more, during which cysteine, prothrombotic factors, small-dense LDL and time the patient is in constant motion and slightly out of highly sensitive C-reactive protein (hsCRP). HbA1C is breath. measured when a patient has known diabetes mellitus.
. Table 32.6. Major monogenic diseases that cause marked hypercholesterolemia. Modified with permission from Rader, Cohen and Hobbs [21]
Disease Defective gene Prevalence LDL-C Metabolic defect
Autosomal dominant
FH LDLR Decreased LDL clearance (10) Heterozygous FH 1 in 500 3X Increased LDL production (20) Homozygous FH 1 in 1 x 106 5X
FDB APOB Decreased LDL clearance Heterozygous FDB 1 in 1000 2X Homozygous FDB 1 in 4 x 106 3X
FH3 PCSK9 Unknown Heterozygous FH3 <1 in 2500 3X
Autosomal recessive
ARH ARH <1 in 5 x 106 4X Decreased LDL clearance Sitosterolemia ABCG5 or <1 in 5 x 106 1X to 5X ABCG8 Decreased cholesterol excretion(10) Decreased LDL clearance (20)
ARH, autosomal recessive hypercholesterolemia; FDB, familial ligand defective apoB-100; FH, familial hypercholesterolemia. X indicates the mean LDL-cholesterol (LDL-C) level in normals 405 32 32.7 · Guidelines for the Clinical Evaluation and Treatment of Dyslipidemia
32.7.3 Goals for Dietary and Hygienic Therapy . Table 32.7. National cholesterol education program diets: Step I and II
Four lipid parameters are used to define abnormal levels and Step I determine therapeutic goals: LDL cholesterol (. Table 32.8), 4 Less than 30% calories as fat: less than 10% saturated, triglycerides (. Table 32.4), HDL cholesterol (low <40 mg/dl) 10–15% monounsaturated, and up to 10% polyunsaturated 4 and non-HDL cholesterol (total cholesterol minus HDL 55% carbohydrates 4 15–20% protein cholesterol) [44]. If the goals for LDL cholesterol are achieved 4 Less than 300 mg cholesterol/day with dietary management alone, drug therapy is not recom- mended. The recommended goal for triglycerides is a level Step II 4 Less than 30% calories as fat: <7% saturated, 10-15% <150 mg/dl in adults; the ideal goal is <100 mg/dl. Values of mono unsaturated, and 10% polyunsaturated triglycerides >200 mg/dl are asso ciated with the presence of 4 Less than 200 mg cholesterol/day small, dense LDL particles in 80% of patients. Low HDL cholesterol is a value <40 mg/dl. The minimum treatment goal for HDL cholesterol is >40 mg/dl. The most recent recommendations from the National LDL cholesterol levels with atorvastatin 80 mg/day reduced Cholesterol Education Program (NCEP) [45] offer guide- cardiovascular event rates in patients with acute coronary lines for assessing risk and initiating treatment in patients syndrome [47] and slowed atherosclerotic progression [48] with hypercholesterolemia. As shown in . Table 32.7, die- more than standard lipid-lowering therapy. In fact, in these tary intervention is used initially in the treatment of pa- studies, a target LDL cholesterol level of <70 mg/dl con- tients with dyslipidemia. A more aggressive reduction in the ferred greater benefit than a level of <100 mg/dl. Sub- total daily allowance of saturated fat and cholesterol is used sequent analyses from these studies showed that highly in patients with CAD or those failing to respond to the Step sensitive C-reactive protein (hsCRP) was an important in- I diet. Patients with CAD should be placed simultaneously dependent predictor of events [49, 50]. Further, patients in on the Step II diet and lipid-lowering drug therapy. Ideally, the Heart Protection Study [51], who had CAD, diabetes, all patients should be formally counseled by a registered and/or hypertension, had a significant reduction in CAD dietitian. Physicians should reinforce the importance of the events and death when treated with 40 mg of simvastatin, dietary plan for their patients. despite baseline LDL cholesterol levels already »at goal« The value of pharmacologically lowering lipid levels to <100 mg/dl. reduce cardiovascular event rates is well established, but the As the result of these latest clinical trials, the NCEP has optimal level of cholesterol has not yet been determined. established new lipid-lowering guidelines for primary and Several recent studies showed that intensive lowering of secondary prevention of CAD [45] (. Table 32.8). As be-
. Table 32.8. NCEP-ATP III guidelines for LDL-lowering pharmacotherapy initiation and goals. Adapted from the National Cholesterol Education Program, Adult Treatment Panel III [44, 45]
Patient category Initiation of drug therapy Therapeutic goal LDL cholesterol (mg/dl) LDL cholesterol (mg/dl)
High risk ≥100 <100 CAD or CAD risk equivalents (<100: consider drug options)1 (optional goal: <70)1 (10-year risk >20%)
Moderately high risk ≥130 <130 No CAD and >2 risk factors (10-year risk 10–20%)2 (100–129: consider drug options)1 (optional goal: <100)1
Moderate risk ≥160 <130 No CAD and <2 risk factors (10-year risk ≤20%)
Lower risk ≥190 <160 0–1 risk factor (160–189: LDL-lowering drug therapy optional)
1 Drug therapy advisable on the basis of clinical trials. The optional goal of LDL cholesterol in high risk patients is <70 mg/dl, or in those with high triglycerides (>200 mg/dl), a non-HDL cholesterol <100 mg/dl. The optional goal of LDL cholesterol in moderately risk patients is <100 mg/dl, or in those with high triglycerides, a non-HDL cholesterol <130 mg/dl. 2 Positive risk factors for CAD are cigarette smoking, hypertension, low HDL cholesterol (<40 mg/dl), age (>45 years in men, >55 years in women), diabetes, obesity, physical inactivity and atherogenic diet). CAD, coronary artery disease; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol. 406 Chapter 32 · Dyslipidemias
fore, the threshold of the LDL cholesterol level to initiate Statins undergo extensive first-pass metabolism via the drug therapy and the target for treatment depends on the hepatic portal system and typically less than 20% of these presence or absence of CAD, CAD risk equivalents, and agents reaches systemic circulation [51]. In the liver the associated risk factors. In this latest classification, for pa- statins inhibit the rate limiting enzyme of cholesterol bio- tients with CAD or CAD risk equivalents, the minimum synthesis, HMG-CoA reductase, (. Fig. 32.1) leading to a target for LDL cholesterol is <100 mg/dl with an optional decrease in hepatic cholesterol stores, increasing the release target of <70 mg/dl For those at moderate risk (at least two of SREBPs, stimulating the production of LDL receptors risk factors for CAD), the minimum target for LDL choles- and lowering the LDL levels significantly. The statins also terol is <130 mg/dl with an optional target of <100 mg/dl. improve endothelial cell function and stabilize unstable The guidelines provide recommendations for complete plaques [49, 50]. screening of TC, LDL cholesterol, HDL cholesterol, and TG, Statins are generally well tolerated, and have an excellent encouraging the use of plant sterols or stanols, and soluble safety profile with minimal side effects. Liver function tests fiber, and treatment using non-HDL cholesterol (total (AST, ALT) should be monitored at baseline, following 6– cholesterol minus HDL cholesterol) guidelines for patients 8 weeks after initiating treatment and every 4 months for with TG t200 mg/dl [44, 45]. For those with hypertri- the first year. After that, patients on a stable dose of a statin glyceridemia (>200 mg/dl), the optional targets for the high can have their liver function tests monitored every six risk and moderate risk groups, are a non-HDL cholesterol months. Consideration should be given to reducing the of <100 mg/dl and <130 mg/dl, respectively. dosage of drug, or its discontinuation, should the liver func- VII tion tests exceed 3 times the upper limits of normal. In clinical trials the discontinuation rate due to elevation of 32.7.4 Lo w Density Lipoprotein-Lowering transaminases was less than 2%. Between 1/500 to 1/1,000 Drugs patients may develop myositis on a statin which can lead to life threatening rhabdomyolysis. Rhabdomyolysis is a rare Agents which will lower LDL cholesterol include inhibitors event, occurring at an incidence of 1.2 per 10,000 patient- of HMG-CoA reductase (the statins), bile acid sequestrants, years [52]. Creatine kinase (CK) should be measured at cholesterol absorption inhibitors, and niacin (nicotinic baseline and repeated if the patient develops muscle aches acid) (. Table 32.9). The fibrates can also modestly reduce and cramps. The statin is discontinued if the CK is >5x the LDL cholesterol levels, but in hypertriglyceridemic pa- upper limit of normal in those with symptoms of myositis, tients with FCHL, LDL levels may stay the same or actually or >10x the upper limit of normal in asymptomatic patients. increase [36]. CK is not routinely measured in patients at follow-up since The statins available in Europe and the U.S.A. include it is not predictive of who will develop rhabdomyolysis. atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Me- Three statins, lovastatin, simvastatin and atorvastatin, vacor), pravastatin (Pravachol), simvastatin (Zocor) and are metabolized by the CYP3A4 isozyme of the cytochrome rosuvastatin (Crestor) [44, 45]. The equivalent doses are P450 microsomal enzyme system, and consequently have about: 5 mg rosuvastatin = 10 mg atorvastatin = 20 mg drug interactions with other agents metabolized by simvastatin = 40 mg lovastatin = 40 mg pravastatin = 80 mg CYP3A4. Inhibitors of CYP3A4 include erythromycin, fluvastatin. Lovastatin, simvastatin and pravastatin are fluvoxamine, grapefruit juice, itraconazole, ketoconazole, derived from a biological product, while atorvastatin, nefazodone, and sertraline. Drugs that are substrates for fluvastatin and rosuvastatin are entirely synthetic pro- CYP3A4 may also increase the level of the statin in the ducts. blood and include: antiarrhythmics (lidocaine, propafenone
. Table 32.9. Effect of drug classes on plasma lipid and lipoprotein levels. Adapted and modified from Gotto AM Jr (1992) Manage- ment of lipid and lipoprotein disorders. In: Gotto AM Jr, Pownall HJ (eds) Manuel of lipid disorders. Williams & Wilkins, Baltimore, MD
Drug class TC LDL-C HDL-C TG
Statins 15–60% 20–60% 3–10% 10–30%
Bile acid resins 10–20% 15–20% 3–5% Variable
Cholesterol absorption inhibitor 10–20% 15–20% 3–5% 5–10%
Niacin 25% 10–15% 15–35% 20–50%
Fibrates 15% Variable 6–15% 20–50%
TC, total cholesterol; LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; TG, triglycerides. 407 32 32.7 · Guidelines for the Clinical Evaluation and Treatment of Dyslipidemia
and quinidine), benzodiazepines, calcium channel blockers, administration with fibrates increased plasma levels of amiodarone, carbamazepine, clozapine, cyclosporine, and ezetimibe. Ezetimibe should not be used in patients on nonsedating antihistamines. Statins are not safe in pregnant cyclosporine until more data are available. or nursing women, and should not be used in patients with Niacin (nicotinic acid) is vitamin B3. When given in active or chronic hepatic disease or cholestasis because of high doses, niacin becomes a lipid-altering agent. Niacin potential hepatotoxicity. inhibits the release of free fatty acids from adipose tissue, The bile acid resins (cholestyramine (Questran), colesti- leading to decreased delivery of FFA to liver and reduced pol (Colestid), and colesevalam (Welchol) do not enter the triglyceride synthesis. As a result, the proteolysis of apo B- blood stream, but bind bile acids in the intestine, preventing 100 is increased, leading to decreased VLDL secretion and their reabsorption (. Fig 32.1). More cholesterol is con- subsequently, to decreased IDL and LDL formation verted into bile acids in the liver, decreasing the cholesterol (. Fig. 32.1). This is associated with a decreased formation pool, increasing the proteolytic release of SREBPs, leading of small, dense LDL particles. Niacin also inhibits the to upregulation of LDL receptors and lower LDL levels uptake of HDL through its catabolic pathway, prolonging (. Table 32.9). There is a compensatory increase in hepatic the half-life of HDL, and presumably increasing reverse cholesterol synthesis that limits the efficacy of the seques- cholesterol transport. Niacin is also the only lipid-altering trants. The side effects of the resins include constipation, drug that reduces Lp(a) lipoprotein. Niacin is commonly heart burn, bloating, decreased serum folate levels, and prescribed in those patients with the dyslipidemic triad interference of the absorption of other drugs. The second (low HDL, elevated triglycerides and increased small, dense generation sequestrant, colesevalam, does not appear to LDL) (. Table 32.9). Niacin is useful in treating FCHL and interfere with the absorption of other drugs, and in general in those with isolated low HDL cholesterol. Niacin should is associated with a lower prevalence of annoying side ef- not be used in patients with active peptic ulcer disease or fects such as constipation, because it is given in a lower dose liver disease. Niacin can precipitate the onset of type II dia- than the first generation sequestrants. betes mellitus or gout. In patients with borderline or elevated The cholesterol absorption inhibitor, ezetimibe, a 2-aze- fasting blood sugar or uric acid levels, niacin should be used tidinone, is currently the only member of this drug class. with care. Niacin is no longer contraindicated in patients Ezetimibe inhibits the intestinal absorption of cholesterol with type II diabetes who are under good control. The derived from the diet and from the bile by about 50% modest increase in blood sugar with niacin can usually be (. Fig. 32.1). Ezetimibe thus reduces the overall delivery of compensated for by adjusting the diabetic medications. cholesterol to the liver, decreasing hepatic cholesterol, in- There are a number of niacin preparations available over creasing the release of SREBPs, promoting the upregulation the counter or by prescription. Immediate crystalline niacin of LDL receptor, and decreasing LDL cholesterol levels. The can be purchased in most pharmacies and health food use of ezetimibe is associated with a compensatory increase stores. The slow release niacin products and the extended in cholesterol biosynthesis, limiting its efficacy. The me- release niacin (Niaspan) are available by prescription. The chanism of action of ezetimibe presumably occurs through slow release niacin is not associated with flushing but the selective inhibition of a newly discovered transporter has been reported to have a greater propensity to increase that moves cholesterol from bile acid micelles into the cells liver function tests. Niaspan also decreases flushing but of the jejunum [54]. The transporter is a Niemann-Pick the prevalence of abnormal liver function tests with Niaspan C1-like 1 (NPC1L1) protein localized at the brush border of is comparable to regular niacin. Niaspan has also been com- enterocytes [54]. Ezetimibe significantly reduces choles- bined with lovastatin (Advicor, Kos Pharmaceuticals), and terol absorption in animals homozygous for wild type can be used in those with an elevated LDL cholesterol, a NPC1L1, but has no effect in NPC1L1 knock-out mice [54]. reduced HDL cholesterol, and hypertriglyceridemia. Ezetimibe is absorbed from the intestine and in the liver is conjugated to a more active glucuronide form, which undergoes enterohepatic circulation. This process increases 32.7.5 Triglyceride Lowering Drugs its elimination half-life to about 22 h. Ezetimibe is usually well-tolerated, and there are generally few drug interactions Those drugs that can effectively lower triglycerides include with this drug. Ezetimibe can be combined with any of the nicotinic acid, fibrates, and statins (particularly when used statins producing, on average, an additional 25% reduction at their highest doses). A 30 to 50% reduction in trigly- in LDL cholesterol. Ezetimibe is also available combined cerides is often achieved (. Table 32.9). with simvastatin in a single formulation (Vytorin). Ezetimibe One theoretical advantage of niacin and fibrate therapy should not be used for combination therapy with a statin in for hypertriglyceridemia is the improvement or shift of patients with active liver disease or unexplained persistent dense subfractions (pattern B) to lighter subfractions (pat- elevations in serum transaminases, or those with chronic or tern A) (54). The measurement of dense LDL or HDL sub- severe liver disease. Co-administration of ezetimibe with fractions can be made by density gradient electrophoresis cholestyramine decreased the levels of ezetimibe, and co- or nuclear magnetic resonance spectroscopy. These dif- 408 Chapter 32 · Dyslipidemias
ferent methodologies have shown the existence of a num- IDL intermediate density lipoproteins ber of lipoprotein subfractions. Prospective epidemiologic LAL lysosomal acid lipase studies, clinical trials, and in vitro studies have all suggested LCAT lecithin:cholesterol acyltransferase that dense LDL is more atherogenic and that a shift to LDL low density lipoproteins lighter subfractions may reduce risk for CAD. Fibrates LPL lipoprotein lipase can also effectively lower triglyceride levels and raise HDL LRP LDL receptor-related protein cholesterol [54] (. Table 32.9). MCT medium-chain triglycerides MTP microsomal triglyceride transfer protein PHLA post-heparin lipolytic activity 32.7.6 Combination Pharmacotherapy SREBP sterol regulating element binding protein TG triglycerides Statin therapy is most often started initially in those with VLDL very low density lipoproteins CAD or CAD risk equivalence. 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