Lipid Disorders in Children and Adolescents

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a major cause of morbidity and mortality among adults in industrialized countries. Dyslipidemia (specifically elevated low-density lipoprotein [LDL] cholesterol, low high-density lipoprotein [HDL] cholesterol, and high non-HDL cholesterol and triglycerides [TGs]) has been identified as an independent risk factor in the development of ASCVD. There is strong evidence that lipoprotein levels track from childhood into adulthood and that abnormal levels of LDL cholesterol and perhaps other lipoproteins are associated with atherosclerosis, and therefore with related adverse outcomes.

This chapter reviews the evidence for the role of lipid abnormalities in the early natural history of atherosclerosis. In addition, a general overview of lipoprotein metabolism is provided—followed by a review of genetic disorders in the metabolism of lipoproteins. Secondary causes of high cholesterol are explained, including the increasing prevalence of obesity and metabolic syndrome, as a cause of lipid abnormalities in the pediatric population. Standards and approaches to screening for hyperlipidemia in children are reviewed, as well as current approaches to the dietary and pharmacologic management of pediatric lipid disorders.

Metabolism

Lipid disorders in children and adolescents can result from defects in the production, transport, or degradation of lipoproteins. To understand the diverse causes of lipoprotein abnormalities, a brief review of lipoprotein structure, function, and metabolism is provided. Table 25.1 summarizes the lipoprotein subclasses, the source of each one, and the constituent lipids and apolipoproteins associated with each particle.

TGs, cholesterol esters, phospholipids, and plant sterols within food postingestion are digested to fatty acids, 2-monoglycerides, lysophospholipids, unesterified cholesterol, and plant sterols. Absorption of these digestive end products occurs through two mechanisms: passive diffusion and carrier-mediated transport. In passive diffusion, nonpolar lipids are solubilized with the aid of bile acids and lysophospholipids into mixed micelles that can diffuse through the apical surface of the enteric membrane. Carrier-mediated transport involves several different transport proteins for fatty acids and sterols. CD 36/scavenger receptor B2 (SR-B2), a fatty acid translocase, promotes long-chain fatty acid and cholesterol absorption in the proximal small intestine. At least two additional transporters, Niemann-Pick C1-like 1 protein (NPC1L1) and SR-B1, play a role in sterol uptake. As such, NPC1L1 and SR-B1 are targets for the cholesterol-lowering medication ezetimibe, a potent inhibitor of cholesterol and plant sterol absorption.

Most of the plant sterols ingested and about half of the absorbed cholesterol are excreted from the intestinal cell back into the lumen by two adenosine triphosphate (ATP)-binding cassette (ABC) half-transporters, G5 and G8, thus limiting the amount of sterols that are absorbed. A rare mutation of either ABCG5 or ABCG8, known as sitosterolemia , results in abnormally high plant sterol levels in plasma and tissues and deposition of sterols in the skin and arteries. Individuals with this disorder are at an increased risk of premature atherosclerosis. Sterols that remain in the enterocyte are converted to sterol esters by acyl-CoA cholesterol acyl transferase (ACAT), which attaches a fatty acid to the sterol for storage within the cytoplasm of the cell. Within the enterocyte, lipids are aggregated into lipoproteins through the action of a chaperone protein, microsomal triglyceride transfer protein (MTTP), and perhaps several additional proteins. MTTP conjugates TGs, phospholipids, cholesterol, and cholesterol ester with apolipoprotein B-48 (apoB-48) on the luminal side of the endoplasmic reticulum (ER) membrane to create a mature chylomicron. A similar process is used to aggregate TG, phospholipids, cholesterol, and cholesterol ester with apoB-100 in the liver to form very low-density lipoprotein (VLDL) particles. In the genetic disorder abetalipoproteinemia, mutations in the gene encoding MTTP result in an inability to produce chylomicrons and VLDL, suggesting the essential nature of MTTP in chylomicron and VLDL biogenesis. The recently approved drug lomitapide inhibits MTTP, reducing lipoprotein assembly and secretion, and lowers plasma cholesterol by around 50% in patients with homozygous familial hypercholesterolemia.

Chylomicrons once formed are too large to penetrate the capillary membrane. Consequently, they are secreted into the lymphatic system and enter the venous plasma compartment through the thoracic lymph duct. As the nascent particles are released into the plasma, several apolipoproteins (including apoC-II, C-III, and apoE) are preferentially transferred to the chylomicrons from circulating HDLs. Fig. 25.1 depicts chylomicron metabolism.

Chylomicrons transport dietary TG and cholesterol to sites of storage or metabolism. The size of the particles varies depending on the amount of fat ingested. They are rapidly cleared from the circulation through the action of lipoprotein lipase (LPL). LPL is a TG hydrolase found on the capillary endothelium of various tissues, with its highest concentration in muscle and adipose tissues. Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) anchors LPL to the capillary endothelium. LPL is activated by apoC-II and inhibited by apoC-III on the chylomicron. Loss-of-function mutations in LPL, apoC-II, and GPIHPB1 can result in marked hypertriglyceridemia. Loss-of-function mutations in apoC-III are associated with increased LPL activity and decreased TG levels. As the TG contained within the chylomicron is hydrolyzed, free fatty acids are liberated for oxidation via a variety of cell types and the particle decreases in size. When approximately 80% of the initial TG has been removed, apoC-II dissociates from its surface. The transfer of apoC-II from chylomicrons to HDL decreases the ability of LPL to further breakdown TGs. The TG-depleted chylomicrons, now considered chylomicron remnants, are taken up by the liver through the LDL receptor (LDLR), a receptor that recognizes apoE on the chylomicron surface and apoB100 on the surface of liver-derived lipoproteins. A smaller fraction of remnants may also be internalized via an LDLR-related protein-1 (LRP1)-mediated endocytosis.

VLDLs originate from the liver, and like chylomicrons they are TG-rich particles ( Fig. 25.2 ). In contrast to the intestinally derived chylomicrons, the fatty acids contained within the VLDL TG come from de novo synthesis from dietary carbohydrate, lipoprotein remnants, or circulating fatty acids, internalized by the liver from plasma. Similar to chylomicrons, the size of the VLDL particles can vary depending on the quantity of the TG carried in the particle. When TG production in the liver is increased, the secreted VLDL particles are large. Within the hepatocyte, TG and cholesterol ester are assembled by an MTTP and surrounded with a phospholipid membrane associated with apoB-100. The mature VLDL particles are released into the lymph and ultimately into the vascular space, where other apolipoproteins (including apoC-II, apoC-III, and apoE) adsorb to the VLDL surface. The metabolism of the VLDL particle follows a route similar to that of the chylomicron: apoC-II on its surface activates LPL, LPL hydrolyzes the VLDL TG, free fatty acids are liberated, the particle decreases in size (after an 80% loss of TG), and ultimately apoC-II dissociates—resulting in the formation of VLDL remnants (also known as intermediate-density lipoproteins [ IDLs ]). Approximately half of the IDL is then removed from plasma through the interaction of apoE with the LDLR and LRP1 on the surface of liver cells. The rest of the IDL is converted to LDL through further hydrolysis of TGs and phospholipids by hepatic TG lipase (HL). ApoE is transferred from IDL to HDL during the transition of the remnant to LDL.

LDL, the major carrier of cholesterol in plasma, is taken up into peripheral tissues and liver cells by the LDLR assisted by an adaptor protein (AP). The AP binds to the LDLR and clathrin, suggesting a role for AP in the recruitment and retention of LDLR in clathrin-coated pits. Upon receptor binding, the LDL particle bound to LDLR/AP is rapidly internalized into clathrin-coated pits by endocytosis. Within the cell, the newly formed endosome becomes acidified through the action of an ATP-dependent proton pump. Acidification causes degradation of the clathrin coat, dissociation of the LDLR from LDL, and subdivision of the endosomal membranes. The endosome containing the LDLR recirculates back to the cell membrane for additional LDL uptake. Alternatively, proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDLR, and short-circuits recycling of LDLR from the endosome, leading to its degradation. The remaining LDL-containing endosome fuses with a lysosome, where hydrolytic enzymes digest the lipoprotein into its component parts: unesterified cholesterol, fatty acids, and free amino acids.

The amount of cholesterol released from endosomal uptake regulates hepatic synthesis of LDLR and cholesterol. When cellular concentration of cholesterol is low, sterol receptor binding proteins (SREBPs) move from the ER to the Golgi, where proteases cleave SREBPs into active transcription factors. SREBPs translocate to the nucleus, where they stimulate the transcription of LDLR and hydroxymethylglutaryl (HMG) CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. If cholesterol levels in the cell are high, SREBPs remains in the ER in an inactive form and do not stimulate LDLR synthesis. In this way, intracellular hepatic cholesterol concentration regulates the amount of cholesterol internalized and synthesized by the cell.

When excess LDL and other small apoB-containing lipoproteins (chylomicron remnants and IDL) are present in the plasma, the capacity of the LDLR to remove them is exceeded and these particles become more susceptible to oxidation. Oxidized apoB-containing lipoproteins can be taken up by scavenger receptors on macrophages in the subendothelium of arteries and may contribute to the formation of atherosclerotic lesions.

HDL transfers cholesterol and other lipids from peripheral tissues (including arterial atheroma) back to the liver. The particles are synthesized predominantly in the liver (and to a lesser extent in the intestine) as lipid-poor precursor particles (pre-beta HDL) containing apoA-I (see Fig. 25.2 ). Nascent HDL interacts with the plasma membrane of cells, collecting lipid through an ABCA1 mechanism. The cholesterol and phospholipids transferred through this process adsorb to the HDL, forming a disk-shaped particle referred to as HDL3 . Dysfunction of ABCA1 will significantly decrease HDL levels and thereby dramatically impair cholesterol and lipid transport functions. A rare autosomal recessive disorder called Tangier disease is caused by lack of functional ABCA1 protein and is characterized by an absence of HDL along with hypertriglyceridemia and low LDL levels. Within the plasma, HDL3 interacts with the enzyme lecithin cholesterol acyl transferase (LCAT)—which catalyzes the esterification of particle-associated cholesterol. ApoA-I on the HDL surface activates LCAT. Once formed, the cholesterol ester is more hydrophobic and moves to the interior of the particle—creating a sphere-shaped HDL particle known as HDL2 .

As HDL2 increases in size, the particle becomes substrate for cholesterol ester transfer protein (CETP). This enzyme promotes the exchange of esterified cholesterol within HDL2 for TG contained within apoB-100–associated lipoproteins. This lipid exchange is the primary mechanism whereby HDL participates in reverse cholesterol transport from tissues back to the liver. The rest of the cholesterol ester is selectively taken up from HDL by hepatocytes via a SR-B1, without concomitant uptake of the entire HDL particle. This latter process may require the action of HL. The lipid-poor pre-beta HDL resulting from this process is released for recycling.

Hypolipidemias