Disorders of Lipoproteins

Rebecca S. Wappner

LIPOPROTEIN METABOLISM

Lipids are a primary source of energy. They also function as the structural components of cell membranes and are precursors of biologically important compounds, including bile acids, vitamin D, and steroid hormones. Plasma lipoproteins vary widely in their composition and consist of spherical particles that have a central core of nonpolar lipids (i.e., triglycerides and cholesterol), surrounded by a surface monolayer of polar lipids (i.e., phospholipids) and apolipoproteins. The plasma lipoproteins are classified according to size, density, and electrophoretic charge.

By ultracentrifugation, plasma lipoproteins are separated by density into chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), intermediate-density lipoproteins (IDL), and high-density lipoproteins (HDL). Chylomicrons are the largest, least dense, and have the lowest protein content, whereas HDL are the smallest, contain the most protein, and are the most dense. Lipoprotein electrophoresis separates the lipoproteins on the basis of charge into chylomicrons, beta-lipoproteins (LDL), pre–beta-lipoproteins (VLDL), and alpha-lipoproteins (HDL). The chylomicrons have the lowest charge and remain near the origin, whereas HDLs have the highest charge and greatest mobility. The electrophoretic findings are the basis for the Fredrickson classification of hyperlipoproteinemias, as shown in Table 388.1.

Apolipoproteins are an integral part of lipoproteins and function as ligands for lipoprotein receptors and as cofactors for many of the enzymes involved with lipoprotein metabolism. Table 388.2 lists the major apolipoproteins with their associated lipoproteins and specific functions.

Several enzymes are involved with lipoprotein metabolism. Lipoprotein lipase (LPL), produced in adipose tissue and striated muscle and present on the endothelial surface of capillaries, hydrolyzes the triglycerides of plasma chylomicrons, VLDL, and IDL to free fatty acids and glycerols. LPL requires activation by apolipoprotein C-II (apoC-II). Hepatic lipase, produced by hepatocytes and present on hepatic endothelial cells, hydrolyzes the triglycerides of VLDL and IDL in the formation of LDL and hydrolyzes the phospholipids and triglycerides of HDL. The free fatty acids and glycerols released by the actions of the lipases may be oxidized as fuel or used for the resynthesis of lipoproteins, depending on the metabolic need at the time. Lecithin-cholesterol acyltransferase (LCAT) catalyzes the transfer of fatty acids from lecithin to cholesterol to create cholesterol esters. ApoA-I is the major cofactor for LCAT. Cholesterol ester transfer protein (CETP) transfers cholesterol esters formed by the action of LCAT to acceptor lipoproteins (i.e., LDL, VLDL, and HDL). A specific species of HDL, with
associated apoD, functions with LCAT and CETP to take up cholesterol esters from peripheral tissues and transfer them to VLDL, IDL, and LDL. IDL and LDL transport the cholesterol esters back to the liver, thereby effecting reverse cholesterol transport and decreasing atherosclerotic risk.

TABLE 388.1. CLASSIFICATION OF HYPERLIPOPROTEINEMIA

Electrophoretic Phenotype	Increased Lipoproteins	Plasma Elevations	Atherosclerotic Risk	Incidence	Associated Defects	Associated Genetic Disorders
Ia	Chylomicrons	Triglycerides	Not increased	Rare	LPL deficiency, LPL inhibitor	LPL deficiency
Ib	Chylomicrons	Triglycerides	Not increased	Rare	ApoC-II deficiency	ApoC-II deficiency
IIa	LDL	Cholesterol	High	1 in 500 (FH); 5 in 100 (PH)	LDL receptor, apoB-100 binding site defects (FH); multifactorial (PH)	FH; PH; familial combined hyperlipoproteinemia
IIb	LDL + VLDL	Cholesterol and triglycerides	High	1 in 200	Overproduction of apoB and VLDL	Familial combined hyperlipo-proteinemia
III	beta-VLDL	Cholesterol and triglycerides	High	1 in 5,000	ApoE-2/E-2 genotype	Familial dysbetalipo-proteinemia
IV	VLDL	Triglycerides	May be increased	Genetic uncommon, secondary common	Overproduction and decreased clearance of VLDL	Familial hypertriglyceridemia (mild forms); familial combined hyper-lipoproteinemia
V	Chylomicrons + VLDL	Triglycerides and cholesterol	May be increased	Uncommon	ApoE mutations	Familial hypertri-glyceridemia (severe forms)
Apo, apolipoprotein; FH, familial hypercholesterolemia; LDL, low-density lipoprotein; LPL, lipoprotein lipase; PH, polygenic hypercholesterolemia; VLDL, very low-density lipoprotein.

Chylomicrons and VLDL are the major transport forms of triglycerides. Chylomicrons, formed from dietary long-chain triglycerides, are considered exogenous triglycerides, whereas VLDLs, formed in the liver, are considered endogenous. Circulating chylomicrons, with associated apoB-48 and apoA-I, acquire apoC-II and apoE and are metabolized to chylomicron remnants with the release of triglycerides by LPL. The chylomicron remnants, now richer in cholesterol ester, are taken up by hepatocytes through receptor-mediated endocytosis and further hydrolyzed to free fatty acids, glycerol, and cholesterol. In the hepatocytes, endogenous triglycerides are formed, which are then secreted into the circulation as VLDL, with associated apoB-100 and small amounts of apoE. After acquiring
apoC-II, the VLDL undergoes hydrolysis of its triglycerides by LPL, with the formation of more cholesterol ester-rich IDL; further hydrolysis of IDL results in LDL. IDL and LDL, with associated apoB-100, are taken up by hepatocytes or adrenal cells through receptor-mediated endocytosis, and the molecules are hydrolyzed further to release free fatty acids, glycerol, and cholesterol. The resultant increase in hepatocyte intracellular concentration of cholesterol, whether from the endocytosis of chylomicron remnants, IDL, or LDL, results in feedback inhibition of de novo synthesis of cholesterol from acetoacetate. This rate-limiting step is catalyzed by 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase. In addition, other feedback effects include down-regulation of receptor synthesis and esterification of cholesterol by acyl-CoA cholesterol acyl transferase.

TABLE 388.2. APOLIPOPROTEINS

Apolipoproteins	Associated Lipoproteins	Function
A-I	Chylomicrons, HDL	Cofactor for LCAT
A-II	Chylomicrons, HDL	Transport of HDL
A-IV	Chylomicrons, HDL	Cofactor for LCAT; promotes cholesterol efflux from cells
B-48	Chylomicrons and chylomicron remnants, VLDL, IDL	Chylomicron transport
B-100	Chylomicrons and chylomicron remnants, VLDL, IDL	Ligand for LDL receptor; transport of VLDL, IDL, LDL
C-I	Chylomicrons, VLDL, IDL, HDL	Cofactor for LCAT; inhibits binding of apoE-containing lipoproteins to LRP and LDL receptor
C-II	Chylomicrons, VLDL, IDL, HDL	Cofactor for LPL
C-III	Chylomicrons, VLDL, IDL, HDL	Inhibits binding of apoE-containing lipoproteins to LDL receptor
D	HDL	Transport of cholesterol esters between lipoproteins
E	Chylomicrons and chylomicron remnants, VLDL, IDL, HDL	Ligand for remnant receptor and LDL receptor
F	HDL	Possibly involved with cholesterol transport or esterification
G	HDL	Unknown
H	Chylomicrons, VLDL, HDL	Cafactor for LPL with apoC-II
HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LRP, low-density lipoprotein receptor-related protein; VLDL, very low-density lipoprotein.

HYPERLIPOPROTEINEMIA

Diagnosis

In children, the diagnosis of a hyperlipoproteinemia is established by a 12to 18-hour fasting lipid profile that includes total cholesterol, LDL (calculated), HDL, and triglyceride levels. Adults and older adolescents should fast for 18 to 24 hours before blood sampling. Younger children, who are less tolerant of fasting, may fast for only 8 to 12 hours. Plasma lipid levels vary with age. Tables of normal values for children and adults are available (see the section, Suggested Readings). In general, total cholesterol levels of less than 170 mg/dL are desirable; levels greater than 200 mg/dL are elevated. LDL levels of less than 110 mg/dL are desirable; levels greater than 130 are elevated. Triglyceride levels greater than 200 mg/dL and HDL levels of less than 35 mg/dL are considered abnormal. Elevated LDL levels and reduced HDL levels correlate positively with an increased risk for premature atherosclerosis. Lipoprotein electrophoresis helps establish the pattern of elevation and also demonstrates chylomicrons, if present.

Family history is frequently helpful in determining which children are at high risk for hyperlipoproteinemia. Questions should be asked concerning the presence of xanthomas, arcus cornea, angina, peripheral vascular disease, strokes, or coronary artery disease before the age of 55 years, and the lipid levels of both parents should be ascertained. Children with a positive family history for hyperlipoproteinemia should have a fasting lipid profile done starting at age 2 years. Most of the familial disorders are inherited as autosomal dominant traits, and each child of an affected parent has a 50% chance to inherit the disorder. Children found to be affected should be started on therapy appropriate for age and the degree and pattern of hyperlipoproteinemia. At-risk children with normal results should have the testing repeated at 5-year intervals. Children with borderline results should have repeat testing done in 1 year. An exception occurs in families in which both parents have a known genetic hyperlipoproteinemia. When both parents have hyperlipoproteinemias, the children have a 50% chance to also have the disorder and inherit it from one of the parents. But, in addition, they have a 25% chance to inherit a gene for the disorder from each parent and have a severe homozygous form of hyperlipoproteinemia. Such children should be tested in infancy so that appropriate therapy may be started before clinical symptoms appear. Any child at any age with symptoms of severe hyperlipoproteinemia (i.e., pancreatitis, angina, arcus cornea, or xanthomas) should have testing done.

Because testing children for hyperlipoproteinemia on the basis of family history alone may miss a significant number of children with hyperlipoproteinemia, screening for hypercholesterolemia in a wider population may be considered. As many as 20% to 25% of children have elevated lipid levels. Only the minority have genetic hyperlipoproteinemias. Most lipid elevations result from a dietary intake high in total and saturated fats, sedentary lifestyle, reduced exercise, and obesity. Other children have increased lipid levels from diabetes, hypothyroidism, nephrosis, liver dysfunction, and medications (i.e., corticosteroids and contraceptives). Hypertension, chronic alcoholism, and smoking also increase the risk for premature atherosclerosis. Children with other risk factors should be considered for cholesterol screening starting at 5 years of age. Children with elevated cholesterol levels on repeated testing should have a fasting lipid profile performed.

Therapy

The American Heart Association Step One and Step Two diets are used for the nutritional therapy of hyperlipoproteinemia. The Step One diet limits total fat intake to 30% of calories, with equal amounts from saturated, monounsaturated, and polyunsaturated fats. Total cholesterol intake is limited to 300 mg/day. An increased intake of complex carbohydrate and fiber also is recommended. The Step One diet is prudent and applicable to the general population, as well as children older than 5 years with hyperlipoproteinemia. It may be used cautiously in children with hyperlipoproteinemia between ages 2 and 5 years. In children, total fat intake should not be lower than 20% of total caloric intake. Dietary modification is indicated if the total cholesterol levels remain persistently higher than 200 mg/dL or LDL levels remain higher than 130 mg/dL. The Step Two diet further reduces the saturated fat intake to 7% of total calories and cholesterol intake to less than 200 mg/day. The Step Two diet should not be implemented in children unless hyperlipoproteinemia persists while on a Step One diet.

In addition to the Step One and Step Two diets, persons with hypertriglyceridemia also should reduce free carbohydrate intake. An American Diabetes Association–type diet, with reduced free sugar intake, reduced total fat and cholesterol intake, and caloric intake to maintain a normal weight-for-height ratio is recommended. In obese individuals, hypertriglyceridemia may resolve with normalization of weight for height. The avoidance of ethanol, a significant source of carbohydrates, is important in adults. Response to dietary therapy may take as long as 3 to 6 months to be appreciated.

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