Basic and Clinical Endocrinology 7th International student edition Edition
Disorders of Lipoprotein Metabolism
Mary J. Malloy MD
John P. Kane MD, PhD
The clinical importance of hyperlipoproteinemia derives chiefly from the role of lipoproteins in atherogenesis. The greatly increased risk of acute pancreatitis associated with severe hypertriglyceridemia is an additional indication for intervention. Disordered lipid metabolism also underlies the syndrome of nonalcoholic steatohepatitis (NASH). Characterization of hyperlipoproteinemia is important for selection of appropriate treatment and may provide clues to underlying primary clinical disorders.
Arteriosclerosis is the leading cause of death in the USA. Abundant epidemiologic evidence establishes its multifactorial character and indicates that the effects of the multiple risk factors are at least additive. Risk factors for atherosclerosis include hyperlipidemia, hypertension, smoking, diabetes, physical inactivity, decreased levels of high-density lipoproteins (HDL), hyperhomocysteinemia, and hypercoagulable states. Certain infectious agents may also be involved. Atheromas are complex lesions containing cellular elements, collagen, and lipids. The progression of the lesion is chiefly attributable to its content of unesterified cholesterol and cholesteryl esters. Cholesterol in the atheroma originates in circulating lipoproteins. Atherogenic lipoproteins include low-density (LDL), intermediate-density (IDL), very low density (VLDL), and Lp(a) species, all of which contain the B-100 apolipoprotein. All the apo B-containing lipoproteins are subject to oxidation by reactive oxygen species in the tissues and also by lipoxygenases secreted by macrophages in atheromas. Oxidized lipoproteins cause impairment of endothelial cell-mediated vasodilation and stimulate endothelium to secrete monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules that recruit monocytes to the lesion. Tocopherols (vitamin E) are natural antioxidants that localize in the surface monolayers of lipoproteins, exerting resistance to oxidation. Increased oxidative stress such as that induced by smoking depletes the tocopherol content. Oxidation of lipoproteins stimulates their endocytosis via scavenger receptors on macrophages and smooth muscle cells, leading to the formation of foam cells. At least four classes of scavenger receptors are recognized. Two are splice variant products of a single gene (class A receptors). Another is a CD36 type protein, and the fourth is an Fc receptor.
Hypertension increases access of lipoproteins to the subintima. Smoking accelerates atherogenesis by reducing HDL and increasing thrombogenesis by platelets—in addition to its pro-oxidant effect. Activated platelets release platelet-derived growth factor (PDGF), stimulating
migration and proliferation of cells of smooth muscle origin into the lesion.
Activated macrophages secrete cytokines that drive an inflammatory and proliferative process. Metalloproteases secreted by macrophages weaken the atheroma so that fissuring and rupture can occur. Exposure of blood to subintimal collagen and tissue factor stimulates thrombogenesis, precipitating acute coronary events. Emerging evidence suggests that infectious agents such as Chlamydia pneumoniae may contribute to the inflammatory component of atherogenesis in some patients. The inverse relationship between HDL levels and atherogenesis probably reflects the role of certain species of HDL in cholesterol retrieval from the atheroma and in protecting lipoproteins against oxidation.
Reversal of Atherosclerosis
Angiographic intervention trials have shown that regression of atherosclerotic lesions occurs with lipid-lowering therapy. Large trials have demonstrated striking reductions in the incidence of new coronary events in individuals with hyperlipidemia who have had no prior clinical coronary disease (primary prevention) as well as in patients with antecedent clinical coronary disease (secondary prevention). Thus, timely hypolipidemic therapy appropriate to the lipid disorder will decrease the incidence of coronary disease and reduce the need for angioplasty, atherectomy, and bypass surgery. In the intervention trials involving treatment with HMG-CoA reductase inhibitors and with niacin, all-cause mortality was significantly reduced. Side effects of treatment have been minimal in comparison with the magnitude of this benefit.
Average levels of LDL in the United States and northern Europe are higher than in many other nations, where the levels appear to approach the biologic norm for humans. This probably accounts in large part for the higher incidence of coronary disease in industrialized Western nations and suggests that dietary changes that reduce lipoprotein levels would be beneficial.
OVERVIEW OF LIPID TRANSPORT
The Plasma Lipoproteins
Because lipids are relatively insoluble in water, they are transported in association with proteins. The simplest complexes are those formed between unesterified, or free, fatty acids (FFA) and albumin, which serve to carry the FFA from peripheral adipocytes to other tissues.
The remainder of the lipids are transported in spherical lipoprotein complexes (Table 19-1), with core regions containing hydrophobic lipids. The principal core lipids are cholesteryl esters and triglycerides. Triglycerides predominate in the cores of chylomicrons, which transport newly absorbed lipids from the intestine, and in VLDL, which originate in liver. The relative content of cholesteryl ester is increased in the cores of remnants derived from these lipoproteins. Cholesteryl esters are the predominant core lipid in LDL and HDL. Surrounding the core in each lipoprotein is a monolayer containing amphiphilic phospholipids and unesterified (free) cholesterol. Apolipoproteins, noncovalently bound to the lipids, are located on this surface monolayer (Figure 19-1).
Table 19-1. Lipoproteins of human serum.
Figure 19-1. Metabolism of chylomicrons. (TG, triglyceride; CE;, cholesteryl esters; A-1, A-II, B-48, and C proteins, apolipoproteins.) See text for details.
Several lipoproteins contain very high molecular weight B apolipoproteins that behave like intrinsic proteins of cell membranes. Unlike the smaller apoproteins, the B proteins do not migrate from one lipoprotein particle to another. VLDL contain the B-100 protein, which is retained in the formation of LDL from VLDL remnants by liver. The intestinal B protein, B-48, is found only in chylomicrons and their remnants. Apo B-100 has a ligand domain that is conformed as VLDL are transformed into LDL for binding to the LDL receptor.
In addition to the B proteins, the following apoproteins are present in lipoproteins. (The distribution of these proteins is shown in Table 19-1.)
C apoproteins are lower molecular weight proteins that equilibrate rapidly among the lipoproteins. There are four distinct species: C-I, C-II, C-III, and C-IV. Apo C-II is a requisite cofactor for lipoprotein lipase.
Three isoforms of E apoproteins—E-2, E-3, and E-4 are the products of allelic genes. Unlike apo E-3 and E-4, apo E-2 does not contain a functional ligand for the LDL receptor. The E-4 alleles are associated with early-onset Alzheimer's disease.
Apoprotein A-I is the major apoprotein of HDL. It is also present in chylomicrons and is the most abundant of the apoproteins of human serum (about 125 mg/dL). It is a cofactor for lecithin:cholesterol acyltransferase (LCAT).
Apoprotein A-II is an important constituent of HDL. It contains cysteine, which permits the formation of disulfide-bridged dimers with apo E.
Apoprotein A-IV is chiefly associated with chylomicrons.
Lp(a) protein is a glycoprotein that has a high degree of sequence homology with plasminogen. It is found as a disulfide-bridged dimer with apo B-100 in LDL-like species of lipoproteins (Lp[a] lipoproteins).
Absorption of Dietary Fat; Secretion of Chylomicrons
Dietary triglycerides are hydrolyzed in the intestine to β-monoglyceride and fatty acids by pancreatic lipase, which is activated by bile acids and a protein cofactor. The partial glycerides and fatty acids form micelles that are absorbed by intestinal epithelium. The fatty acids are reesterified with beta monoglycerides to form triglycerides, and free cholesterol is esterified with fatty acids by acyl-CoA:cholesterol acyltransferase (ACAT). Droplets of triglyceride with small amounts of cholesteryl esters, associated with B-48, acquire a monolayer of phospholipid and free cholesterol. Apo A-I and apo A-II are added, and the nascent chylomicron emerges into the extracellular lymph space (Figure 19-1). The
new chylomicron begins to exchange surface components with HDL, acquiring apo C and apo E and losing phospholipids. This process continues as the chylomicron is carried via the intestinal lymphatics to the thoracic duct and thence into the bloodstream.
Formation of Very Low Density Lipoproteins
The liver exports triglycerides to peripheral tissues in the cores of VLDL (Figure 19-2). These triglycerides are synthesized in liver from free fatty acids abstracted from plasma and from fatty acids synthesized de novo. Release of VLDL by liver is augmented by any condition that results in increased flux of FFA to liver in the absence of compensating ketogenesis. Obesity, increased caloric intake, ingestion of ethanol, and estrogens stimulate release of VLDL and are important factors in hypertriglyceridemia.
Metabolism of Triglyceride-Rich Lipoproteins in Plasma
- HYDROLYSIS BY LIPOPROTEIN LIPASE
Fatty acids derived from the triglycerides of chylomicrons and VLDL are delivered to tissues through a common pathway involving hydrolysis by the lipoprotein lipase (LPL) system. Lipoprotein lipase is bound to capillary endothelium in heart, skeletal muscle, adipose tissue, mammary gland, and other tissues.
- BIOLOGIC REGULATION OF LIPOPROTEIN LIPASE
When glucose levels in plasma are elevated and the release of insulin is stimulated, LPL activity in adipose tissue increases, and fatty acids derived from triglycerides of circulating lipoproteins are stored. During prolonged fasting, LPL activity of adipose tissue falls, preventing storage of fatty acids. Heparin is a cofactor for LPL. When it is given intravenously (0.1–0.2 mg/kg), LPL
activity is displaced into plasma, permitting its measurement. Apo C-II is an obligatory cofactor.
Figure 19-2. Metabolism of VLdL. (TG, triglyceride; CE, cholesteryl esters; A-I, A-II, B-48, and C proteins, apolipoproteins.) See text for details.
- FORMATION OF LIPOPROTEIN REMNANTS
Hydrolysis by LPL results in depletion of triglycerides in the cores of chylomicrons and VLDL, producing progressive decreases in particle diameter. Lipids from the surface and C proteins are transferred to HDL. The “remnant” lipoproteins thus formed contain their original complement of apo B, significant amounts of apo E, and little apo C. They have lost about 70% of their original content of triglyceride and are enriched in cholesteryl esters.
- FATE OF LIPOPROTEIN REMNANTS
Chylomicron remnants are removed from blood quantitatively by high-affinity, receptor-mediated endocytosis in the liver. The receptors include the LDL (B-100:E) receptors and the related LRP receptors. Endocytosis of chylomicron remnants by both requires the presence of apo E-3 or apo E-4. The lipids enter hepatic pools, and B-48 protein is degraded. Cholesterol derived from chylomicron remnants exerts feedback control of cholesterol biosynthesis in liver. Some VLDL remnants are removed from blood via the B-100:E receptors (see below) and are degraded. Those which escape uptake are transformed into LDL. Thus, the rate of removal of VLDL remnants by liver is a determinant of LDL production. Formation of LDL involves the removal of residual triglycerides by hepatic lipase, facilitated by apo E. LDL contain cholesteryl esters in their cores and retain apo B-100. In normal individuals, a major fraction of VLDL is converted to LDL, and all of the LDL apo B comes from VLDL. In certain hypertriglyceridemic states, conversion of VLDL to LDL is decreased. In the absence of impaired conversion, increased secretion of VLDL results in increased production of LDL. This precursor-product relationship explains the clinical phenomenon referred to as the “beta shift,” an increase of LDL (beta-lipoprotein) as hypertriglyceridemia resolves. An example of this occurs temporarily following institution of insulin treatment in uncontrolled diabetes with lipemia. Insulin induces LPL activity, resulting in rapid conversion of VLDL to LDL. Because of its longer half-life, LDL accumulates in plasma. Elevated levels of LDL may persist beyond the time when levels of triglyceride-rich lipoproteins have returned to normal. A similar phenomenon may occur when patients with familial combined hyperlipidemia are treated with fibric acid derivatives.
- HALF-LIVES OF LIPOPROTEINS
Normally, the half-life of chylomicrons is 5–20 minutes; that of VLDL is 0.5–1 hour; and that of LDL is about 2˝ days. At triglyceride levels of 800–1000 mg/dL, LPL is at kinetic saturation. Increased input of triglycerides into plasma at those levels rapidly augments the hypertriglyceridemia.
- EFFECT OF DIETARY FAT RESTRICTION
Individuals consuming a typical North American diet transport 75–100 g or more of triglyceride per day in chylomicrons, whereas the liver exports 10–30 g in VLDL. Thus, the flux of triglyceride into plasma can be influenced most acutely by restriction of dietary fat. When LPL is saturated and triglycerides are measured in thousands of milligrams per deciliter, acute restriction of dietary triglyceride intake will produce a significant reduction in levels. This intervention is especially important in the lipemic patient with impending pancreatitis. If symptoms suggest that pancreatitis is imminent, oral intake should be eliminated, gastric acid should be suppressed with H2 blockade, and the patient should not be fed by mouth until the symptoms subside and triglycerides decrease to less than 800–1000 mg/dL.
Catabolism of Low-Density Lipoproteins
LDL catabolism is mediated by high-affinity receptors on the cell membranes of virtually all nucleated cells but most importantly hepatocytes. Ligands for these LDL receptors exist in apo B-100 and apo E. After endocytosis, apo B is degraded and the receptor returns to the cell membrane. The cholesteryl esters of LDL are hydrolyzed to free cholesterol for production of cell membrane bilayers. Free cholesterol down-regulates hydroxymethylglutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme in the biosynthetic pathway for cholesterol. Cholesterol in excess of need for membrane synthesis is esterified by ACAT for storage. In addition to suppression of cholesterol biosynthesis, the entry of cholesterol via the LDL pathway leads to down-regulation of LDL receptors, an effect also observed with dietary saturated fat.
Metabolism of High-Density Lipoproteins
When isolated by ultracentrifugation, HDL appear to comprise two major classes: HDL2 and HDL3. Similar quantities of HDL3 are isolated from serum of men and women, but about twice as much HDL2 is found in premenopausal women. Immunochemical studies indicate that there are as many as ten discrete species of HDL that are obscured by ultracentrifugation. One of these, the 67-kDa prebeta-1 HDL, appears to be the primary acquisitor of cholesterol in the retrieval pathway from peripheral tissues.
- SOURCES OF HDL
Both liver and intestine produce HDL apoproteins, which organize with lipids into the native species of HDL in lymph and plasma. Excess free cholesterol and phospholipids liberated from the surface monolayers of chylomicrons and VLDL as hydrolysis of triglycerides proceeds are transferred to HDL by phospholipid transfer protein (PLTP). Free cholesterol acquired by HDL is esterified by LCAT. This enzyme transfers 1 mol of fatty acid from a lecithin molecule to the hydroxyl group of unesterified cholesterol, forming cholesteryl esters. LCAT is secreted by liver. In severe hepatic parenchymal disease, levels in plasma are low and esterification of cholesterol is impeded, leading to the accumulation of free cholesterol in lipoproteins and in membranes of erythrocytes. This transforms them into the target cells classically associated with hepatic disease.
- METABOLIC ROLES FOR HDL
HDL serve as carriers for the C apoproteins, transferring them to nascent VLDL and chylomicrons. HDL as well as LDL deliver cholesterol to the adrenal cortex and gonads in support of steroidogenesis. HDL play a major role in the centripetal transport of cholesterol. Unesterified cholesterol, exported by the ABCA-1 transporter, is acquired from the membranes of peripheral tissues by prebeta-1 HDL and is esterified by LCAT, passing through other HDL species before the cholesteryl esters are incorporated into HDL of alpha electrophoretic mobility. The cholesteryl esters are then transferred to LDL and to triglyceride-rich lipoproteins mediated by cholesteryl ester transfer protein (CETP). Remnants of chylomicrons and a significant fraction of VLDL remnants and LDL are taken up by liver, providing cholesteryl esters to hepatocytes. Cholesteryl esters are also transferred from HDL to hepatocytes by SR-BI receptors.
- CATABOLISM OF HDL
The pathways of catabolism of HDL are not yet known. Radiochemical studies indicate that apo A-I and apo A-II are removed from plasma synchronously and that a portion of the degradation occurs in liver and in kidney.
The Cholesterol Economy
Cholesterol is an essential constituent of the plasma membranes of cells and of myelin. It is required for adrenal and gonadal steroidogenesis and for production of bile acids by liver. Cells synthesize cholesterol, commencing with acetyl-CoA. Formation of HMG-CoA is the initial step. The first committed step, mediated by HMG-CoA reductase, is the formation of mevalonic acid, which is then metabolized via a series of isoprenoid intermediaries to squalene. The latter cyclizes to form a series of sterols leading to cholesterol. A small amount of the mevalonate is converted to the isoprenoid substances ubiquinone, dolichol, and isopentenyl pyrophosphate. This pathway also yields the isoprenoid intermediaries geranyl pyrophosphate and farnesyl pyrophosphate that are involved in prenylation of proteins. Prenylation provides an anchor so that proteins such as RAS can bind to membranes. Cholesterol synthesis is tightly regulated by cholesterol or its metabolites, which down-regulate HMG-CoA reductase. Thus, cells can produce cholesterol not provided by circulating lipoproteins. Cholesterol is required for production of cell membranes. Hepatocytes and intestinal epithelial cells use cholesterol for secretion of lipoproteins. In addition, cells constantly transfer cholesterol to circulating lipoproteins, chiefly HDL. Cholesterol is converted to bile acids in liver via a pathway initiated by cholesterol 7α-hydroxylase. Most of the bile acids are reabsorbed from the intestine, but the small amount that is lost in stool provides a means of elimination of cholesterol from the body. Activity of cholesterol 7α-hydroxylase is decreased in hypothyroidism, as are the expression of LDL receptors and hepatic lipase.
Humans do not absorb dietary cholesterol quantitatively. At usual levels of intake, about one-third of the amount ingested is absorbed. Most is transported to liver in chylomicron remnants, leading to suppression of hepatic cholesterogenesis. Individuals may differ substantially in the effect of dietary cholesterol on serum lipoproteins, reflecting differences in the efficiency of absorption.
DIFFERENTIATION OF DISORDERS OF LIPOPROTEIN METABOLISM
Laboratory Analyses of Lipids & Lipoproteins
Because chylomicrons normally may be present in plasma up to 10 hours after a meal, they contribute as much as 600 mg/dL (6.9 mmol/L) to the triglycerides measured during that period. This alimentary lipemia can be prolonged if alcohol is consumed with the meal. Thus, serum lipids and lipoproteins should be measured after a 10-hour fast. If blood glucose is not to be measured, patients may have fruit juice and black coffee with sugar (which provide no triglyceride) for breakfast.
Much useful information is gained from inspection of the serum, especially before and after overnight refrigeration.
Opalescence is due to light scattering by large triglyceride-rich lipoproteins. Serum begins to appear hazy when the level of triglycerides reaches 200 mg/dL (2.3 mmol/L). Chylomicrons are readily detected, because they form a white supernatant layer. Uncommon cases in which binding of immunoglobulins to lipoproteins takes place can be detected by the formation of a curd-like lipoprotein aggregate or a snowy precipitate as serum cools. If one of these disorders is suspected, blood should be kept at 37 °C during the formation of the clot and separation of the serum, because the critical temperatures for precipitation of the cryoglobulin complex may be higher than room temperature.
- LABORATORY TECHNIQUES
Several chemical techniques provide reliable measures of cholesterol and triglycerides, an essential minimum for differentiation of disorders of lipoproteins. Unesterified and esterified cholesterol are usually measured together, so that the reported value is the total content of cholesterol in serum. A more complete characterization of lipoproteins is achieved by measurement of the cholesterol and triglyceride contents of individual lipoprotein fractions, separated by preparative ultracentrifugation, a technique usually available only in research laboratories. An efficient quantitative method employs vertical rotor ultracentrifugation, affording assessment of lipoprotein particle diameters. LDL particle size can also be assessed by electrophoresis. The content of HDL can be measured using a technique in which they are the only lipoproteins that remain in solution after treatment of the serum with heparin and manganese. Albeit rapid, the results of this technique tend to be unacceptably variable unless rigid quality control is exercised. Prognostic implications of small changes in HDL cholesterol make such controls necessary. An important determinant of the content of cholesteryl esters in HDL is the amount of triglyceride-rich lipoproteins to which the HDL are exposed in plasma. Cholesteryl esters from HDL transfer into triglyceride-rich lipoproteins, leading to an inverse logarithmic dependence of HDL cholesterol upon plasma triglycerides. HDL cholesterol cannot be interpreted without knowledge of the level of serum triglycerides. For example, a level of HDL that would normally contain 45 mg/dL (1.17 mmol/L) of cholesterol would contain 37 mg/dL (0.96 mmol/L) when the triglycerides were 200 mg/dL (2.3 mmol/L) and 30 mg/dL (0.78 mmol/L) when they reach 500 mg/dL (5.7 mmol/L).
More sophisticated tests of composition of isolated lipoprotein fractions are of use in certain instances. The most important of these is analysis of the ratio of cholesterol to triglycerides by chemical techniques and of the apolipoproteins of VLDL by isoelectric focusing. The latter reveals the absence of the normal isoforms of apo E, the underlying molecular defect in familial dysbetalipoproteinemia. In this disorder, there is an unusually high content of cholesterol in VLDL. The apo E genotype can be determined on genomic DNA. Immunoassays are available for a number of apolipoproteins of which apo B and Lp(a) are clinically useful.
Epidemiologic evidence suggests that LDL particles of smaller than normal diameter are associated with an increased risk of atherosclerosis. Small, dense LDL are a constant finding when triglyceride levels are elevated even marginally. Laboratory measurement of LDL diameters is therefore unnecessary in patients with hypertriglyceridemia.
Clinical Differentiation of Abnormal Patterns of Plasma Lipoproteins
- PRELIMINARY SCREENING
Serum cholesterol and triglyceride levels are both continuously distributed in the population; therefore, some arbitrary levels must be established to define significant hyperlipidemia. Epidemiologic studies in Europe and the USA have shown that there is a progressive increase in risk of coronary artery disease as levels of serum cholesterol increase. Physicians should at least encourage patients at risk to eat diets low in saturated fats and cholesterol to minimize the burden of LDL in plasma.
The National Cholesterol Education Program has developed guidelines for treatment of hypercholesterolemia in adults (Table 19-2). Triglyceride levels above 150 mg/dL (1.7 mmol/L) merit investigation. One abnormality associated with increased risk of coronary artery disease that will not be detected if screening is limited to hyperlipidemia is hypoalphalipoproteinemia, or deficiency of HDL. Many affected individuals
have normal levels of cholesterol and triglycerides and no clinical features to alert the physician. HDL deficiency underscores the importance of controlling other risk factors and avoiding factors that reduce HDL levels, such as smoking, the use of some drugs, and obesity. Niacin can effect major increases in HDL cholesterol in many subjects.
Table 19-2. National Cholesterol Education Program: Adult Treatment Guidelines (2001).
- IDENTIFICATION OF ABNORMAL PATTERNS
The second step in investigation of hyperlipidemia is determination of the species of lipoproteins that account for the increased content of lipids in serum. In some cases, multiple species may be involved; in others, qualitative properties of the lipoproteins are of diagnostic importance. The physician must search for underlying disorders that cause secondary hyperlipidemias of similar pattern. These may be the sole cause of the lipoprotein abnormality or may aggravate primary disorders of lipoprotein metabolism. The differentiation of specific primary disorders usually requires additional clinical and genetic information.
The following diagnostic protocol, based upon initial measurement of cholesterol, triglycerides, and HDL in serum after a 10-hour fast, supplemented by observation of serum and by additional laboratory measurements where essential, will serve as a guide in identifying abnormal lipoprotein patterns. The term “hyperlipidemia” denotes high levels of any class of lipoprotein;“hyperlipemia” denotes high levels of any of the triglyceride-rich lipoproteins.
Case 1: Serum Cholesterol Levels Increased; Triglycerides Normal
If the serum cholesterol level is modestly elevated (up to 260 mg/dL [6.72 mmol/L]), elevated levels of HDL may account for the observed increase in serum cholesterol. This is usually not associated with disease processes. The LDL cholesterol (in mg/dL) may be estimated by subtracting the HDL cholesterol and the estimated cholesterol contribution of VLDL from the total cholesterol level. The VLDL cholesterol is approximated as one-fifth of the serum triglyceride level.
Calculated values of LDL cholesterol over 130 mg/dL (3.36 mmol/L) are clinically significant. If the patient has atherosclerosis or a family history of premature atherosclerosis, levels in excess of 90-100 mg/dL should be considered significant.
Very high levels of HDL measured by the precipitation technique can signal the presence of the abnormal lipoprotein of cholestasis (Lp-X). This disorder is characterized by elevated alkaline phosphatase activity. Rarely, deficiency of CETP or hepatic lipase can cause high levels of HDL.
Case 2: Predominant Increase of Triglycerides; Moderate Increase in Cholesterol May Be Present
Here it is apparent that the primary abnormality is an increase in triglyceride-rich VLDL (hyperprebetalipoproteinemia) or chylomicrons (chylomicronemia), or both (mixed lipemia). Because VLDL and chylomicrons contain free cholesterol in their surface monolayers and a small amount of cholesteryl ester in their cores, the total cholesterol may be increased, though to a much smaller extent than is the triglyceride level. The contribution of cholesterol in these lipoproteins to the total in serum is about 8–25% of the triglyceride content. Low levels of LDL cholesterol often seen in hypertriglyceridemia may offset the increase in cholesterol due to the triglyceride-rich lipoproteins, especially in primary chylomicronemia. Because VLDL and chylomicrons compete as substrates in a common removal pathway, chylomicrons will nearly always be present when triglyceride levels exceed 1000 mg/dL (11.5 mmol/L).
Case 3: Cholesterol & Triglyceride Levels Both Elevated
This pattern can be the result of either of two abnormal lipoprotein distributions. One is a combined increase of VLDL, which provide most of the increase in triglycerides, and LDL, which account for the bulk of the increase in cholesterol. This pattern is termed combined hyperlipidemia and is one of the three phenotypic patterns encountered in kindreds with the disorder termed familial combined hyperlipidemia. The second phenotype is an increase of remnant lipoproteins derived from VLDL and chylomicrons. These lipoprotein particles have been partially depleted of triglyceride by LPL and enriched with cholesteryl esters by the LCAT system, such that the total content of cholesterol in serum is similar to that of triglycerides. This pattern is almost always an expression of familial dysbetalipoproteinemia. Presumptive differentiation can be made with high-quality agarose gel electrophoresis. Diagnosis of this disorder is confirmed by a genotype demonstrating absence of the E-3 and E-4 alleles.
- CLINICAL DESCRIPTIONS OF PRIMARY & SECONDARY DISORDERS OF LIPOPROTEIN METABOLISM
Epidemiologic evidence supports the atherogenicity of VLDL and their remnants. They have been demonstrated in atherosclerotic plaques from humans. Impaired capacity of the VLDL of some individuals to accept cholesteryl esters from the LCAT reaction may also contribute to atherogenesis by impeding centripetal transport of cholesterol.
Cause of Pancreatitis
Very high levels of triglycerides in plasma are associated with a risk of acute pancreatitis, probably from the local release of FFA and lysolecithin from lipoprotein substrates in the pancreatic capillary bed. When the concentrations of these lipids exceed the binding capacity of albumin, they could lyse membranes of parenchymal cells, initiating a chemical pancreatitis. Many patients with lipemia have intermittent episodes of epigastric pain during which serum amylase does not reach levels commonly considered diagnostic for pancreatitis. This is especially true in patients who have had previous attacks. The observation that these episodes frequently evolve into classic pancreatitis suggests that they represent incipient pancreatic inflammation. The progression of pancreatitis can be prevented by rapid reduction of triglycerides, usually accomplished by restriction of all dietary fat. In some cases, parenteral feeding, excluding fat emulsions, may be required for a few days. The clinical course of pancreatitis in patients with lipemia is typical of the general experience with this disease. Fatal hemorrhagic pancreatitis occurs in a few; many develop pseudocysts; and some progress to pancreatic exocrine insufficiency or compromised insulinogenic capacity.
When triglyceride levels in serum exceed 3000–4000 mg/dL (34.5–46 mmol/L), light scattering by these particles in the blood lends a whitish cast to the venous vascular bed of the retina, a sign known as lipemia retinalis. Markedly elevated levels of VLDL or chylomicrons may be associated with the appearance of eruptive cutaneous xanthomas (Figure 19-3E). These lesions, filled with foam cells, appear as yellow morbilliform eruptions 2–5 mm in diameter, often with erythematous areolae. They usually occur in clusters on extensor surfaces such as the elbows, knees, and buttocks. They are transient and disappear within a few weeks after triglyceride levels are reduced below 2000–3000 mg/dL (23–34.5 mmol/L).
Effects of Hypertriglyceridemia on Laboratory Measurements
Very high levels of triglyceride-rich lipoproteins may introduce important errors in clinical laboratory measurements. Light scattering from these large particles can cause erroneous results in most chemical determinations involving photometric measurements in spite of corrections for blank values. Amylase activity in serum may be inhibited by triglyceride-rich lipoproteins; therefore, lipemic specimens should be diluted for measurement of this enzyme. Because the lipoproteins are not permeable to ionic or polar molecules, their core regions constitute a second phase in plasma. When the volume of this phase becomes appreciable, electrolytes and other hydrophilic species will be underestimated with respect to their true concentration in plasma. A practical rule for correcting these values is as follows: For each 1000 mg/dL (11.5 mmol/L) of triglyceride in serum, the measured concentrations of all hydrophilic molecules and ions should be adjusted upward by 1%.
- Deficiency of Lipoprotein Lipase or Its Cofactor
- SYMPTOMS AND SIGNS
Because the clinical expressions of these defects are identical, they will be considered together. Both are autosomal recessive traits. On a typical North American diet, lipemia is usually severe (triglyceride levels of 2000–25,000 mg/dL) (23–287.5 mmol/L). Hepatomegaly and splenomegaly are frequently present. Foam cells laden with lipid are found in liver, spleen, and bone marrow. Splenic infarct has been described and may be a source of abdominal pain. Hypersplenism with anemia, granulocytopenia, and thrombocytopenia can occur. Recurrent epigastric pain and overt pancreatitis are frequently encountered. Eruptive xanthomas may be present. These disorders may be recognized in early infancy or may go unnoticed until an attack of acute pancreatitis occurs or lipemic serum is noted on blood sampling as late as middle age. Patients with these disorders are usually not obese and have normal carbohydrate metabolism unless pancreatitis impairs insulinogenic
capacity. Estrogens intensify the lipemia by stimulating hepatic production of VLDL. Therefore, in pregnancy and lactation or during the administration of estrogenic steroids, the risk of pancreatitis increases.
Figure 19-3. Clinical manifestations of hyperlipidemias. A: Xanthelasma involving medial and lateral canthi. B: Severe xanthelasma and arcus corneae. C: Tuberous xanthomas. D: Large tuberous xanthoma of elbow. E: Eruptive xanthomas, singly and in rosettes. F:Xanthomas of extensor tendons of the hands. G: Xeroradiogram of Achilles tendon xanthoma. H: Xanthoma of Achilles tendon. (Normal Achilles tendons do not exceed 7 mm in diameter in the region between the calcaneus and the point at which the tendon fibers begin to radiate toward their origins.)
- LABORATORY FINDINGS
There is a preponderance of chylomicrons in serum such that the infranatant layer of serum refrigerated overnight may be nearly clear. Many patients have a moderate increase in VLDL, however, and in pregnant women or those receiving estrogens, a pattern of mixed lipemia is usually present. Levels of LDL in serum are decreased, probably representing the predominant catabolism of VLDL by pathways that do not involve the production of LDL. Levels of HDL are also decreased. A presumptive diagnosis of these disorders can be made by restricting oral intake of fat to 10–15 g/d for 3–5 days. Triglycerides drop precipitously, usually reaching 200–600 mg/dL (2.3–6.9 mmol/L) within 3–4 days. Confirmation of deficiency of LPL is obtained by measurement of the lipolytic activity of plasma prepared from blood drawn 10 minutes after heparin, 0.2 mg/kg, is injected intravenously. Analysis of lipolysis is done with and without 0.5 mol/L sodium chloride, which inhibits LPL but does not suppress the activity of other plasma lipases, including hepatic lipase. Absence of the cofactor protein of LPL, apo C-II, can be demonstrated most readily by electrophoresis or isoelectric focusing of the proteins of VLDL.
Treatment of primary chylomicronemia is entirely dietary. Intake of fat should be reduced to 10% or less of total calories. In an adult, this represents 15–30 g/d. Because the defect involves lipolysis, both saturated and unsaturated fats must be curtailed. The diet should contain at least 5 g of polyunsaturated fat as a source of essential fatty acids, and fat-soluble vitamins must be provided. Administration of 500 mg daily of marine omega-3 fatty acids is also recommended. Adherence to this diet will invariably maintain triglyceride levels below 1000 mg/dL (11.2 mmol/L) in the absence of pregnancy, lactation, or the administration of exogenous estrogens. Because this is below the level at which pancreatitis usually occurs, compliant patients are at low risk. Pregnant women with these disorders require particularly close monitoring.
- Endogenous & Mixed Lipemias
Etiology & Pathogenesis
Endogenous lipemia (elevated VLDL) and mixed lipemia probably both result from several genetically determined disorders. Because VLDL and chylomicrons are competing substrates in the intravascular lipolytic pathway, saturating levels of VLDL will cause an impedance in the removal of chylomicrons. Therefore, as the severity of endogenous lipemia increases, a pattern of mixed lipemia may supervene. In other cases, the pattern of mixed lipemia appears to be present continuously. Though specific pathophysiologic mechanisms remain obscure, certain familial patterns are known. In all forms, factors that increase the rate of secretion of VLDL aggravate the hypertriglyceridemia—ie, obesity with insulin resistance, or the appearance of fully developed type 2 diabetes mellitus; alcohol; and exogenous estrogens. Studies of VLDL turnover indicate that either increased production or impaired removal of VLDL may be operative in different individuals. A substantial number of patients with mixed lipemia have partial defects in catabolism of triglyceride-rich lipoproteins, often due to heterozygosity for mutations in lipoprotein lipase. Some patients with mixed lipemia have decreased LPL activity in plasma. Most patients with significant endogenous or mixed lipemia have the hypertrophic form of obesity, in which there is a reduced population of insulin receptors on cell membranes associated with impaired effectiveness of insulin. Mobilization of FFA is maintained at a higher than normal rate, providing an increased flux of fatty acids to the liver, in turn increasing the secretion of triglyceride-rich VLDL.
Clinical features of these forms of hypertriglyceridemia depend upon their severity and include eruptive xanthomas, lipemia retinalis, recurrent epigastric pain, and acute pancreatitis. One constellation of clinical features that may be genetically determined is endogenous lipemia with central obesity, insulin resistance, hyperglycemia, and hyperuricemia (metabolic syndrome; syndrome X). There is also a tendency toward the development of hypertension in such patients.
The first element of treatment is dietary. In the short term, severe restriction of total fat intake will usually result in a rapid decline of serum triglycerides to 1000-3000 mg/dL (11.2-33.6 mmol/L), averting pancreatitis. The objective of long-term dietary management is reduction to ideal body weight. Because alcohol causes significant augmentation of VLDL production, abstinence is important. If weight loss is achieved, the triglycerides almost always show a marked response, often approaching normal values. When the fall in triglyceride levels is not satisfactory, a fibrate or nicotinic acid (in the absence of insulin resistance), singly or in combination, will usually produce further reductions.
When insulin resistance is present, metformin—with or without a thiazolidinedione—may be a useful adjunct. Pioglitazone appears to have more impact on lipids than other agents in this class.
- Familial Combined Hyperlipidemia
Epidemiologic studies of the kindreds of survivors of myocardial infarction revealed this heredofamilial disorder, which is the most common form of hyperlipidemia, occurring in 1-2% of the population. The underlying process involves overproduction of VLDL. Some affected individuals have increased levels of both VLDL and LDL (combined hyperlipidemia); some have increased levels of only VLDL or LDL. The level of apo B-100 is increased. Patterns in the serum of an individual patient may change with time. It is known that mating of an individual having any one of the three phenotypic patterns with a normal individual can result in the appearance of one of the other patterns. Affected children often have hyperlipidemia, but the disorder may not be fully expressed until adulthood.
Neither tendinous nor cutaneous xanthomas other than xanthelasma occur. This disorder appears to be inherited as a mendelian dominant trait involving alternative loci. Factors that increase the severity of hypertriglyceridemia in other disorders aggravate the lipemia in this syndrome as well.
The risk of coronary disease is significantly increased, and patients should be treated aggressively with diet and drugs. Because LDL often increase with fibrate therapy in these patients and because resins increase triglycerides, the recommended treatment is an HMG-CoA reductase inhibitor. The addition of niacin may be required if triglycerides remain elevated or if HDL deficiency is also present.
- Familial Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
Etiology & Pathogenesis
A permissive genetic constitution for this disease occurs commonly, but expression of hyperlipidemia apparently requires additional genetic or environmental determinants. The molecular basis is the presence of isoforms of apo E that are poor ligands for high-affinity receptors. In its fully expressed form, the lipoprotein pattern is dominated by the accumulation of remnants of VLDL and chylomicrons. Two populations of VLDL are usually present: normal prebetalipoproteins and remnants with beta-electrophoretic mobility. Remnant particles of intermediate density are also present. Levels of LDL are decreased, reflecting interruption of the transformation of VLDL remnants to LDL. The primary defect is impaired hepatic uptake of remnants of triglyceride-rich lipoproteins. The remnant particles are enriched in cholesteryl esters such that the level of cholesterol in serum is often as high as that of triglycerides. Absence of the E-3 and E-4 genes on allele-specific screening of genomic DNA—or of the corresponding proteins on isoelectric focusing of VLDL proteins—confirms the diagnosis. Whereas homozygosity for apo E-2 is present in about 1% of the population, the incidence of clinical hyperlipidemia among these patients is much smaller. Additional mutations of apo E that cannot be distinguished from E-3 by isoelectric focusing are now known to result in dysbetalipoproteinemia. Some of these cause hyperlipidemia in the heterozygous state, a disorder termed dominant dysbetalipoproteinemia.
Hyperlipidemia and clinical signs are not usually evident before age 20. In younger patients with hyperlipidemia, hypothyroidism or obesity is likely to be present. Adults frequently have tuberous or tuberoeruptive xanthomas (Figure 19-3C). Both tend to occur on extensor surfaces, especially elbows and knees. Tuberoeruptive xanthomas are pink or yellowish skin nodules 3-8 mm in diameter that often become confluent. Tuberous xanthomas—shiny reddish or orange nodules up to 3 cm or more in diameter—are usually moveable and nontender. Another type, planar xanthomas of the palmar creases, strongly suggests dysbetalipoproteinemia. The skin creases assume an orange color from deposition of carotenoids and other lipids. They occasionally are raised above the level of adjacent skin and are not tender. (Planar xanthomas are also seen in cholestatic disease.)
Some patients have impaired glucose tolerance, which is usually associated with higher levels of blood lipids. Obesity is commonly present and tends to aggravate the lipemia. Patients with the genetic constitution for dysbetalipoproteinemia often develop severe hyperlipidemia if they are hypothyroid.
Atherosclerosis of the coronary and peripheral vessels occurs with increased frequency, and the prevalence of disease of the iliac and femoral vessels is especially high.
Management includes a weight reduction diet providing a reduced intake of cholesterol, fat, and alcohol. When the hyperlipidemia does not respond satisfactorily to diet, a fibrate or niacin in low doses (if the patient does not have type 2 diabetes or insulin resistance) is usually effective. These agents can be used together in resistant cases. Some patients respond to the more potent reductase inhibitors alone, and the addition of niacin normalizes the lipid levels in most.
In patients with diabetes, levels of VLDL in plasma are frequently elevated. The severe lipemia associated with absence or marked insufficiency of insulin is attributable to deficiency of LPL activity, because this enzyme is induced by insulin. The administration of insulin usually restores triglyceride levels to normal within a few days. However, if massive fatty liver is present, weeks may be required for the VLDL to return to normal while the liver secretes its triglyceride into plasma. Conversion of massive amounts of VLDL to LDL as the impedance of VLDL catabolism is relieved leads to marked accumulation of LDL that may persist for weeks, leading to a spurious diagnosis of primary hypercholesterolemia.
The moderately elevated VLDL seen in diabetes under average control probably reflects chiefly an increased flux of FFA to liver that stimulates production of triglycerides and their secretion in VLDL. In addition to VLDL, LDL levels are also somewhat increased in diabetics under poor control, probably accounting in part for their increased risk of coronary heart disease. Mild increases in VLDL and in FFA occur in many patients with type 2 diabetes. Some have much higher levels of VLDL, suggesting that an additional genetic factor predisposing to lipemia is present. Still another cause of lipemic diabetes is the compromised insulinogenic capacity that can result from acute pancreatitis in individuals with severe primary lipemias. The deficiency may be severe enough to require exogenous insulin, often only in small doses. In diabetics who develop nephrosis, the secondary lipemia of nephrosis compounds their hypertriglyceridemia. In hyperglycemia, lipoproteins become glycosylated, leading to their uptake by macrophages.
Lipemia may be very severe, with elevated levels of both VLDL and chylomicrons when control is poor. Lipemic patients usually have ketoacidosis when they are insulin-deficient, but lipemia can occur in its absence. Patients with type 1 diabetes who have been chronically undertreated with insulin may have mobilized most of the triglyceride from peripheral adipose tissue, so that they no longer have sufficient substrate for significant ketogenesis. These emaciated individuals may have severe lipemia and striking hepatomegaly.
In type 1 diabetes, the rigid control of blood glucose levels, which can be attained with continuous subcutaneous insulin infusion, is associated with sustained normalization of levels of both LDL and VLDL. The lipemia of type 2 diabetes usually responds well to control of the underlying disorder. In obese insulin-resistant individuals, weight loss is an essential feature of management. Diets containing slowly absorbed carbohydrates are well tolerated, allowing a decrease in the burden of chylomicron triglycerides in plasma (see Chapter 17).
Uremia is associated with modest isolated increases in VLDL. The most important underlying mechanisms are probably insulin resistance and impairment of catabolism of VLDL. Many uremic patients are also nephrotic. The additional effects of nephrosis upon lipoprotein metabolism may produce a combined hyperlipidemia. Patients who have had renal transplants may be receiving glucocorticoids, which induce elevation of LDL.
- Human Immunodeficiency Virus Infection
HIV infection per se is associated with hypertriglyceridemia. A syndrome of partial lipodystrophy and insulin resistance, often with marked lipemia, occurs with multidrug treatment that includes inhibitors of viral protease. Acute pancreatitis can ensue. Limited clinical experience suggests that fibric acid derivatives are of some value. Alcohol must be avoided.
- Corticosteroid Excess
In endogenous Cushing's syndrome, insulin resistance is present and levels of LDL are increased. It appears that the combined hyperlipidemia is primarily due to increased secretion of VLDL, which is then catabolized to LDL. More severe lipemia ensues when steroidogenic diabetes appears, reducing catabolism of triglyceride-rich lipoproteins via the LPL pathway.
- Exogenous Estrogens
When estrogens are administered to normal women, triglyceride levels may increase by as much as 15%, reflecting increased production of VLDL. Paradoxically,
estrogens increase the efficiency of catabolism of triglyceride-rich lipoproteins. Whereas estrogens tend to induce insulin resistance, it is not clear that this is an important mechanism, because certain nortestosterone derivatives decrease plasma triglycerides despite the induction of appreciable insulin resistance.
Certain individuals, usually those with preexisting mild lipemia, develop marked hypertriglyceridemia when receiving estrogens even in relatively small doses. Thus, triglycerides should be monitored in these women. Contraceptive combinations with predominantly progestational effects produce less hypertriglyceridemia than purely estrogenic compounds. Transdermal delivery of estrogen probably results in lesser increases in VLDL secretion because it avoids the hepatic first-pass effect.
- Alcohol Ingestion
Ingestion of appreciable amounts of alcohol does not necessarily result in significantly elevated levels of triglycerides, but many alcoholics are lipemic. Alcohol profoundly increases triglycerides in patients with primary or secondary hyperlipemias. In Zieve's syndrome, the alcohol-induced lipemia is associated with hemolytic anemia and hyperbilirubinemia. Because LCAT originates in liver, severe hepatic parenchymal dysfunction may lead to deficiency in the activity of this enzyme. A resultant accumulation of unesterified cholesterol in erythrocyte membranes may account for the hemolysis seen in Zieve's syndrome.
Alcohol is converted to acetate, exerting a sparing effect on the oxidation of fatty acids. The fatty acids are incorporated into triglyceride in liver, resulting in hepatomegaly due to fatty infiltration and in marked enhancement of secretion of VLDL. In many individuals, there is sufficient adaptive increase in the removal capacity for triglycerides from plasma that levels are normal. In individuals in whom the adaptive response is impaired, marked lipemia may ensue.
- Nonalcoholic Steatohepatitis (NASH)
This syndrome is characterized by hepatic steatosis and abnormalities of liver enzymes, leading in many cases to cirrhosis in the absence of alcohol ingestion. Many patients have hypertriglyceridemia. The cause is not yet understood, but it is likely that NASH involves misdirection of fatty acids from oxidative pathways to hepatic triglyceride synthesis. Weight reduction in obese patients and treatment of insulin resistance, if present, can mitigate the steatosis and reduce levels of triglycerides.
The hyperlipidemia of nephrosis is biphasic. Before serum albumin levels fall below 2 g/dL, LDL increases selectively. The synthesis and secretion of VLDL appear to be coupled to that of albumin. The increased flux of VLDL from liver increases production of LDL. As albumin levels fall below 1-2 g/dL, lipemia ensues. Impaired hydrolysis of triglycerides by LPL is due to lack of albumin as an FFA receptor. Free fatty acids, which normally circulate complexed to albumin, bind to lipoproteins when albumin levels are low. The ability of these altered lipoproteins to undergo hydrolysis is thus impaired.
Because coronary disease is prevalent in patients with long-standing nephrotic syndrome, treatment of the hyperlipidemia is indicated, though few studies of the effect of treatment have been reported. The hyperlipidemia is resistant to diet. Fibrates may precipitate myopathy even in small doses. Bile acid-binding resins, niacin, and reductase inhibitors are useful.
- Glycogen Storage Disease
In type I glycogenosis, insulin secretion is decreased. This leads to an increased flux of FFA to the liver, where a substantial fraction is converted to triglycerides, increasing secretion of VLDL. The low levels of insulin in plasma are the probable cause of reduced activity of LPL, which may impair removal of triglycerides. The fatty liver in these patients tends to progress to cirrhosis.
Frequent small feedings help to maintain blood glucose levels and ameliorate the lipemia. Nocturnal nasogastric drip feeding is of considerable benefit. Other forms of hepatic glycogen storage disease may be associated with elevated levels of VLDL and LDL in serum.
- Hypopituitarism & Acromegaly
Part of the hyperlipidemia of hypopituitarism is attributable to secondary hypothyroidism, but hypertriglyceridemia persists after thyroxine replacement. Deficiency of growth hormone is associated with higher than normal levels of both LDL and VLDL. Decreased insulin levels may be the major underlying defect; however, deficiency of growth hormone may impair the disposal of FFA by oxidation and ketogenesis in the liver, favoring synthesis of triglycerides. Mild hypertriglyceridemia is often associated with acromegaly, probably resulting from insulin resistance. Though growth hormone acutely stimulates lipolysis in adipose tissue, FFA levels are normal in acromegaly.
Whereas significant hypothyroidism produces elevated levels of LDL in nearly all individuals, only a few develop hypertriglyceridemia. The increase in LDL results at least in part from decreased conversion of cholesterol to bile acids and down-regulation of LDL receptors. Lipemia, when present, is usually mild, though serum triglycerides in excess of 3000 mg/dL (34.5 mmol/L) can occur in patients with myxedema. It is probable that impaired removal of triglycerides is involved, reflecting decreased activity of hepatic lipase. Increased content of cholesteryl esters and apo E in the triglyceride-rich lipoproteins suggests that accumulation of remnant particles occurs. Hypothyroidism, even of very mild degree, often causes expression of hyperlipidemia in individuals with dysbetalipoproteinemia.
- Immunoglobulin-Lipoprotein Complex Disorders
Both polyclonal and monoclonal hypergammaglobulinemias may cause hypertriglyceridemia. IgG, IgM, and IgA have each been involved. Of the underlying monoclonal disorders, myeloma and macroglobulinemia are the most important, but lymphomas and lymphocytic leukemias have also been implicated. Lupus erythematosus and other autoimmune disorders have been associated with the polyclonal type. Binding of heparin by immunoglobulin, with resulting inhibition of LPL, can cause severe mixed lipemia. More commonly, the triglyceride-rich lipoproteins have an abnormally high density, probably as a result of bound immunoglobulin, though some may be remnant-like particles. These complexes, which bind lipophilic stains, usually have gamma mobility on electrophoresis.
Xanthomatosis associated with immunoglobulin complex disease includes tuberous and eruptive xanthomas, xanthelasma, and planar xanthomas of large areas of skin. The latter are otherwise seen only in patients with cholestasis. Deposits of lipid-rich hyaline material can occur in the lamina propria of the intestine, causing malabsorption and protein-losing enteropathy. Circulating immunoglobulin-lipoprotein complexes can fix complement, leading to hypocomplementemia. In such patients, administration of whole blood or plasma can cause anaphylaxis. Hence, washed red cells or albumin are recommended when blood volume replacement is required.
Treatment is directed at the underlying disorder. Because the critical temperature of cryoprecipitation of some of these complexes is close to body temperature, plasmapheresis should be done at a temperature above the critical temperature measured in serum.
THE PRIMARY HYPERCHOLESTEROLEMIAS
Etiology & Pathogenesis
This disorder, which in its heterozygous form occurs in approximately one in 500 individuals, is a codominant trait with high penetrance. Because half of first-degree relatives are affected, all members of a family should be screened. A selective increase in LDL exists from birth. Levels of LDL tend to increase during childhood and adolescence such that serum cholesterol in adult heterozygotes usually varies from about 260 mg/dL to 400 mg/dL (6.7-10.4 mmol/L). Aside from an increase in content of cholesteryl esters, the LDL are normal in structure. Some individuals—especially those in kindreds in which hypertriglyceridemia is present—may have higher than normal levels of VLDL and IDL. In a few patients with familial hypercholesterolemia mutations, the expression is blunted by independent genetic determinants.
The underlying defect is a deficiency of normal LDL receptors on cell membranes. A number of genetic defects affecting the structure, translation, modification, or transport of the receptor protein have been identified.
Some individuals have combined heterozygosity. In cases in which a kinetic mutant is combined with an ablative mutant, the hypercholesterolemia is greater than that seen in simple heterozygosity, usually in the range of 500-800 mg/dL (13-20.8 mmol/L). Those patients who are homozygous for null alleles have extremely severe hypercholesterolemia (approaching 1000 mg/dL [26 mmol/L] or greater) and fulminant arteriosclerosis.
Production rates for LDL are moderately increased in heterozygotes and are higher in homozygotes because of increased conversion of VLDL to LDL. In the heterozygote, a greater fraction of LDL is removed by non-receptor-dependent mechanisms than in normal subjects. In homozygotes, all removal of LDL proceeds through such pathways.
A frequent clinical feature is tendinous xanthomatosis. These become more apparent in early adulthood, causing a broadening or fusiform mass in the tendon. They can occur in almost any tendon but are most readily detected in the Achilles and patellar tendons and in the extensor tendons of the hands (Figure 19-3F, G, H). Patients who are physically active may complain of
achillodynia. Arcus corneae (Figure 19-3B) may occur as early as the third decade. Xanthelasma (Figure 19-3A) may also be present. Both arcus and xanthelasma are seen in some individuals who do not have hyperlipidemia, however. Coronary atherosclerosis tends to occur prematurely in heterozygotes. It is particularly prominent in individuals who are relatively deficient in HDL. It is probable that this represents a coincident inheritance of both traits. Homozygous familial hypercholesterolemia is catastrophic. Xanthomatosis progresses rapidly. Patients may have tuberous xanthomas (Figure 19-3C and D) and elevated plaque-like xanthomas of the extremities, buttocks, interdigital webs, and aortic valves. Coronary disease may be evident in the first decade of life.
A serum cholesterol in excess of 300 mg/dL (7.8 mmol/L) in the absence of significant hypertriglyceridemia makes the diagnosis of heterozygous familial hypercholesterolemia likely. The presence of affected first-degree relatives is supportive of this diagnosis, especially if no other phenotypes of hyperlipidemia are present in the family that would suggest familial combined hyperlipidemia. The finding of tendon xanthomas is nearly pathognomonic—betasitosterolemia, cerebrotendinous xanthomatosis (cholestanolosis), and ligand-defective apo B excepted. Although the cholesterol content of umbilical cord blood is usually elevated, the diagnosis is most easily established by measuring serum cholesterol after the first year of life.
Treatment with HMG-CoA reductase inhibitors may normalize LDL levels. However, achieving optimal levels may require one of the binary combinations involving reductase inhibitors, niacin, bile acid sequestrants, or ezetimibe. Levels of LDL cholesterol less than 100 mg/dL (2.6 mmol/L) can be obtained with combinations of these drugs in most patients. Treatment of homozygotes is extremely difficult. Partial control may be achieved with LDL apheresis in conjunction with niacin and atorvastatin. Striking reduction of LDL levels is observed after liver transplantation, illustrating the important role of hepatic receptors in LDL clearance.
FAMILIAL COMBINED HYPERLIPIDEMIA
In some individuals in kindreds with this disorder (see Primary Hypertriglyceridemia, above), LDL and IDL are the only lipoproteins that are elevated. This pattern may vary in an individual over time, and elevated VLDL alone or combined elevations of LDL and VLDL may be observed in the patient or the patient's relatives. Some affected children express hyperlipidemia. In contrast to most cases of familial hypercholesterolemia, the cholesterol level may be as low as 250 mg/dL (6.5 mmol/L) and xanthomas are absent. Studies of kindreds suggest codominant transmission. Coronary atherosclerosis is accelerated, accounting for about 15% of coronary events. The underlying mechanism involves increased secretion of VLDL.
Treatment of the hypercholesterolemia should begin with diet and either niacin or a reductase inhibitor. It may be necessary to use a combination of these agents to normalize levels of LDL and triglycerides.
Lp(a) normally comprises a very minor fraction of circulating lipoproteins, but it may be present in high concentrations in some individuals. It contains apo B-100 and the Lp(a) protein, a homolog of plasminogen that can inhibit fibrinolysis. It has been demonstrated in atherosclerotic plaques, and many but not all studies implicate it as an independent risk factor for coronary disease. Plasma levels of Lp(a) can be measured by immunoassay. Whereas most individuals have levels below 10 mg/dL, some may have as much as 200 mg/dL. Levels above 30-50 mg/dL present additional risk of coronary disease. Levels of Lp(a) primarily reflect genetic determinants. Niacin is essentially the only effective treatment, though not all patients respond.
FAMILIAL LIGAND-DEFECTIVE APO B
Mutations involving the ligand domain in apo B-100 impair the ability of LDL to bind to its receptor. Two prevalent mutations at codon 3500 or 3531 occur in about one in 500 individuals and may be found in compound states with familial hypercholesterolemia. The hypercholesterolemia with ligand defects alone is generally less severe than in familial hypercholesterolemia because the removal of VLDL remnants is normal, resulting in a lower production of LDL. Patients may have tendon xanthomas and are at increased risk for coronary disease. Response to reductase inhibitors varies, but many show some resistance because up-regulation of receptors cannot correct the defect completely (though it can decrease LDL production because IDL are endocytosed by liver via interaction of the LDL receptor with apo E).
CHOLESTEROL 7-α-HYDROXYLASE DEFICIENCY
Loss of function mutations in cholesterol 7α-hydroxylase result in diminished catabolism of cholesterol to bile acids and accumulation of cholesterol in hepatocytes.
Down-regulation of LDL receptors causes elevated LDL in plasma. VLDL may also be increased. Homozygous patients have marked resistance to reductase inhibitors and may have premature cholesterol gallstone disease. Heterozygous patients have moderately elevated LDL. The hyperlipidemia responds well to niacin.
In hypothyroidism, LDL and IDL are elevated. Some patients may have lipemia, as described in the section on secondary hyperlipemia. Hyperlipidemia may occur with no overt signs or symptoms of decreased thyroid function. Biliary excretion of cholesterol and bile acids is depressed. Cholesterol stores in tissues appear to be increased, though the number of LDL receptors on cells is decreased. Activity of hepatic lipase is markedly decreased, and atherogenesis is accelerated by myxedema. The hyperlipidemia responds dramatically to treatment with thyroxine.
As described in the section on secondary hypertriglyceridemias, nephrosis produces a biphasic hyperlipoproteinemia. The earliest alteration of lipoproteins in nephrosis is elevation of LDL. Increased secretion of VLDL by liver is probably involved. Because the lipids of the lipoprotein surfaces are altered by enrichment with sphingomyelin, lysolecithin, and FFA, the catabolism of LDL could be impaired. Perhaps the low metabolic rate in affected patients introduces metabolic changes similar to those associated with hypothyroidism. The hyperlipidemia may be an important element in the markedly increased risk of atherosclerosis in these patients. The treatment of choice is a reductase inhibitor or bile acid-binding resin with niacin.
One of the lipoprotein abnormalities that can be associated with monoclonal gammopathy is elevation of LDL. A “gamma lipoprotein” that is a stable complex of immunoglobulin and lipoprotein may be observed on electrophoresis. Cryoprecipitation, often in the temperature range encountered in peripheral tissues when the environmental temperature is low, may occur. Patients may have symptoms from the vascular effect of complement fixation resulting from complex formation and may have hyperviscosity syndrome from the elevated immunoglobulins per se. Planar xanthomas may be present.
Treatment is directed at the underlying process. Plasmapheresis is often effective. If cryoprecipitation occurs at critical temperatures near or above room temperature, the procedure must be carried out in a special warm environment. Transfusion of whole blood or serum may be dangerous in these patients because of rapid production of anaphylatoxins from fresh complement in the serum, resulting from interaction with circulating antibody-antigen complexes. This risk can be minimized by the use of packed red blood cells and albumin in place of whole blood.
About 40% of patients with anorexia nervosa have elevated LDL, and levels of cholesterol may reach 400-600 mg/dL (10.4-15.6 mmol/L). The hyperlipidemia, which persists despite correction of hypothyroidism, is probably a result of decreased fecal excretion of bile acids and cholesterol. Serum lipoproteins return to normal when proper nutrition is restored.
The hyperlipidemia associated with obstruction of biliary flow is complex. Levels of cholesterol exceeding 400 mg/dL (10.4 mmol/L) usually are associated with extrahepatic obstruction or with intrahepatic tumor. Several types of abnormal lipoproteins are present. The most abundant, termed Lp-X, is a bilayer vesicle composed of unesterified cholesterol and lecithin, with associated apolipoproteins but no apo B. Lp-X is apparent on electrophoresis as a band of zero to gamma mobility which shows metachromatic staining with Sudan black. It is these vesicular particles that cause the serum phospholipid and unesterified cholesterol content to be extremely high. Another abnormal species, called Lp-Y, contains appreciable amounts of triglycerides and apo B. The LDL in cholestasis also contain an unusually large amount of triglycerides.
Patients may have planar xanthomas, especially at sites of minor trauma, and xanthomas of the palmar creases. Occasionally, eruptive xanthomas are present. Xanthomatous involvement of nerves may lead to symptoms of peripheral neuropathy, and the abnormal lipoproteins may be atherogenic. Whereas bilirubin levels are nearly normal in some patients with chronic cholestasis, all have elevated serum alkaline phosphatase activity.
Neuropathy is the chief indication for treatment of the hyperlipidemia. Bile acid-binding resins are of some value, whereas fibric acid derivatives may cause an increase in cholesterol. Plasmapheresis is the most effective treatment. Large doses of vitamin E are indicated to overcome severe impairment of absorption. Deficiency of other fat-soluble vitamins also occurs.
THE PRIMARY HYPOLIPIDEMIAS
Although the clinician is confronted less frequently by the problem of a striking deficiency in plasma lipids, it is important to recognize the primary and secondary hypolipidemias. A serum cholesterol less than 110 mg/dL (2.9 mmol/L) is noteworthy. Since levels of triglycerides in normal fasting serum may be as low as 25 mg/dL (0.29 mmol/L), significance is limited to cases in which they are virtually absent.
PRIMARY HYPOLIPIDEMIA DUE TO DEFICIENCY OF HIGH-DENSITY LIPOPROTEINS
- Tangier Disease
Etiology & Pathogenesis
Severe deficiency of HDL occurs in Tangier disease. Heterozygotes lack clinical signs but have about one-half or less of the normal complement of HDL and apo A-I in plasma. Homozygotes lack normal HDL, and apo A-I and apo A-II are present at extremely low levels. Serum cholesterol is usually below 120 mg/dL (3.12 mmol/L) and may be half that value. Mild hypertriglyceridemia is usually present, and LDL are greatly enriched in triglycerides. Mutations in the ATP-dependent transporter ABCA1 underlie this disorder, causing defective efflux of cholesterol from peripheral cells.
The clinical features of this rare autosomal-recessive disease include large, orange-colored, lipid-filled tonsils, accumulation of cholesteryl esters in the reticuloendothelial system, and an episodic and recurrent peripheral neuropathy with predominant motor weakness in the later stages. The course of the disease is benign in early childhood, but the neuropathy may appear as early as age 8. Cholesteryl ester accumulates most prominently in peripheral nerve sheaths. Carotenoid pigment may be apparent in pharyngeal and rectal mucous membranes. Splenomegaly and corneal infiltration may also be present. There is some increase in risk of coronary atherosclerosis.
Because some of the lamellar lipoprotein material in plasma is believed to originate in chylomicrons, restriction of dietary fats and cholesterol is suggested.
- Familial Hypoalphalipoproteinemia
Etiology & Pathogenesis
This phenotypic pattern is a partial deficiency of HDL that may involve heterogeneous mechanisms. These presumed constitutional disorders must be differentiated from the condition in which moderately low levels of HDL are seen in individuals consuming a diet very low in fat. White and Asian men on such diets usually have HDL cholesterol levels of 38-42 mg/dL (1-1.1 mmol/L) by ultracentrifugal analysis, in contrast to a median value of 49 mg/dL (1.3 mmol/L) when consuming a typical North American diet. Such levels are common in Asiatic populations and among vegetarians, where the risk of coronary disease is small. HDL cholesterol must also be interpreted in the light of the amount of triglyceride-rich lipoproteins in plasma. Because cholesteryl esters are progressively transferred to the cores of triglyceride-rich lipoproteins as triglyceride levels rise, HDL cholesterol will decrease as an inverse logarithmic function of the triglyceride level.
Etiologic Factor in Coronary Disease
Familial hypoalphalipoproteinemia is fairly common and is an important risk factor in atherosclerosis. This abnormality may be the only apparent risk factor in many cases of premature coronary or peripheral vascular disease and accelerates the appearance of coronary disease in patients with familial hypercholesterolemia or other hyperlipidemias. Hypoalphalipoproteinemia shows a strong familial incidence. Although several mechanisms and modes of transmission may be involved, many kindreds show distributions consistent with autosomal dominance. HDL cholesterol levels are usually below 35 mg/dL (0.9 mmol/L).
Increases in HDL cholesterol in several coronary intervention trials have been independently associated with plaque regression. Only limited means of raising HDL levels are at hand. Findings that HDL are composed of
ten or more discrete species further complicate this problem. It is not yet known which of these species may be involved in protecting against atherosclerosis or whether their levels can be increased. Though alcohol ingestion can increase total HDL in some individuals, it appears that the effect is primarily on the HDL3 ultracentrifugal fraction, which correlates poorly with decreased risk. No recommendation for increased alcohol consumption should be made.
Heavy exercise is associated with increases in HDL in some individuals but must be approached with caution in patients who may have coronary disease. Niacin increases total HDL in many subjects, chiefly the HDL2 ultracentrifugal fraction. Smaller increments in HDL occur with reductase inhibitors and fibric acid derivatives.
The most important reason for measuring HDL cholesterol levels is to identify patients who are at increased risk. Thus, just as with patients who have premature vascular disease or a family history of early arteriosclerosis, patients with low HDL should be treated more aggressively for elevated levels of the atherogenic lipoproteins. Furthermore, vigorous efforts should be directed at the control of other risk factors such as hypertension. Smoking and obesity are known to decrease HDL significantly.
- Deficiency of LCAT
Another disorder associated with low serum levels of HDL is lecithin-cholesterol acyltransferase deficiency. This rare autosomal recessive disorder is not expressed in clinical or biochemical form in the heterozygote. In the homozygote, clinical characteristics are variable. The diagnosis is usually made in adults, though corneal opacities may begin in childhood. Proteinuria may be an early sign. Deposits of unesterified cholesterol and phospholipid in the renal microvasculature lead to progressive loss of nephrons and ultimate renal failure. Many patients have mild to moderate normochromic anemia with target cells. Hyperbilirubinemia or peripheral neuropathy may be present. Red blood cell lipid composition is abnormal, with increased content of unesterified cholesterol and lecithin. Most have elevated plasma triglycerides (200-1000 mg/dL [2.3-11.2 mmol/L]), and levels of serum cholesterol vary from low normal to 500 mg/dL (13 mmol/L), only a small fraction of which is esterified. The large triglyceride-containing lipoproteins are unusually rich in unesterified cholesterol and appear to have abnormal surface monolayers. LDL are rich in triglycerides, and abnormal vesicular lipoproteins are present in the LDL density interval. Two abnormal HDL species are present: bilayer disks and small spherical particles. Marked restriction of dietary fat and cholesterol delays the onset of renal disease.
PRIMARY HYPOLIPIDEMIA DUE TO DEFICIENCY OF APO B-CONTAINING LIPOPROTEINS
- Recessive Abetalipoproteinemia
Etiology & Pathogenesis
This disorder could represent a number of mutations involving the processing of apo B or the secretion of apo B-containing lipoproteins. The predominant cause is mutations involving the microsomal triglyceride transfer protein (MTTP). Heterozygous patients have no abnormalities of lipoproteins or clinical signs. In homozygotes, all forms of apo B are essentially absent. No chylomicrons, VLDL, or LDL are found in plasma, leaving only HDL. Plasma triglycerides are usually less than 10 mg/dL (0.12 mmol/L) and fail to rise after a fat load. Total cholesterol is usually less than 90 mg/dL (2.3 mmol/L). There is a defect in the incorporation of newly synthesized triglycerides into chylomicrons. However, at low levels of fat intake, about 80% of the ingested triglycerides are absorbed, probably by direct absorption of fatty acids via the portal vein.
Clinical features include a paucity of adipose tissue associated with malabsorption of long-chain fatty acids due to failure of the intestine to secrete chylomicrons. Red blood cells may be acanthocytic, with a high cholesterol:phospholipid ratio. There may be progressive degeneration of the central nervous system, including cerebellar degeneration and posterior and lateral spinal tract disease. Retinal degeneration may be severe. Levels of fat-soluble vitamins in plasma may be very low. The neurologic defects are due to deficiency of vitamin E (normally transported largely in LDL). Patients are apparently normal at birth and develop steatorrhea with impaired growth in infancy. The neuromuscular disorder often appears in late childhood with ataxia, night blindness, decreased visual acuity, and nystagmus. Cardiomyopathy with arrhythmias has been reported and may be a cause of death.
Treatment includes administration of fat-soluble vitamins and essential fatty acids. Very large doses of tocopherol (vitamin E) (1000-10,000 IU/d) limit the progressive central nervous system degeneration. Although
vitamin A seems to correct the night blindness, it does not alter the course of retinitis pigmentosa. Vitamins D and K may also be indicated. Restriction of dietary fat minimizes steatorrhea.
- Familial Hypobetalipoproteinemia
This disorder is usually attributable to defects at the apo B locus, resulting in decreased production of the protein or in the production of truncated gene products. LDL and apo B in heterozygotes are often present at about half of normal levels. If a mutant allele resulting in the complete interdiction of apo B synthesis is present in the homozygous state, the clinical and biochemical features may be indistinguishable from those of recessive abetalipoproteinemia, and treatment is the same as for that disorder. Very short truncations of apo B-100 only allow the formation of abnormally dense, small LDL. Longer truncations permit the formation of larger lipoproteins, even including VLDL-like particles. The latter may be present in the virtual absence of LDL.
Clinical features may be absent in patients who produce at least low levels of LDL-like particles. However, signs and symptoms of tocopherol deficiency may be present. Treatment with tocopherols (800 IU/d) is recommended for all patients.
- Chylomicron Retention Disease
This disorder presents in the neonate and appears to be based upon the selective inability of intestinal epithelial cells to secrete chylomicrons. Affected individuals have severe malabsorption of triglycerides with steatorrhea. Levels of LDL and VLDL are about half of normal, presumably secondary to malnutrition. Tocopherol levels may be very low and may be associated with neurologic abnormalities. Clinical symptoms diminish somewhat with time if the patient is managed with a low-fat diet and tocopherol supplementation.
Hypolipidemia may be secondary to a number of diseases characterized by chronic cachexia, eg, advanced cancer. Myeloproliferative disorders can lead to extremely low levels of LDL, probably owing to increased uptake related to rapid proliferation and membrane synthesis. A wide variety of conditions leading to intestinal malabsorption produce hypolipidemia. In these situations, levels of chylomicrons, VLDL, and LDL in serum are low but never absent. Because most of the lipoprotein mass of fasting serum is of hepatic origin, massive parenchymal liver failure—eg, in Reye's syndrome—can cause severe hypolipidemia. A precipitous fall in lipoprotein levels during drug treatment of hyperlipidemia can signal hepatic toxicity. Secondary hypobetalipoproteinemia occurs in oroticaciduria.
The hypolipidemias associated with immunoglobulin disorders result from diverse mechanisms. Affected patients usually have myeloma or macroglobulinemia but may have lymphomas or lymphocytic leukemia. Any of the major classes of immunoglobulins may be involved. In many cases, the immunoglobulins are cryoprecipitins; thus, the diagnosis may be missed if blood is not drawn and serum prepared at 37 °C and observed for cryoprecipitation. Immunoglobulin-lipoprotein complexes may precipitate in various tissues. When this occurs in the lamina propria of the intestine, a syndrome of malabsorption and protein-losing enteropathy may result. Monoclonal IgA in myeloma may precipitate with lipoproteins, causing xanthomas of the gingiva and cervix. Lesions in the skin are usually planar and xanthomatous and may involve intracutaneous hemorrhage, producing a classic purple xanthoma. Planar xanthomas occurring in cholestasis may be confused with this condition because the abnormal lipoprotein of cholestasis (Lp-X), like the circulating lipoprotein complex of immunoglobulin and lipoprotein, has gamma mobility on electrophoresis.
OTHER DISORDERS OF LIPOPROTEIN METABOLISM
Classification of the lipodystrophies is based on their familial or acquired origin and the regional or generalized nature of the fat loss. Insulin resistance is a common feature. Two of these disorders are known to be inherited.
Familial generalized lipodystrophy (Seip-Berardinelli syndrome) is a rare recessive trait associated with mutations in the gene for seipin. It may be diagnosed at birth and is associated with macrosomia. Genital hypertrophy, hypertrichosis, acanthosis nigricans, hepatomegaly, insulin resistance, hypertriglyceridemia, and glucose intolerance are regularly observed.
Familial lipodystrophy of limbs and trunk (Köbberling-Dunningan syndrome) appears to be transmitted as a dominant trait associated with mutations in the lamin A gene. Because sequence anomalies in other regions of the gene are associated with muscular dystrophy, cardiac conduction defects, cardiomyopathy, or
axonal neuropathies, overlapping phenotypes may occur. It affects women predominantly and is not evident until puberty. The face, neck, and upper trunk are usually spared. Growth is normal, but otherwise this syndrome shares features of the generalized form noted above. It is frequently associated with Stein-Leventhal syndrome and often progresses to fatal cirrhosis.
Acquired forms of lipodystrophy, generalized (Lawrence syndrome) and partial (Barraquer-Simmons syndrome), usually begin in childhood, affect females predominantly, and often follow an acute febrile illness. The generalized type commonly shares the features described above, invariably involving the trunk and extremities but sometimes sparing the face. A sclerosing panniculitis, as seen in Weber-Christian syndrome, may appear at the outset. The partial type usually begins in the face and then involves the neck, upper limbs, and trunk. In this disorder, reduced levels of C3 complement are frequently encountered. Most patients have proteinuria, and some develop overt vascular nephritis.
Because a number of patients with disorders resembling both familial and acquired types of lipodystrophy have tumors or other lesions of the hypothalamus, appropriate neurologic evaluation should be obtained. Similarly, the physician should be alert to the association of collagen-vascular disorders, including scleroderma and dermatomyositis, with some cases of acquired lipodystrophy.
Autosomal Recessive Hypercholesterolemia
In this disorder, LDL are markedly elevated, resulting in total cholesterol levels between 400 and 700 mg/dL (10.4 and 18.1 mmol/L). It is attributed to mutations in the gene for a protein that appears to act as an adaptor with the LDL receptor in liver.
Werner's Syndrome, Progeria, Infantile Hypercalcemia, & Sphingolipidoses
These disorders may be associated with hypercholesterolemia, but levels of triglycerides are usually normal. HDL deficiency is typical of Gaucher's disease, in which hypertriglyceridemia may also occur. Niemann-Pick disease is attributable in most cases to mutations in theNCP1 gene and may be associated with hypercholesterolemia or hypertriglyceridemia. However, a similar disorder results from mutations in the NCP2 locus. The NCP1 gene product is involved in the postlysosomal transport of lipids.
Wolman's Disease & Cholesteryl Ester Storage Disease
These recessive lipid storage disorders involve the absence and partial deficiency, respectively, of lysosomal acid lipase, resulting in abnormal cholesteryl ester and triglyceride stores in liver, spleen, adrenals, small intestine, and bone marrow. Most patients have elevated levels of both LDL and VLDL. Wolman's disease is fatal in infancy.
In this recessive disorder, impaired synthesis of bile acids due to mutations in the sterol 27-hydroxylase gene results in increased production of cholesterol and cholestanol that accumulate in tissues. Plasma levels of cholesterol and cholestanol are normal or elevated. Cataracts, tendinous xanthomas, progressive neurologic dysfunction, and premature coronary atherosclerosis are hallmarks of this disease. Its central nervous system effects include dementia, spasticity, and ataxia. Death usually ensues before age 50 from neurologic degeneration or coronary disease. Treatment with chenodiol (chenodeoxycholic acid) appears useful. Resins must be avoided because they aggravate the underlying defect.
Mutations in the cassette half transporters ABCG5 or ABCG8 underlie this disorder, which is characterized by normal or elevated plasma cholesterol levels; high concentrations of plant sterol in serum, adipose tissue, and skin; and prominent tendinous and tuberous xanthomas. Substantially larger fractions of phytosterols and cholesterol are absorbed from the intestine than in normal individuals. Serum cholesterol levels may be as high as 700 mg/dL (18.2 mmol/L), reflecting an increase in LDL that contain sitosterol esters in addition to cholesteryl esters. Diagnosis is established by quantitation of phytosterols in plasma by gas-liquid chromatography. Premature coronary atherosclerosis is common, and polyarthritis and leukocytoclastic vasculopathy are frequent. Treatment consists of a diet restricted in plant sterols and cholesterol and the use of bile acid-binding resins, reductase inhibitors, and a selective cholesterol absorption inhibitor (ezetimibe).
Cholesteryl Ester Transfer Protein (CETP) Deficiency
Mutations have been identified that impair the function of CETP, resulting in the retention of cholesteryl esters in HDL. Total HDL cholesterol is increased by 30-50% in heterozygotes and by as much as 200 mg/dL in homozygotes. The risk of atherosclerosis is moderately increased.
- TREATMENT OF HYPERLIPIDEMIA
Initial therapy in all forms of hyperlipidemia is an appropriate diet. In most cases, a “universal” diet (see below) is indicated. In many subjects with lipemia or with mild hypercholesterolemia, compliance with diet is sufficient to control lipoprotein levels. Most patients with severe hypercholesterolemia or lipemia will require drug therapy. Diet must be continued to achieve the full potential of the medications. LDL cholesterol and triglycerides should be below 90 mg/dL (2.3 mmol/L) and 130 mg/dL (1.5 mmol/L), respectively, in patients with known atherosclerosis.
Caution Regarding Drug Therapy
There are insufficient data on which to base an evaluation of the effects on the fetus of drugs used in treatment of hyperlipoproteinemia. Women of childbearing age should be advised of the potential risk and should be given these agents only if pregnancy is being actively avoided. If contraceptives are prescribed, estrogens should be used with caution in patients with hypertriglyceridemia.
In children, hyperlipidemias other than familial hypercholesterolemia rarely require medication. The severity and age at onset of symptomatic coronary disease in the child's family and the presence of other risk factors, especially hypoalphalipoproteinemia and hyper-Lp(a)lipoproteinemia, in the child should be considered in deciding when drug treatment should be started. Dietary treatment is indicated for all children with hyperlipidemia and should be started after the second year. The exception is primary chylomicronemia, in which an appropriate diet should be instituted as soon as the disease is detected.
DIETARY FACTORS IN THE MANAGEMENT OF LIPOPROTEIN DISORDERS
Restriction of Caloric Intake
The secretion of VLDL by liver is greatly stimulated by caloric intake in excess of requirements for physical activity and basal metabolism. Therefore, the total caloric content of the diet is of greater importance than its specific composition in treating endogenous hyperlipemia. There is a positive correlation between serum levels of VLDL triglyceride and various measures of obesity, but many obese patients have normal serum lipids. On the other hand, most patients with hypertriglyceridemia—except those with lipoprotein lipase deficiency—are obese. This association is more consistently observed in persons with centripetal obesity whose weight gain occurred in later childhood or adulthood and who have insulin resistance. As obese patients lose weight, VLDL stabilize at lower levels. There is a modest correlation of LDL levels with body weight in the general population.
Restriction of Fat Intake
In primary chylomicronemia, all types of fats must be restricted rigidly. In the acute management of mixed lipemia with impending pancreatitis, elimination of dietary fat leads to a rapid decrease in triglycerides.
The cholesterol-lowering effect of a significant reduction in total fat is well known. It has also been shown that a 10–15% fall in cholesterol is achieved when individuals who have been consuming a typical North American diet restrict their intake of saturated fats to 8% of total calories. Most saturated and trans fatty acids cause increased levels of LDL cholesterol by down-regulating hepatic LDL receptors. Whereas polyunsaturated fatty acids do not have this effect, they may reduce levels of HDL and are potentially carcinogenic. Monounsaturated fatty acids increase HDL but do not increase LDL. Moderate use of monounsaturated fats such as olive oil, oleic acid-rich safflower oil, or canola oil is indicated.
The omega-3 fatty acids found in fish oils have special properties relevant to the treatment of hypertriglyceridemia and tend to protect against fatal arrhythmias in ischemic myocardium. Substantial decreases in triglyceride levels can be induced in some patients with severe endogenous or mixed lipemia at doses of 3–10 g/d. Certain members of this class of fatty acids, such as eicosapentaenoic acid, are potent inhibitors of platelet reactivity.
Reduction of Cholesterol Intake
The amount of cholesterol in the diet affects serum cholesterol levels, but individual responses vary. Restriction of dietary cholesterol to less than 200 mg/d (5.2 mmol/d) in normal individuals can result in a decrease of up to 10–15% in serum cholesterol, primarily reflecting a decrease in LDL. Dietary cholesterol and saturated fat content have independent effects on levels of serum cholesterol.
Role of Carbohydrate in Diet
When a high-carbohydrate diet is consumed, hypertriglyceridemia often develops within 48–72 hours, and levels of triglycerides rise to a maximum in 1–5 weeks.
Persons with higher basal triglycerides and those consuming hypercaloric diets show the greatest effect. In type 2 diabetics, a high-carbohydrate diet tends to increase insulin resistance. Substitution of monounsaturated fats for the carbohydrate improves insulin resistance and optimizes lipoprotein levels.
Ingestion of alcohol is a common cause of secondary hypertriglyceridemia owing to overproduction of VLDL. Some individuals with familial hypertriglyceridemia are particularly sensitive to the effects of alcohol, and abstinence may normalize their triglycerides. Occasionally, chronic alcohol intake may also be associated with hypercholesterolemia. Increased cholesterol synthesis and decreased conversion to bile acids have been observed. Alcohol may account for alimentary lipemia persisting beyond 12–14 hours. This possibility should be excluded by the history or a repeat lipid analysis. A positive correlation has been found between alcohol intake and HDL cholesterol levels; however, increased HDL levels are not observed in all individuals. Because alcohol-induced changes in HDL appear primarily to involve the HDL3subfraction, there is no justification for the use of alcohol to increase the “protective effect” of HDL against atherosclerosis. If the low HDL cholesterol is secondary to hypertriglyceridemia, alcohol must be avoided.
Both alpha and gamma tocopherols (vitamin E) have recognized roles in the elimination of free radicals. Vitamin C assists this activity by restoring the tocopheroxyl radical to active tocopherol. These vitamins have been shown to restore normal vascular reactivity in hyperlipidemic patients, and some epidemiologic evidence suggests that they have an antiatherogenic effect. It is therefore reasonable to include at least 50 IU of mixed tocopherols and 250 mg of vitamin C in the diet each day. Larger doses may partially vitiate the effects of certain hypolipidemic drug regimens and have not been shown to have antiatherogenic potential. Selenium may also be important because it is a cofactor for one species of superoxide dismutase. Diets rich in fruits and vegetables appear to be important, providing isoflavones, quinols, and a number of carotenoid species.
A significant percentage of Americans carry at least one allele for mutations in the methylene tetrahydrofolate reductase gene that diminishes its efficiency by reducing its affinity for folic acid. This leads to elevated levels of a metabolite of methionine—homocysteine—that has toxic effects on endothelium. Supplementation with 0.8–2 mg of folic acid mitigates this problem. Vitamins B6 and B12 participate in the metabolism of homocysteine. Thus, a B complex supplement should be used. Dietary protein should be restricted to the amount required for replacement of essential amino acids (about 0.5–1 g/kg) in patients with hyperhomocysteinemia.
Other Dietary Substances
Several other nutrients have been studied in relation to atherosclerosis. Caffeine and sucrose have negligible effects on serum lipids, and their statistical relationship to coronary heart disease is generally unimpressive when data are corrected for cigarette smoking. However, when coffee is prepared by protracted boiling of the grounds, a lipid substance (cafestol) is extracted that contributes to hypercholesterolemia. Lecithin has no effect on plasma lipoproteins. A minor reduction in LDL cholesterol is associated with the addition of oat bran and certain other brans to the diet.
The “Universal Diet”
Dietary treatment is an important aspect of the management of all forms of lipoprotein disorders and may in some cases be all that is required. Knowledge of the dietary factors mentioned above allows selection of appropriate modifications for an individual. However, a basic diet is useful in the treatment of most patients, the elements of which are as follows:
- A normal BMI should be achieved and maintained.
- Fat should provide less than 35% and saturated fat less than 7% of total calories. Monounsaturated oils should predominate and be used for all high-temperature cooking.
- Cholesterol should be reduced to less than 200 mg/d.
- Complex carbohydrates should predominate among total carbohydrates.
- Alcohol should be avoided in patients with hypertriglyceridemia or those requiring weight loss.
- Intake of trans fatty acids should be minimized or avoided.
- Peroxidized fats resulting from protracted heating should be avoided.
Caloric restriction and reduction of adipose tissue mass are particularly important for patients with increased levels of VLDL and IDL. Levels of VLDL and LDL tend to be lower during periods of substantial weight loss than can be maintained under isocaloric conditions even at ideal body weight.
DRUGS USED IN TREATMENT OF HYPERLIPOPROTEINEMIA (Table 19-3)
BILE ACID SEQUESTRANTS
Mechanism of Action
Cholestyramine, colestipol, and colesevelam are cationic resins that bind bile acids in the intestinal lumen. They are not absorbed and therefore increase the excretion of bile acids in the stool up to tenfold. LDL levels decrease as a consequence of increased expression of high-affinity receptors on hepatic cell membranes. These agents are useful only in disorders involving elevated LDL. Patients who have increased levels of VLDL may have further increases in serum triglycerides during treatment with resins. In combined hyperlipidemia, where the resins may be given to reduce LDL, a second agent such as niacin may be required to control the hypertriglyceridemia. Levels of LDL fall 15–30% in compliant patients with heterozygous familial hypercholesterolemia who are receiving maximal doses of the resins.
In disorders involving moderately high levels of LDL, 20 g of cholestyramine or colestipol daily may reduce cholesterol levels effectively. Treatment should commence at one-half this dosage to minimize gastrointestinal side effects. Maximum doses of 30 g of colestipol, 32 g of cholestyramine, or 3.89 g of colesevelam daily are required in more severe cases. These agents are only effective if taken with meals.
Because the resins are not absorbed, systemic side effects are absent. Patients frequently complain of a bloated sensation and constipation, both of which may be relieved by the addition of psyllium to the resin mixture. Malabsorption of fat or fat-soluble vitamins with a daily dose of resin up to 30 g occurs only in individuals with preexisting bowel disease or cholestasis. Hypoprothrombinemia has been observed in patients with malabsorption due to these causes. Cholestyramine and colestipol bind thyroxine, digitalis glycosides, and warfarin and impair the absorption of iron, thiazides, beta-blockers, and other drugs. Absorption of all these is ensured if they are administered 1 hour before the resin. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors. Because they change the composition of bile micelles, bile acid sequestrants theoretically may increase the risk of cholelithiasis, particularly in obese subjects. In practice, this risk appears to be very small. The resins should not be used as single agents in patients with hypertriglyceridemia. They should be avoided in those with diverticulitis.
NIACIN (Nicotinic Acid)
Mechanism of Action
Niacin (but not its amide) is able to effect major reductions in LDL and triglyceride-rich lipoproteins. It inhibits secretion of VLDL. It increases sterol excretion acutely, mobilizes cholesterol from tissue pools until a new steady state is established, and decreases cholesterol biosynthesis. That it can cause a continued decrease in hepatic cholesterol production even when given with bile acid-binding resins is probably an important feature of the complementary action of these agents. Levels of HDL, particularly HDL2, are significantly increased, reflecting a decrease in the fractional catabolic rate of these lipoproteins. Niacin stimulates production of tissue plasminogen activator, an effect that may be of value in preventing thrombotic events. Small, dense LDL are converted to particles of larger diameter during treatment with niacin.
The dose of niacin required varies with the diagnosis. Optimal effect on LDL in heterozygous FH is usually only achieved when 4.5–6 g of niacin daily is combined with a resin or reductase inhibitor. For other forms of hypercholesterolemia, dysbetalipoproteinemia, and hypertriglyceridemia, 1.5–3.5 g/d often has a dramatic effect. Because niacin causes cutaneous flushing, it is usually started at a dosage of 100 mg three times daily and increased slowly. Tachyphylaxis to the flushing often occurs within a few days at any dose, allowing stepwise increases. Many patients have no or only occasional flushing when stabilized on a given dose, but most must reach about 3 g/d before flushing ceases. Because the flush is prostaglandin-mediated, 0.3 g of aspirin given 20–30 minutes before each dose when treatment is initiated or the dose increased (or equivalent doses of other cyclooxygenase inhibitors) may mitigate this symptom. It is important to counsel the patient that the flushing is a harmless cutaneous vasodilation and that the drug should be taken with meals two or three times daily. A daily dose of 6.5 g is the maximum under any circumstances.
Some patients have reversible elevations of serum glutamic aminotransferase or alkaline phosphatase activities up to three times the upper limit of normal that do
not appear to be clinically significant. In a group of patients treated continuously for up to 15 years, no significant liver disease developed despite such enzyme abnormalities. Rarely, patients develop a chemical hepatitis signaled by malaise, anorexia, and nausea. Aminotransferase levels are significantly elevated, and levels of lipoproteins may fall precipitously. Treatment should be stopped immediately. About one-fifth of patients have mild hyperuricemia that tends to be asymptomatic unless the patient has had gout. In such cases, allopurinol can be added to the regimen. A few patients will have moderate elevations of blood glucose during treatment. Again, this is reversible except in some patients who have latent type 2 diabetes. Niacin should be avoided in most patients with insulin resistance unless they are receiving insulin. A more common side effect is gastric irritation, which responds well to H2 blockers and antacids. Antacids that contain aluminum should be avoided. Rarely, patients develop acanthosis nigricans, which clears if the drug is discontinued. Some patients can have cardiac arrhythmias while taking niacin. Reversible macular degeneration has been described rarely.
Table 19-3. Reductase inhibitors.
Niacin should be avoided in patients with peptic ulcer or hepatic parenchymal disease. Liver function, uric acid, and blood glucose should be evaluated before commencing treatment and periodically thereafter.
Most timed-release preparations of niacin should be avoided because of the risk of fulminant hepatic failure. However, if the daily dose is limited to 2 g or less, this rare consequence is unlikely.
FIBRIC ACID DERIVATIVES
Mechanism of Action
These agents—gemfibrozil and fenofibrate—which are ligands for PPARα decrease lipolysis in adipose tissue, reduce levels of circulating triglycerides, and cause modest reductions in LDL. However, in some patients, reductions in VLDL levels are attended by increases in LDL. They cause moderate increases in levels of HDL, including the protein moiety.
The fibrates may be useful in the treatment of patients with severe endogenous lipemia, familial dysbetalipoproteinemia, and some patients with combined hyperlipidemia who are intolerant of niacin. The usual dose of gemfibrozil is 600 mg twice daily; that of fenofibrate is one to three 54-mg tablets daily or a single dose of 160 mg.
Skin eruptions, gastrointestinal symptoms, and muscle symptoms have been described as well as blood dyscrasias and elevated levels of aminotransferases and alkaline phosphatase. These drugs enhance the effects of the coumarin and indanedione anticoagulants and increase lithogenicity of bile. Concomitant use of fibrates with reductase inhibitors increases the risk of myopathy. Fibrates should be avoided during pregnancy and lactation and are contraindicated if hepatic or renal disease is present.
HMG-CoA REDUCTASE INHIBITORS
Mechanism of Action
Several closely related structural analogs of HMG-CoA act as competitive inhibitors of HMG-CoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Of these, lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin are approved for use in the USA. Inhibition of cholesterol biosynthesis induces an increase in high-affinity LDL receptors in the liver, increasing removal of LDL from plasma and decreasing production of LDL. The latter results from increased uptake of lipoprotein precursors of LDL by hepatic receptors. Modest increases in HDL cholesterol and limited decreases in VLDL levels can be achieved. These drugs have no appreciable effect in patients with severe hypertriglyceridemia. Some of the cholesterol-independent effects of reductase inhibitors appear to involve enhanced stability of atherosclerotic lesions and decreased oxidative stress and vascular inflammation, with improved endothelial function. Institution of treatment with a reductase inhibitor should begin immediately in all patients with myocardial infarction regardless of cholesterol level.
These drugs are the most effective individual agents for treatment of hypercholesterolemia. Their effects are amplified significantly when combined with niacin or resin. Daily dosage ranges are presented in Table 19-3. Because the rate of cholesterol synthesis is higher at
night, reductase inhibitors should be given with the evening meal or at bedtime for greatest effect. Atorvastatin has a longer half life and may be taken at any time. Pravastatin is absorbed optimally when taken more than 3 hours after a meal. At higher doses, a twice-daily regimen is recommended. Patients with heterozygous familial hypercholesterolemia usually require higher doses. Because information on long-term safety is lacking, use of these agents in children should be restricted to those with homozygous familial hypercholesterolemia and selected heterozygotes who are at particularly high risk. Women who are lactating, pregnant, or likely to become pregnant should not be given these drugs.
These agents are generally well tolerated. Side effects, often transient, include changes in bowel function and rashes. Myopathy with markedly elevated creatine kinase levels occurs infrequently. Rarely, myopathy can progress to rhabdomyolysis with myoglobinuria and renal shutdown. There is an increased incidence of myopathy in patients receiving several of the reductase inhibitors with cyclosporine, fibric acid derivatives, macrolides, HIV protease inhibitors, nefazodone, verapamil, and ketoconazole. Other drugs that compete for metabolism by cytochrome P450 3A4 can be expected to have the same effect. Because pravastatin does not compete with these agents for metabolism by cytochrome P450 enzymes, it appears to be compatible at lower dosage with them. Fluvastatin is chiefly metabolized by cytochrome P450 2C9. Thus, competitors for that pathway may cause accumulation of this reductase inhibitor. The myopathy is rapidly reversible upon cessation of therapy. Minor elevations of creatine kinase activity in plasma are noted more frequently, especially with unusual physical activity. Creatine kinase levels should be measured before starting therapy and monitored at regular intervals. Older patients, those taking higher doses and multiple other drugs, those who consume large amounts of alcohol, and diabetics or others with renal insufficiency should be observed more frequently.
Moderate, often intermittent elevations of serum aminotransferases (up to three times normal) occur in some patients. If the patient is asymptomatic, therapy may be continued if activity is measured frequently (at 1- to 2-month intervals) and the levels are stable. In about 2% of patients, some of whom have underlying liver disease or a history of alcohol use, aminotransferase activity may exceed three times the normal limit. This usually occurs after 3–16 months of continuous therapy and may portend more severe hepatic toxicity such as that described in the section on niacin. The reductase inhibitor should be discontinued promptly in these patients. These agents are contraindicated in the presence of active liver disease and should be used with caution in patients with a history of liver disease. They should be discontinued temporarily during hospitalization for major surgery.
Cholesterol absorption inhibitors
Mechanism of Action
Ezetimibe, the first of this class, inhibits the absorption of cholesterol and phytosterols by enterocytes. By interrupting the enterohepatic circulation of sterols secreted in bile, it increases sterol efflux from the body.
Ezetimibe is useful in treating primary hypercholesterolemias and phytosterolemia. Concomitant use of fibric acid derivatives can increase the blood concentration of this drug. Resins can decrease its absorption. It should be avoided in pregnant or lactating women and in patients with liver disease, and used with caution in patients receiving cyclosporine. A single dose of 10 mg daily reduces cholesterol by 15 to 20 percent.
Very few side effects have been reported. The prevalence of elevated liver enzymes may be modestly increased when ezetimibe is given with a reductase inhibitor.
COMBINED DRUG THERAPY (Table 19-4)
Combinations of drugs may be useful (1) when LDL and VLDL levels are both elevated; (2) in cases of hypercholesterolemia in which significant increases of VLDL occur during treatment with bile acid-binding resins; and (3) where a complementary effect is required to normalize LDL levels, as in familial hypercholesterolemia or familial combined hyperlipidemia.
Fibric Acid Derivatives with Niacin
The combination of a fibrate with niacin may be more effective than either drug alone in managing marked hypertriglyceridemia.
Niacin & Resins
Niacin usually normalizes triglycerides in individuals who have increased levels of VLDL while taking resins. The combination of niacin and resins is more effective
than either agent alone in decreasing LDL levels in familial hypercholesterolemia. The combination is also very useful in the treatment of familial combined hyperlipidemia. The absorption of niacin from the intestine is unimpeded by the presence of resin; the two medications may therefore be taken together. Because the resins have potent acid-neutralizing properties, there is further reason to give the two medications together when a patient complains of the gastric irritation that sometimes occurs as an adverse effect of niacin.
Table 19-4. The primary hyperlipoproteinemias and their drug treatment.
HMG-CoA Reductase Inhibitors with Other Agents
The addition of resin or niacin to a reductase inhibitor further decreases plasma levels of LDL in patients with primary hypercholesterolemias. Liver function and plasma creatine kinase activity should be monitored frequently when the combination includes niacin. These three drugs used together are more effective, frequently at lower doses, than any of their binary combinations in reducing LDL. Ezetimibe is synergistic with reductase inhibitors.
POSSIBLE UNTOWARD CONSEQUENCES OF LIPID-LOWERING THERAPY
The risk of coronary heart disease has been found to increase with LDL cholesterol levels in virtually all epidemiologic surveys. Total mortality tends to be slightly higher among individuals with cholesterol levels below 160 mg/dL, however, raising a question about whether very low levels of cholesterol may increase the risk of noncoronary disease. The correlation between deaths from certain digestive and respiratory disorders and low cholesterol levels probably reflect the effect of wasting illnesses on LDL. For instance, the low cholesterol levels seen in hepatic cirrhosis most certainly reflect impaired lipoprotein production by the liver. Increased uptake of LDL by malignant cells is known to decrease LDL in plasma. However, two studies have shown a modest increase in the risk of hemorrhagic stroke at cholesterol levels below 130 mg/dL. In one, the effect was confined to hypertensive patients. In large clinical trials employing niacin or reductase inhibitors, no excess deaths from noncoronary causes occurred in the course of 5 years or more, though impressive reductions in deaths from coronary disease were observed, resulting
in significant reduction in all-cause mortality. In a secondary intervention trial (the Four S trial), patients receiving simvastatin had a 37% reduction in new coronary events over a 5- to 6-year period. In the West of Scotland study, treatment with pravastatin resulted in a 22% reduction in all-cause mortality. In the MRFIT study, a proportionate hazards analysis adjusting for covariance demonstrated that the lowest net death rate occurs at a cholesterol level of 122 mg/dL.
Populations in which many individuals have cholesterol levels below 160 mg/dL, such as in Japan, do not have an excess incidence of the noncoronary causes of death. Of great importance in resolving the question of the relative benefit of lipid-lowering therapy is the fact that about 45% of deaths in the USA and Europe are attributable to cardiovascular disease, predominantly coronary disease. Thus, projection of a significant reduction in fatal occlusive coronary events into the age range where coronary disease predominates would be expected to far outweigh the marginal increases that might occur in other causes of death. In the light of the relationship of very low cholesterol levels (< 130 mg/dL) to hemorrhagic stroke, the therapeutic goal for LDL cholesterol in patients with known coronary disease should not be below the 60 mg/dL (1.55 mmol/L) range until that relationship is better understood.
Mechanisms of Atherogenesis
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Seman LJ, McNamara JR, Schaefer EJ: Lipoprotein(a), homocysteine, and remnantlike particles: emerging risk factors. Curr Opin Cardiol 1999;14:186.
Disorders of Lipoprotein Metabolism
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