Rudolph's Pediatrics, 22nd Ed.

CHAPTER 166. Disorders of Lipid and Lipoprotein Metabolism

Peter O. Kwiterovich Jr.

Disorders of lipid and lipoprotein metabolism are characterized by dyslipidemia, which is defined as either elevated or low levels of one or more of the major lipoprotein classes: chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Dyslipidemia can result from the expression of a mutation in a single gene that plays a paramount role in lipoprotein metabolism. More often, dyslipidemia reflects the influence of multiple genes. Environmental influences such as excessive dietary intake of fat and calories and limited physical activity, particularly when associated with overweight or obesity, can also contribute significantly to dyslipidemia.  The major clinical complication of dyslipidemia is a predilection to atherosclerosis starting early in life and leading to cardiovascular disease (CVD) in adulthood. At the extremes of dyslipidemia, where inherited disorders of lipid and lipoprotein metabolism are more likely to occur, premature CVD is more frequent and can be accompanied by deposition of lipid in various tissues. Children with profound hypertriglyceridemia are at high risk of pancreatitis.


A number of clinical, epidemiological, metabolic, genetic, and randomized clinical trials strongly support the tenet that the origins of atherosclerosis and CVD risk factors begin in childhood and adolescence and that treatment should begin early in life.1

Several longitudinal pathological studies from the general population have found that early atherosclerotic lesions of fatty streaks and fibrous plaques in children, adolescents, and young adults who died from accidental causes are significantly related to higher antecedent levels of total cholesterol (TC) and LDL-C (LDL-C); to lower levels of HDL-C (HDL-C); and to other CVD risk factors such as obesity, higher blood pressure, and cigarette smoking.1 These risk factors’ effects on coronary lesion severity are multiplicative rather than additive.

Four major prospective population studies from Muscatine, Bogalusa, the Coronary Artery Risk Development in Young Adults (CARDIA) and the Special Turku Coronary Risk Factor Intervention Project (STRIP) showed that CVD risk factors in children and adolescents, particularly LDL-C and obesity, predicted clinical manifestations of atherosclerosis in young adults.

Studies have also been performed in high-risk youth; these individuals were selected because one parent had CVD or because they have inherited a known metabolic disorder of lipoprotein metabolism that produces premature CVD. Half of the young progeny of men who had CVD before age 50 had one of seven dyslipidemic profiles.

Examples of inherited lipoprotein disorders that often present in youth at high risk of future CVD include familial hypercholesterolemia (FH; which is caused by a defect in the LDL receptor, LDLR); familial combined hyperlipidemia (FCHL); and its metabolic cousin hyperapoB, the prototypes for hepatic overproduction of VLDL.


Plasma lipoproteins are spherical particles consisting of a core of nonpolar lipids—TG and cholesteryl ester—surrounded by a surface coating consisting of proteins (apolipoproteins) and more polar lipids, phospholipids, and unesterified (free) cholesterol. Plasma lipoproteins are classified by their density and electrophoretic mobility into four major groups: chylomicrons, VLDL, LDL, and HDL (Table 166-1). After electrophoresis, chylomicrons remain at the origin, and VLDL, LDL, and HDL migrate in the same positions as pre-β-, β-, and α-globulins, respectively. The hydrated density of the lipoproteins is related to their chemical composition and the relative content of lipid and apolipoprotein. Chylomicrons are 99% lipid, most of it being TG (Table 166-1). After plasma has stood overnight, these large particles (80–500 nm) will rise to the top, where they appear as a creamy layer. VLDL is about 90% lipid, the majority of it being TG, with lesser amounts of cholesterol. When present in plasma in increased amounts, VLDL are large enough (30–80 nm) to create a cloudy or turbid appearance to plasma. LDL are the major carriers of cholesterol in plasma, and about 50% of their weight is cholesteryl ester and cholesterol. HDL comprise about equal amounts of apolipoprotein and lipid, principally phospholipids and cholesterol.


Lipoproteins are associated with several apolipoproteins (Table 166-2). Nomenclature for the apolipoproteins follows an alphabetical scheme.  The nucleotide sequences of cDNA for the apolipoproteins have been determined.


The transport of plasma lipids by lipoproteins may be divided into exogenous (dietary) and endogenous systems (Fig. 166-1).

Exogenous Lipid Transport

Most dietary lipid is in the form of neutral fat or TG (75–150 g/d). The amount of cholesterol in the diet is usually about 300 mg/day but varies from 100 to 600 mg/day. In addition to dietary cholesterol, about 1100 mg of biliary cholesterol is secreted each day from liver into the intestine (Fig. 166-1). In the small intestine, lipids are emulsified by bile salts and hydrolyzed by pancreatic lipases. The bile acids are then reabsorbed by the intestinal bile acid transporter (IBAT) for return to the liver through the enterohepatic pathway (Fig. 166-1). TG is broken down into fatty acids and 2-monoglycerides; cholesteryl ester is hydrolyzed into fatty acids and unesterified cholesterol. These components are then absorbed by the intestinal cells. The absorption of cholesterol occurs in the jejunum, through the high-affinity uptake of dietary and biliary cholesterol by the Niemann-Pick C-1L-1 (NP-C-1L-1) protein (Fig. 166-1). Normally, about half the dietary and biliary cholesterol is absorbed daily. Excessive cholesterol absorption is prevented by the ABCG5/ABCG8 transporters, which act together to pump excess cholesterol and plant sterols from the intestine back into the lumen for excretion into the stool (Fig. 166-1).

Table 166-1. Classification and Properties of the Major Human Plasma Lipoproteins

Table 166-2. Classification and Properties of Major Human Plasma Apolipoproteins

FIGURE 166-1. Overview of lipoprotein metabolism. Three major pathways of plasma lipoprotein metabolism are shown: transport of dietary (exogenous) fat (left); transport of hepatic (endogenous) fat (center); reverse cholesterol transport (bottom). A detailed description appears in the text. The sites of action of the six major lipid-altering drugs on exogenous and endogenous pathways of lipoprotein metabolism are (1) inhibition of hydroxymethylglutaryl (HMG) CoA reductase by statins; (2) binding of bile acids by sequestrants, interfering with their reabsorption by the ileal bile acid transporter (IBAT); (3) binding of a cholesterol absorption inhibitor to the Niemann-Pick C1L1, decreasing the absorption of dietary and biliary cholesterol; (4) decreased mobilization of free fatty acids (FFA) by nicotinic acid, leading to decreased uptake of FFA by liver and reduced VLDL, IDL, and LDL production; (5) inhibition of TG synthesis by omega-3 fatty acids; (6) upregulation of lipoprotein lipase (LPL) and decreased production of apoC-III, an inhibitor of LPL, by a fibric acid derivative, leading to decreased VLDL-TG. The hepatic cholesterol pool is decreased by the agents at steps 1, 2, and 3, each leading to an upregulation of the LDLR.

In intestinal cells, monoglycerides are reesterified into TG, and cholesterol is esterified by acyl cholesterol acyltransferase (ACAT). Both lipids are packaged into chylomicrons, along with apolipoproteins apoA-I, apoA-II, apoA-IV, and apoB-48. Chylomicrons are secreted into the thoracic duct; from there, they enter the peripheral circulation, where they acquire apoC-II and apoE from HDL. Chylomicrons are too large to cross the endothelial barrier, and apoC-II, a cofactor for lipoprotein lipase (LPL), facilitates the hydrolysis of TG near the endothelial lining of blood vessels. The fatty acids that are released are taken up by muscle cells for energy utilization or by adipose cells for re-esterification into TG. As a result, a chylomicron remnant is produced that is enriched in cholesteryl ester and apoE. This remnant is rapidly taken up by the liver by receptor-mediated endocytosis of remnants through the interaction of apoE with the chylomicron remnant receptor (LRP), or the LDLR on the surface of parenchymal cells (Fig. 166-1).

The uptake of dietary and biliary cholesterol is part of a process that regulates the pool of hepatic cholesterol by downregulating the LDLR and by inhibiting the rate-limiting enzyme of cholesterol biosynthesis, hydroxymethylglutaryl (HMG)-CoA reductase (see also below).

Endogenous Lipid Transport

In the fasting state, most TG in plasma is carried by VLDL. TG is synthesized in the liver, packaged into VLDL with other lipids and apolipoproteins (Table 166-1)—primarily apoB-100, apoE, apoC-I, apoC-II, and apoC-III—and secreted into plasma. VLDL TG is subsequently hydrolyzed by LPL and its cofactor apoC-II to produce VLDL remnants and then intermediate-density lipoproteins (IDL; d, 1.006–1.019 g/mL). TG can be transferred from VLDL and IDL to HDL and LDL in exchange for cholesteryl ester by the cholesterol ester transfer protein (CETP) (Fig. 166-1). Compared with VLDL, IDL are relatively enriched in cholesteryl ester and depleted in TG. Some IDL are taken up directly by the liver, but others are hydrolyzed by hepatic lipase (HL) to produce LDL, the final end product of VLDL metabolism (Fig. 166-1).

The apoB-100 component of the cholesteryl ester-rich LDL are recognized and bound by the high-affinity LDLR either in the liver or in extrahepatic cells (Fig. 166-1). The bound LDL are internalized by absorptive endocytosis. In lysosomes, apolipoprotein B-100 is broken down into amino acids, cholesteryl esters are hydrolyzed, and unesterified cholesterol are released. Cholesterol mediates the proteolytic release of a transcription factor, the sterol regulatory element binding protein (SREBP), from the endoplasmic reticulum (ER).2 This effect occurs through the SREBP cleavage-activating protein (SCAP) that is both a sensor of sterols and an escort of SREBP. For example, when hepatocytes are depleted of cholesterol, SCAP transports SREBP from the ER to the Golgi, where two proteases—site-1 protease and site-2 protease—act in sequence to release the NH2-terminal of SREBP from the membrane.2 The NH2-terminal of SREBP containing the bHLH-zip domain of SREBP enters the nucleus and binds to a sterol response element (SRE) in the promoter area of the LDLR and HMG-CoA reductase genes, increasing their transcription. As the cholesterol content of the hepatocyte increases, the SREBP/SCAP complex is not incorporated into the ER, SREBP cannot reach the Golgi, the NH2-terminal domain of SREBP cannot be released from the membrane for transport into the nucleus, and the transcription of the LDLR and HMG-CoA reductase genes decreases.2

This pathway has important clinical implications. For example, excess dietary and biliary cholesterol leads to the downregulation of the LDLR and HMG-CoA reductase and an increase in LDL-C. Dietary saturated fat content has an even more profound effect on LDL-C than dietary cholesterol. When cholesterol is reesterified by ACAT, SCAP senses a decrease in hepatic cholesterol, leading to the upregulation of the LDLR and HMG-CoA reductase genes by SREBP. However, the preferred substrate for ACAT is oleic acid. Thus, excess saturated fatty acids decrease ACAT activity and thereby increase unesterified cholesterol, which inhibits the proteolysis and release of SREBP and thereby downregulates the LDLR and HMG-CoA reductase genes, followed by an increase in LDL-C. Decreasing dietary cholesterol and saturated fatty acids or decreasing the hepatic cholesterol content with drugs, such as cholesterol absorption inhibitors and the bile acid sequestrants (Fig. 166-1), leads to an upregulation of LDLR and HMG-CoA reductase genes and lower LDL-C. Inhibitors of HMG-CoA reductase (the statins) also reduce the liver’s cholesterol content, leading to an upregulation of LDLR but without the concomitant increase in HMG-CoA reductase activity (Fig. 166-1).

When plasma LDL-C exceeds 100 mg/dL, the capacity to process LDL through the LDLR pathway is exceeded. Increased numbers of LDL particles cross the endothelial barrier; LDL are trapped in the vascular wall by proteoglycans and are then modified by either oxidation or glycation. Such modified LDL binds to the scavenger receptors CD36 and SRA (Fig. 166-1) and enter cells such as macrophages by a low-affinity, LDL-receptor-independent mechanism. This alternate pathway is not subject to feedback inhibition of LDLR synthesis by LDL-derived cholesterol. Thus, LDL continues to be taken up in an unregulated fashion, leading to excess deposition of cholesterol and cholesteryl ester in macrophages (Fig. 166-1). Dyslipidemias that favor an increased uptake of LDL through the scavenger pathway promote the production of foam cells and the associated atherosclerosis and xanthomas.

Reverse Cholesterol Transport

HDL are synthesized as nascent particles primarily in the liver but also in the intestine. After entering plasma, HDL participates in two important reactions. In the process of lipolysis, apoA-I is transferred from chylomicrons to HDL, and apoC-II and apoE on HDL are transferred to the TG-rich lipoproteins. ApoA-I is a cofactor for the enzyme lecithin cholesterol acyltransferase (LCAT; see Tables 166-1 and 166-2). Unesterified cholesterol is removed from peripheral cells through the ATP-binding cassette (ABC) protein ABCA1 and esterified through the action of LCAT and apoA-I (Fig. 166-1). These cholesteryl esters are then transferred from HDL to the apoB-containing lipoproteins by CETP, from which they are taken up by LDLR and LRP (Fig. 166-1). Cholesteryl ester may also be delivered directly to the liver through an HDL receptor (SRB1). These reactions reflect a process called reverse cholesterol transport and may explain the protective effect that HDL and apoA-I have against the development of atherosclerosis. Conversely, factors that impede this process appear to promote atherosclerosis.


Two major approaches have been considered to detect dyslipidemia in youth, namely screening in the general population or in a selected population.

Traditionally, screening for dyslipidemias in high-risk children was recommended, because they have multiple CVD risk factors or a family history of premature CVD and/or hypercholesterolemia. LDL-C has been the main focus of diagnosis and treatment. Less attention has been paid to HDL-C and TG. Now, with obesity and the metabolic syndrome evident in our youth,1,4 the focus of screening will likely include other factors such as obesity, low HDL-C, non-HDL-C (TC minus HDL-C), elevated TG, elevated apoB (reflecting increased small dense LDL-P), glucose intolerance and insulin resistance, and higher blood pressure levels. Both the current and evolving concepts in screening for dyslipidemia in youth will now be discussed.


Selective Screening

In 1992, the National Cholesterol Education Program (NCEP) Expert Panel on Blood Cholesterol Levels in Children and Adolescents5 recommended that selective, not general, screening be performed. We have expanded some of these recommendations (in italics) in the following NCEP guidelines for screening:

1. A lipoprotein profile in youth whose parents and/or grandparents required coronary artery bypass surgery or balloon angioplasty prior to age 55 years

2. A lipoprotein profile in those with a family history of myocardial infarction, angina pectoris, peripheral or cerebral vascular disease, or sudden death prior to age 55

3. A TC in those whose parents have high TC levels (>240 mg/dl). This recommendation might be usefully expanded to a lipoprotein profile in offspring of parents who have any dyslipidemia involving elevated LDL-C, non-HDL-C, apoB, TG, or low HDL-C.

4. A lipoprotein profile if the parental/grandparental family history is not known, and the patient has two or more other risk factors for CAD, including obesity (BMI > 30), hypertension, cigarette smoking, low HDL-C, physical inactivity, and diabetes mellitus. A new recommendation for a specific category is proposed here: A lipoprotein profile if either obesity (BMI > 95th percentile) or overweight (BMI 85 to 94th percentile) is detected, regardless of the presence of other non-lipid CVD risk factors.

Universal Screening

Universal lipid screening of all children is controversial.3,5

Ideally, each child and adolescent should have an assessment of their plasma lipids and lipoproteins. While there are practical problems (see below), and no longitudinal studies are available to show that treatment starting in childhood decreases adult CVD,3 one might argue that universal screening seems all the more urgent, given the epidemic of obesity and metabolic syndrome in American youth.


For selective screening, a lipoprotein profile after an overnight fast is measured for youth who have a positive family history of premature CVD or dyslipidemia, obesity, multiple CVD risk factors, and for those suspected of having secondary dyslipidemia. Such a profile includes TC, TG, LDL-C, HDL-C, and non-HDL-C. Levels of lipoproteins are typically measured and expressed in terms of their cholesterol content. LDL-C is calculated from the Friedewald equation: LDL-C = TC – HDL-C – (TG/5). Total TG in the fasting state divided by 5 is used to estimate the levels of VLDL-C. If the TG is >400 mg/dl, this formula cannot be used and a direct LDL-C may be measured. If the patient is nonfasting, TC HDL-C and non-HDL-C levels can be measured.

ApoB and apoA-I might also be determined, using well-standardized immunochemical methods.8,9 Such measurements might provide additional useful information, particularly in youth whose parents have premature CAD.1ApoB provides an assessment of the total number of apoB-containing lipoprotein particles.9


Non-HDL-C is determined by subtracting HDL-C from TC and can be measured in plasma from nonfasting patients. Non-HDL-C reflects the amount of cholesterol carried by the “atherogenic” apoB-containing lipoproteins (VLDL, IDL, LDL, and Lp [a]). In adults, non-HDL appears to be a better independent predictor of CVD than LDL-C.9 In children, non-HDL-C is at least as good a predictor as LDL of future dyslipidemia in adulthood.1

Summary For universal screening, the simplest approach is measuring TC, HDL-C, and non-HDL in nonfasting patients. However, treatment algorithms in pediatrics are usually focused on fasting LDL-C. HyperTG is usually assessed as part of the dyslipidemic triad and is often elevated in obesity and the metabolic syndrome.1,4 Thus, in an ideal screening program, TC, TG, LDL-C, HDL-C, and non-HDL-C would be assessed by performing a lipoprotein profile in the fasting state.


Therefore, screening for dyslipidemia is not generally recommended before 2 years of age. After 2 years of age, the levels of the lipids and lipoproteins become quite constant up to adolescence.5

Ten years of age has been proposed as a good time to obtain a lipoprotein profile.6 Children this age are able to fast easier, the values are predictive of future adult lipoprotein profiles, and adolescence has not yet set in. Since TC and LDL-C may fall 10% to 20% (or more) during adolescence,1 it is preferable to screen children at risk for familial dyslipidemias before adolescence, between ages 2 and 10. Even in FH heterozygotes, there is a significant fall in the 1:1 ratio of affected to normal in adolescence.1 If sampling occurs during adolescence and the results are abnormal, then they are likely to be even higher after adolescence. If the results during adolescence are normal, then sampling will need to be repeated toward the end of adolescence (for girls, age 16 and for boys, age 18).


Cut points to define elevated TC, LDL-C, apoB, non-HDL-C, and TG, and low HDL-C and apoA-I in children and adolescents are found in Table 166-3. Dyslipidemia is present if one or more of these lipid, lipoprotein, or apolipoprotein factors are abnormal. In offspring of men who had CVD before 50 years of age, seven different dyslipidemic profiles were present.1 Such results emphasize the importance of evaluating a lipoprotein profile in the fasting state.

Table 166-3. Acceptable, Borderline, and High Plasma Lipid, Lipoprotein, and Apolipoprotein Concentrations (mg/dL) for Children and Adolescents*


Before considering a dyslipoproteinemia to be a primary disorder, secondary causes must be excluded (Table 166-4). Each child with dyslipidemia should have routine blood tests to help rule out secondary causes of the disease. These include fasting blood sugar and tests of kidney, liver, and thyroid function. In secondary dyslipidemia, the associated disorder producing the dyslipidemia should be treated first in an attempt to normalize lipoprotein levels; however, if the dyslipidemia persists—for example, as it often does in type 1 diabetes and the nephrotic syndrome—the patient will require dietary treatment and, if indicated, drug therapy using the same guidelines as in primary dyslipidemias.


General guidelines for the dietary and pharmacological treatment of primary and secondary dyslipidemias in youth are presented here. Specific guidelines germane to each inherited disorder of dyslipidemia are provided as necessary in subsequent sections of this chapter.


The first form of therapy for children with dyslipidemia is a diet containing decreased amounts of total fat, saturated fat, cholesterol, and simple sugars but containing increased complex carbohydrates. No decrease in total protein is recommended. Calories are sufficient to maintain normal growth and development. The NCEP pediatric panel recommended diet treatment after 2 years of age.5 Recent data from randomized clinical trials in general populations, such as STRIP, indicate that a diet low in total fat, saturated fat, and cholesterol may be instituted safely and effectively under medical supervision at 6 months of age.1

When to Initiate Treatment with Diet

If the first lipoprotein profile indicates that TC, LDL-C, non-HDL-C, or TG is elevated, or if the HDL-C is low (Table 166-3), then another confirmatory profile is obtained at least 3 weeks later. If dyslipidemia persists, secondary causes (Table 166-4) are ruled out and dietary treatment begun. A Step-One diet is usually started and the lipoprotein profile repeated in 6 to 8 weeks. If the dyslipidemia persists, then a Step-Two diet is initiated. Both diets require dietary counseling and physician monitoring. The Step-One diet calls for less than 10% of total calories from saturated fatty acids, no more than 30% of calories from total fat, and less than 300 mg/day of cholesterol. The Step-One diet is evaluated for at least 3 months before prescribing the Step-Two diet. The Step-Two diet entails further reduction of the saturated fatty acid intake to less than 7% of calories and reduced cholesterol intake to less than 200 mg/day.5

Safety and Efficacy of Dietary Therapy in Infants, Children, and Adolescents

The efficacy and safety of diets to treat dyslipidemia in youth have been demonstrated across the age spectrum of pediatric patients1—for example, from age 7 months to 7 years and from age 7 to age 11 in STRIP1 and from ages 8 to 10 throughout adolescence in the Dietary Intervention Study in Children (DISC).1 In some studies, there were lower intakes of calcium, zinc, vitamin E, and phosphorus on low-fat diets.1 Therefore, while normal growth is maintained on low-fat diets, attention needs to be paid to ensure adequate intake of these key nutritional elements.

Human milk remains the gold standard for infant feeding.

Using margarines (about three servings daily) high in either plant stanol esters1 or plant sterol esters1 can reduce LDL-C an additional 10% to 15% when added to a low-fat diet. Water-soluble fibers such as psyllium can lower LDL-C an additional 5% to 10%.1

Consuming a soy protein beverage does not appear to lower LDL-C but does lower VLDL-C and TG and increases HDL-C.1 Garlic extract therapy does not lower LDL-C in hyper-lipidemic children.1

Overall, a diet low in fat for children with dyslipidemia appears both safe and efficacious. Medical and nutritional support is necessary to reinforce good dietary behaviors and to ensure nutritional adequacy. Human milk remains the gold standard for infant feeding.

Effect of a Low-Fat Diet in Childhood on Future CVD in Adulthood

That a low-saturated-fat, low-cholesterol diet in childhood will prevent CVD in adulthood can only be inferred from epidemiological studies.5 Obesity already promotes insulin resistance in childhood. In that regard, a low-saturated-fat dietary counseling program starting in infancy in STRIP improved insulin sensitivity in 9-year-old healthy children.1


There are six main classes of lipid-altering drugs (Fig. 166-1): (1) inhibitors of HMG-CoA reductase (the statins), (2) bile acid sequestrants (BAS), (3) cholesterol absorption inhibitors (CAI), (4) niacin (nicotinic acid), (5) fish oils as omega-3 fatty acids (ecosapentanoic acid and decahexanoic acid), and (6) fibric acid derivatives.

Table 166-4. Causes of Secondary Dyslipidemia in Children and Adolescents



Oral contraceptives


Anabolic steroids

13-cis-Retinoic acid

Endocrine and Metabolic

Acute intermittent porphyria

Type 1 and type 2 diabetes






Chronic renal failure

Hemolytic-uremic syndrome

Nephrotic syndrome


Benign recurrent intrahepatic cholestasis

Congenital biliary atresia

Alagille syndrome

Storage Disease

Cystine storage disease

Gaucher disease

Glycogen storage disease

Juvenile Tay-Sachs disease

Niemann-Pick disease

Tay-Sachs disease

Acute and Transient




Anorexia nervosa

Cancer survivor

Heart transplantation

Idiopathic hypercalcemia

Kawasaki disease

Klinefelter syndrome

Progeria (Hutchinson-Gilford syndrome)

Rheumatoid arthritis

Systemic lupus erythematosus

Werner syndrome

Guidelines for Instituting Drug Therapy

The primary use of drugs in pediatrics is to lower significantly elevated LDL-C levels, primarily but not exclusively in those from families with premature CVD or significant dyslipidemia. Drug treatment to lower LDL-C is initiated when the postdietary LDL-C is greater than 190 mg/dl and there is a negative or unobtainable family history of premature CVD. If the postdietary LDL-C is greater than 160 mg/dl and there is a family history of premature CVD, two or more risk factors for CVD, or the metabolic syndrome is present, drug treatment is started after 10 years of age.5

The statins and the BAS are the two main classes of pharmaceutical agents currently used in children over 10 years of age who have sufficiently elevated LDL-C. Ezetimibe, a CAI that blocks the absorption of cholesterol and plant sterols through the Niemann-Pick C1 Like 1 (NPC1L1) protein (Fig. 166-1), is also effective but is not yet approved by the FDA for use in children, except in those rare children with homozygous FH or sitosterolemia (see below). The statins, BAS and CAI, act by reducing hepatic cholesterol, leading to release of SREBP from the cytoplasm into the nucleus, where SREBP binds to the SRE element of the LDLR gene promoter, increases the number of LDLR, and decreases LDL-C.2 Since SREBP also upregulates the gene for HMG-CoA reductase,2 the BAS and CAI are both associated with a compensatory increase in cholesterol biosynthesis, limiting their efficacy (Fig. 166-1). Therefore, both classes of agents might effectively be used in conjunction with the statins, which reduce hepatic cholesterol by inhibiting HMG-CoA reductase and decreasing cholesterol biosynthesis.

Niacin is not routinely used in pediatrics, although some FH homozygotes respond well to it (55 to 87 mg/kg per day in divided doses) due to the significant reduction of VLDL production, leading to a decreased synthesis of LDL. Since aspirin is not used in children because of Reye’s syndrome, ibuprofen can be used if necessary to prevent flushing. The fibrates (48 mg, 96 mg, or 145 mg/d) are also not routinely used in pediatrics, except in the adolescent with a TG level of 500 mg/dL or higher who may be at increased risk of pancreatitis (see also below). Fish oils (1 to 2 gm/d) may also be used to treat marked hyperTG in children and adolescents by decreasing the biosynthesis of TG (Fig. 166-1), but the prescription version of omega-3 fatty acids is not yet approved by the FDA for use in children.

Bile Acid Sequestrants

BAS was the only class of pharmacological agents recommended by NCEP for lipid-lowering therapy because of their extensive track record of safety over three decades.5 In fact, the sequestrants have never been approved by the FDA for use in children. These agents suffer from significant tolerability issues and provide only a modest LDL-C reduction of about 15%.1 The second-generation sequestrant colesevelam (625 mg tablets) has a greater affinity for bile salts and therefore can be used in a lower total dose (3 to 6 tablets daily). In comparison with the first-generation BAS, colesevalam is associated with less annoying side effects such as constipation and gritty taste and does not interfere with the absorption of other drugs.

HMG-CoA Reductase Inhibitors (Statins)

The statins are widely used to lower TC and LDL-C in adults. Numerous randomized controlled trials have demonstrated the safety and efficacy of the statins in male and female adolescents with FH.15Atorvastatin, lovastatin, pravastatin, and simvastatin are approved by the FDA for use in adolescents with FH. Starting doses are atorvastatin, 10 mg/d; lovastatin, 40 mg/d; pravastatin, 40 mg/d; and simvastatin, 20 mg/d. All except atorvastatin are available generically.

Thus, early intervention with statins appears likely to reduce future atherosclerosis and CVD in those with FH.

The statins may also be useful in those adolescents with FCHL and metabolic syndrome, whose LDL-C is greater than 160 mg/dL after diet and weight control and who have multiple risk factors or a family history of premature CVD.

Side Effects of the Statins in Children and Adolescents

Liver and Muscle Increases in liver function tests up to 3× upper limit of normal levels have been reported in several adolescents treated with higher doses of simvastatin (40 mg/day) and atorvastatin (20 mg/day).15 Instances of asymptomatic increases (>tenfold) in creatine kinase (CK), while unusual, have been reported in adolescents receiving statin therapy. No cases of rhabdomyolysis have been reported.15Such adolescents are monitored for elevations in hepatic transaminases and CK concentrations. Liver function tests are monitored at each clinic visit two to three times per year. CK is measured at baseline and is repeated if myalgias develop.

Special Issues in Young Females Adult women with FH and CVD may be more responsive to LDL-C-lowering therapy than similarly affected men, as assessed by regression of coronary plaques and tendon xanthomas.1 Statin therapy in adult women with CVD has an overall favorable safety profile, but fewer studies have been performed in adolescent girls.15 Nevertheless, there has been no adverse effect on growth and development or on adrenal and gonadal hormones.15

Statins are contraindicated during pregnancy because of the potential risk to a developing fetus. Statins should be administered to adolescent girls only when they are highly unlikely to conceive. Birth control is mandatory for those who are sexually active. Because of the above concerns and the long-term commitment to therapy and because CAD often occurs after menopause, some believe that statins should not be used to treat adolescent females.

Although treating adolescent patients with FH appears indicated, especially in those with a strong family history of premature CAD, additional studies are needed to document the long-term safety of statin therapy and to determine its potential effects on the prevention of adult atherosclerosis and coronary events.

Metabolic Syndrome Beyond Dyslipidemia

Statin therapy is recommended in patients whose LDL-C level is greater than 160 mg/dL. For most patients, however, LDL-C will be lower than 160 mg/dL, and a low-fat diet, exercise, and weight reduction is paramount. Metformin has been used in several studies of obese adolescents who have metabolic syndrome and hyperinsulinemia.1


Type I Diabetes

Children with type 1 diabetes often have a dyslipidemia, the severity of which is related to diabetic control. The American Diabetes Association (ADA) recommends dietary and other hygienic measures as the first step in treating these children. However, if the LDL-C is greater than 160 mg/dL after such treatment, the ADA strongly recommends using statins.16 This recommendation is based on the high risk of CVD in affected adults and on the abnormal carotid IMT in children with type 1 diabetes.

Nephrotic Syndrome

The dyslipidemia in children with nephrotic syndrome can be marked. LDL-C is close to that in FH heterozygotes (Table 166-5). TG can approach 300 mg/dL.1 Twenty percent of patients with nephrotic syndrome are unresponsive to steroids, most cases of which can be attributed to focal segmental glomerulosclerosis. Such individuals with an LDL-C greater than 160 mg/dL may be at an increased risk for developing atherosclerosis and CVD1 and may warrant treatment with a statin.

Table 166-5. Levels of Lipids, Lipoproteins, and Apolipoprotein B in Children with the Most Common Lipoprotein Abnormalities*



There are five disorders expressed in pediatrics that result from mutations in the LDLR or from mutations in other genes that impact LDLR activity (Fig. 166-2). Elevated LDL-C can vary considerably in these five conditions (see also below), but each disorder causes early atherosclerosis and premature CVD.17,18 These five disorders include FH; familial defective apoB-100 (FDB); autosomal recessive hypercholesterolemia (ARH); sitosterolemia; and mutations in proprotein convertase subtilisin-like kexin type 9 (PCSK9).17-19 Each disorder warrants diet and drug therapy in childhood to try decreasing atherosclerosis and subsequent CVD.


FH Heterozygotes

FH is the prototype for the diagnosis and treatment of dyslipidemia in children. Heterozygous FH, an autosomal dominant disorder, presents at birth and early in life with a two- to threefold elevation in TC and LDL-C1 (Table 166-5). Half the children of an FH parent and a normal parent will have FH; in such families, the cut point for LDL-C that minimizes misclassification is 160 mg/dL.1 FH affects about 1 in 500 people and is due to one of more than 900 different mutations in the LDLR gene that can affect the normal synthesis, transport, LDL-binding ability, and clustering (in coated pits) of the LDLR17,18 (Fig. 166-2). FH heterozygous children and adolescents manifest increased carotid IMT, decreased brachial endothelial reactivity, but rarely overt CAD.1 Less than 10% of FH adolescent heterozygotes develop tendon xanthomas. HDL-C is below average in FH children (Table 166-5). In FH adults, about half of untreated male heterozygotes and 25 percent of untreated female heterozygotes will develop CVD by 50 years of age.17,18

Treatment of FH heterozygotes includes a diet low in cholesterol and saturated fat that can usefully be supplemented with plant stanol esters or plant sterol esters and water-soluble fiber.1 BAS are safe and moderately effective in FH heterozygotes, but compliance is an issue. The dose of BAS required to achieve an LDL-C below 160 mg/dL is related to the baseline LDL-C level and not to body weight; an adult dose is usually required.1 FH heterozygous children respond well to statins, which are well tolerated.15 However, adding a BAS or CAI (see also above) to a statin is often necessary to achieve LDL-C goals. Niacin is generally not used to treat FH heterozygous children, unless LDL-C is persistently elevated or unusual hyperTG, low HDL-C, or elevated Lp (a) lipoprotein are present.

FIGURE 166-2. Schema depicting five inherited disorders of lipoprotein metabolism that present in childhood with marked elevations of low-density lipoproteins (LDL), leading to premature atherosclerosis. Apolipoprotein B (apoB), the major apolipoprotein of very-low-density lipoproteins (VLDL) and LDL, is necessary for the secretion of VLDL and the uptake of its catabolic product, LDL, by the LDL receptor (LDLR). Defects in the structure of apoB (defective ApoB-100) or in the LDLR (familial hypercholesterolemia, FH) affect the normal binding, internalization, or recycling of the LDLR. Autosomal recessive hypercholesterolemia (ARH) results from a defect in the ARH protein that normally interacts with the cytoplasmic component of the LDLR, allowing the tyrosine phosphorylation and internalization of the LDLR. The proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a serine protease that promotes the degradation of the LDL receptor. Gain-of-function mutations that increase PCSK9 activity decrease LDLR activity. Proposed mechanisms include targeting of the LDLR in the Golgi for degradation in the lysosome, interfering with the recycling of the LDLR after secreted PCSK9 binds to the LDLR at the cell surface, or directing the LDLR to the lysosome to be degraded. The molecular defects responsible for sitosterolemia are caused by mutations in two genes that encode the half-transporters, ABCG5 and ABCG8, preventing their normal dual functions of limiting the absorption of cholesterol and plant sterols and promoting their excretion from liver into bile.

FH Homozygotes

About one in a million children inherit a mutant allele for FH from both parents, leading to a four-to eightfold elevated LDL-C that often leads to precocious atherosclerosis and death from CVD in the second decade.17,18Atherosclerosis also often affects the aortic valve, leading to life-threatening supravalvular aortic stenosis. Virtually all FH homozygotes have planar xanthomas by the age of 5 years, notably in the webbing of fingers and toes and over the buttocks. The seminal studies of such FH homozygous children17,18 led to the discovery of the LDLR, which is absent or markedly deficient in such children.

FH homozygotes respond somewhat to high doses of potent statins and to niacin.1 Since FH homozygotes have markedly diminished, if any, LDLR activity, the statins and niacin both work by decreasing hepatic VLDL production, leading to decreased LDL production. A CAI also lowers LDL in FH homozygotes, especially in combination with a more potent statin.1 In the end, however, FH homozygotes will invariably require LDL apheresis every 2 weeks to further lower LDL into a less atherogenic range.1

Familial Defective ApoB-100

FDB results from mutations in the gene encoding apoB-100, resulting in an impaired ability of the apoB-100 ligand on LDL to bind to the LDLR; decreased clearance of LDL; and elevated LDL-C of mild, moderate, or marked degree17,18 (Fig. 166-2). Heterozygotes for FDB are relatively common (eg, 1 per 1,000 in Europeans).18 About 1 in 20 patients with FDB has tendon xanthomas and appears clinically similar to adult heterozygous FH patients. Some adult patients with FDB develop premature CAD, but FDB itself is not a common cause of premature CAD. Treatment of FDB is similar to that for heterozygous FH.18

Autosomal Recessive Hypercholesterolemia

Children with ARH are clinically similar to those with homozygous FH, although LDL-C is not usually as elevated (between 350 and 550 mg/dL).18 Both parents of an ARH child usually have a normal lipoprotein profile. The ARH protein normally interacts with the cytoplasmic component of the LDLR and other cell surface–oriented molecules, allowing their tyrosine phosphorylation. The deficiency of the ARH protein prevents the normal internalization of the LDLR, leading to marked elevations of LDL-C (Fig. 166-2). Those patients with ARH manifest a dramatic response to statins alone or when combined with the CAI ezetimibe.18


Sitosterolemia (also called phytosterolemia) is a rare autosomal recessive disorder expressed in childhood and characterized by markedly elevated (>thirtyfold) plasma levels of plant sterols.17,18 This is due to hyperabsorption and inefficient excretion of plant sterols. TC and LDL-C can be normal, moderately elevated, or markedly elevated, depending on the dietary content of cholesterol and plant sterol. Sitosterolemics absorb a higher percentage of dietary cholesterol than normal, and they secrete less cholesterol into bile, which decreases LDLR activity and in turn increases LDL-C17,18 (Fig. 166-2).

The diagnosis of sitosterolemia is considered and plant sterols measured in any child or adolescent who has xanthomas despite disproportionately low LDL-C. In addition, previously undiagnosed adults can mimic FH heterozygotes. Patients with sitosterolemia may develop aortic stenosis as do those with homozygous FH.18 CVD can present in the first or second decade of life but is usually delayed until early to middle adulthood.

The molecular defects responsible for sitosterolemia are caused by mutations in two genes that encode the half-transporters, ABCG5 and ABCG8,18 which are located on chromosome 2p in a head-to-head orientation. ABCG5 and ABCG8 are expressed exclusively in human liver and intestine, the sites of the two metabolic abnormalities in sitosterolemia (Fig. 166-2). The dual functions of ABCG5 and ABCG8 are to limit the absorption of cholesterol and plant sterols and to promote their excretion from liver into bile.19

The dietary treatment of sitosterolemia is important, and both cholesterol and plant sterols must be markedly reduced by avoiding high-fat animal and plant products. Saturated fats are also restricted. Statins are less effective in this disorder, since the high sterol content in the liver reduces cholesterol production.18 Bile acid sequestrants are quite effective, as is ezetimibe.1,18

Mutations in Proprotein Convertase Subtilisin-Like Kexin Type 9 (PCSK9)

PCSK9 is a serine protease that facilitates the degradation of LDLR.19 Gain-of-function mutations that increase PCSK9 activity decrease LDLR activity, producing a phenotype similar to FH. Loss-of-function mutations that decrease PCSK9 activity increase LDLR activity, leading to a lifetime of low LDL-C and a markedly reduced incidence of CVD.19

The mechanism(s) of action of PCSK9 on LDLR is not completely understood.  Patients with hypercholesterolemia and the gain-of-function PCSK9 mutation respond well to the treatment similar to that used for FH heterozygotes.


Familial Combined Hyperlipidemia

FCHL is an autosomal dominant disorder with variable lipid phenotypic expression: elevated LDL-C level alone (type IIa); elevated LDL-C with hyperTG (type IIb); or normal LDL-C with hyperTG (type IV).1 The expression of FCHL can be delayed until adulthood,1 but it is not unusual to see FCHL children in families with premature CAD.20 Total apoB can also be elevated in normolipidemic adolescents and young adults with FCHL before the combined dyslipidemia expresses itself.1 The mean TC and LDL-C in children with FCHL is about 100 mg/dL lower than in those with FH, and TG is elevated (Table 166-5). The ratio of LDL-C to apoB is low in FCHL, indicating the presence of small, dense LDL particles, in contrast to FH, where the LDL-C/apoB ratio is high, manifesting the underlying large LDL particles (Table 166-5). In a pediatric lipid clinic population, FCHL was three times as prevalent as FH.20 Tendon xanthomas are not present in children or adults with FCHL. Adolescents with FCHL are at risk for developing glucose intolerance, insulin resistance, visceral obesity, hypertension, and CVD as adults.

Metabolic Basis of FCHL, HyperapoB, and Other Small Dense LDL Syndromes

The abnormal FFA metabolism in FCHL and other small dense LDL syndromes may reflect the primary defect in these patients (Fig. 166-3).1,9 Impaired insulin-mediated suppression of hormone-sensitive lipase in adipocytes leads to an elevation in FFA1,9 (Fig. 166-3). Elevated FFA may drive hepatic overproduction of TG and apoB, leading to a two- to threefold increased production of VLDL and the dyslipidemic triad (Fig. 166-3).9 Insulin resistance also interferes with insulin’s normal upregulation of lipoprotein lipase, leading to decreased lipolysis of TG in VLDL and in intestinally derived TG-rich lipoproteins. This paradigm may also result from a cellular defect that prevents the normal effect of acylation stimulatory protein (ASP; Fig. 166-3), namely, stimulation of incorporating FFA into TG in the adipocyte.1 Insulin resistance may also occur in the liver, leading to an increase rather than a normal decrease in hepatic gluconeogenesis.1 Finally, FFA and glucose compete as oxidative fuel sources in muscle, such that increased concentrations of FFA inhibit glucose uptake and result in insulin resistance.

Genetic and Molecular Defects

This group of disorders is clearly genetically heterogeneous, and several genes1 (oligogenic effect) may influence the expression of increased small dense LDL, low HDL-C, FCHL,1,21 and the other small dense LDL syndromes.1,21Pa-junta and coworkers recently provided strong evidence that the gene underlying the linkage of FCHL to chromosome 1q21–23 is the upstream transcription factor-1 (USF-1) gene,1 which regulates many important genes in lipid metabolism, including hepatic lipase (Fig. 166-3), and is linked to type 2 diabetes mellitus.22

Metabolic Syndrome

Obesity is of critical importance in the development of metabolic syndrome.19,23 There is no current consensus regarding the definition of metabolic syndrome in youth, one proposal for children aged 12–17 years was presented by Cook et al in the third NHANES survey.24 An adolescent is considered to have metabolic syndrome if three or more of these factors are present: (1) TG > or = 110; (2) HDL-C < or = 40 mg/dL; (3) waist circumference > or = 90th percentile; (4) fasting glucose > or = 110 mg/dL; (5) blood pressure > or = 90th percentile for age, sex, and height. One alternative to waist circumference may be a BMI greater than the 95th percentile for age and gender.

The prevalence of metabolic syndrome in adolescents increases with the severity of obesity and insulin resistance, as does the dyslipidemic triad, elevated highly sensitive C-reactive protein (hsCRP), and decreased adiponectin.4Higher LDL-C levels and obesity1 as well as higher blood pressure levels in such adolescents increase carotid IMT as adults. Of note, metabolic syndrome in childhood predicts adult metabolic syndrome and CVD two to three decades later.23 The finding of acanthosis nigricans is a sign of the underlying insulin resistance.

Treatment of Disorders of VLDL Overproduction

A diet reduced in total and saturated fat and simple sugars, regular aerobic exercise (1,000 calories per week), and reaching an ideal body weight are critical factors for reducing VLDL and for improving insulin resistance. Two classes of drugs, fibric acids and niacin acid, lower TG and increase HDL-C in adults and may also convert small dense LDL to larger LDL.1 However, fibrates and niacin are not ordinarily used in pediatric patients.5 The statins are the most effective in lowering LDL-C and the total number of atherogenic, small dense LDL particles1,15 and are reserved for those adolescents with FCHL or the metabolic syndrome who have an elevation of LDL-C greater than 160 mg/dL (see also above). Cholestyramine can be used to treat pediatric patients with FCHL with sufficiently elevated LDL-C.1

Use of Metformin in Metabolic Syndrome

Metformin has been used to treat obese hyperinsulinemic adolescents with metabolic syndrome.1 Metformin can enhance insulin sensitivity and can reduce fasting blood glucose, insulin levels, plasma lipids, FFA, and leptin.

Polycystic Ovarian Syndrome

PCOS often presents in adolescence with menstrual disorders, acne, and hirsutism.1 Insulin resistance, considered an important underlying cause of PCOS, puts more adolescent girls at risk for PCOS and its complications, including dyslipidemia. After diet and weight control, the majority of endocrinologists use an estrogen/progesterone combination for treating PCOS.1 While only about one in three specialists consider metformin to treat adolescents with PCOS, almost 70% use metformin in obese teenagers with PCOS.1 Increased carotid IMT has been detected in young adults with PCOS,1 and earlier diagnosis and treatment of this disorder in adolescence may prevent its full-blown expression and CVD complications in adulthood.


Metabolic disorders involving the TG-rich lipoproteins—chylomicrons, VLDL, and their remnants—are heterogeneous. HyperTGemia may result from increased synthesis or decreased catabolism of one or more of these lipoprotein classes or from a combination of enhanced synthesis and suppressed catabolism. Most hyperTG in children and adolescents is due to VLDL overproduction, often accompanied by obesity or overweight and other components of metabolic syndrome (see above). The focus here is on inherited disorders of marked hyperTG.

FIGURE 166-3. Pathophysiology of the dyslipidemic triad. The dyslipidemic triad is often present in familial combined hyperlipidemia (FCHL), hyperapoB, and metabolic syndrome. In the dyslipidemic triad (high VLDL-TG, increased numbers of small dense LDL-P, and decreased HDL-C), increased flux of free fatty acids (FFA) from adipose tissue, often due to insulin resistance or defects in the action of the acylation stimulatory protein (ASP), enhances hepatic uptake of FFA, leading to increased production of TG, apoB, and VLDL. The increased secretion of VLDL-TG promotes a greater exchange of TG (triglyceride) in VLDL for cholesteryl esters (CE) in LDL and HDL by cholesterol ester transfer protein (CETP). This results in CE-depleted but TG-enriched LDL and HDL. When TG in LDL and HDL is hydrolyzed by hepatic lipase (HL), smaller, denser LDL and HDL are produced. Such HDL is more likely to be excreted by the kidneys, resulting in low HDL-C levels.

Table 166-6. Clinical Findings in Hypolipoproteinemia Due to Deficiencies in HDL


Most hyperTGemia in children and adolescents is due to VLDL overproduction that results in one of the small dense syndromes (see above). There are a few rare disorders that are expressed as marked hyperTG: lipoprotein lipase (LPL) deficiency; defects in apolipoprotein C-II (apoC-II), the cofactor for LPL; and hepatic lipase (HL) deficiency.23 Once hyperTG exceeds 1000 mg/dL, pancreatitis is a major concern, and eruptive xanthomas, lipemia retinalis, and creamy blood can also be found. The diagnosis requires a determination of lipolytic activity in plasma after the intravenous injection of heparin (60 U/kg). LPL deficiency presents at birth or in the first year of life, while the expression of the other two disorders are usually delayed until adulthood. HL deficiency is associated with premature CAD, while LPL and apoC-II defects are not.

Table 166-7. Laboratory Findings in Hypolipoproteinemia Due to Deficiencies in HDL

Table 166-8. Clinical Findings in Hypolipoproteinemia Caused by Deficiencies in ApoB-Containing Lipoproteins

Treatment of each of these disorders includes a very low fat diet (10–15% of calories) that can also be usefully supplemented with medium-chain triglycerides (MCT).23 Portagen, a soybean-based formula enriched in MCT, is available for infants with LPL deficiency. Lipid-lowering drugs are ineffective in the LPL and apoC-II disorders. HL deficiency responds to treatment with statins and, to a lesser extent, fibrates.


This unusual disorder usually presents with about equally elevated TC and TG levels (>300 mg/dl). The more common recessive form has a delayed penetrance until adulthood and is due to the combination of an E2/E2 genotype (promotes slower uptake of TG-rich lipoproteins by the LDLR) and overproduction of VLDL (Fig. 166-3). The more rare dominant form of the disorder is expressed as dyslipidemia, starting in adolescence. A low-fat diet and treatment with fibrates, niacin, or statins are very effective. Tendon, tuberous, and planar (especially in the palms) xanthomas; CVD; and glucose intolerance often occur in adulthood.


Most of the time, low levels of HDL-C, associated with increased CVD, are secondary to VLDL overproduction (see above) and are expressed as a component of the dyslipidemic triad.1,9 There are, however, primary HDL disorders that present as low HDL-C levels and CVD and that include familial hypoalphalipoproteinemia (hypoalpha),1,24 apolipoprotein A-I mutations,1,24 and rarer disorders such as Tangier disease25 and lecithin cholesterol acyl transferase (LCAT) deficiency.26 The clinical and chemical characteristics of these disorders are summarized in Tables 166-6 and 166-7. An opposite disorder, CETP deficiency, often presents as high HDL-C and may be associated with reduced risk of CVD.1 A low-fat diet is also indicated in children with inherited disorders of low HDL. Drugs, including niacin, are rarely used in such children.


Lp (a) lipoprotein is a very large lipoprotein (Mr 3 × 106) found in the density range 1.050 to 1.080 g/mL.1,27 Its lipid composition is similar to LDL, but Lp(a) contains two proteins, apoB-100, and a large glycoprotein called apo(a). The latter is attached to apoB-100 through a disulfide bond. Apo(a) is homologous to plasminogen andhas a variable number of repeats of the kringle 4 region, which are under genetic control. An inverse relationship exists between the size of apo(a) and the levels of Lp(a).27 Lp(a) is measured by immunochemical methods. Elevated Lp (a) appears to be inherited and is often strongly associated with premature CVD in some families. Lp (a) levels should be measured in a child who has had a stroke. Niacin is the only lipid-altering drug that reduces Lp (a). It is not known if treatment of elevated Lp (a) will prevent future or recurrent CVD.

Table 166-9. Laboratory Findings in Hypolipoproteinemia Due to Deficiencies in ApoB-Containing Lipoproteins


The clinical and chemical findings associated with four inherited disorders of deficiencies in apoB-containing lipoproteins—abetalipoproteinemia, heterozygous hypobetalipoproteinemia, homozygous hypobetalipoproteinemia (either null alleles in the apoB gene, or compound heterozygotes for truncated apoB)—are summarized in Tables 166-8 and 166-9.

Abetalipoproteinemia is a rare autosomal recessive disorder whose clinical expression in childhood includes fat malabsorption, severe hypolipidemia, retinitis pigmentosa, cerebellar ataxia, and acanthocytosis28 (Table 166-8; see Chapter 408).

Hypobetalipoproteinemia can be secondary to anemia, dysproteinemias, hyperthyroidism, intestinal lymphangiectasia with malabsorption, myocardial infarction, severe infections, and trauma. Children or adults have few clinical symptoms (Table 166-8; see Chapter 408).


Patients with abetalipoproteinemia and those who are null-allele homozygotes for hypobetlipoproteinemia (Table 166-8) require similar treatment approaches (see Chapter 408).

In Tangier disease, a low-fat diet diminishes the abnormal lipoprotein species that are believed to be remnants of abnormal chylomicron metabolism. The large LDL species found in LCAT deficiency is also thought to be a remnant of abnormal chylomicron metabolism. Its disappearance on a low-fat diet may have a beneficial effect, because large LDL may be involved in the pathogenesis of renal disease. Patients with other syndromes associated with deficiencies of HDL and premature atherosclerosis are also treated with a diet modified in total fat, saturated fat, and cholesterol.