3135 Disorders of Lipoprotein Metabolism CHAPTER 407

somatostatin analogue octreotide can be used to suppress insulin

secretion in sulfonylurea-induced hypoglycemia. These treatments

raise plasma glucose concentrations only transiently, and patients

should therefore be urged to eat as soon as is practical to replete

glycogen stores.

PREVENTION OF RECURRENT HYPOGLYCEMIA

Prevention of recurrent hypoglycemia requires an understanding of

the hypoglycemic mechanism. Offending drugs can be discontinued or their doses reduced. Hypoglycemia caused by a sulfonylurea

can persist for hours or even days. Underlying critical illnesses can

often be treated. Cortisol and growth hormone can be replaced if

levels are deficient. Surgical, radiotherapeutic, or chemotherapeutic

reduction of a non–islet cell tumor can alleviate hypoglycemia even

if the tumor cannot be cured; glucocorticoid or growth hormone

administration also may reduce hypoglycemic episodes in such

patients. Surgical resection of an insulinoma is curative; medical

therapy with diazoxide or octreotide can be used if resection is

not possible and in patients with a nontumor β-cell disorder. Partial pancreatectomy may be necessary in the latter patients. The

treatment of autoimmune hypoglycemia (e.g., with glucocorticoid

or immunosuppressive drugs) is problematic, but these disorders

are sometimes self-limited. Failing these treatments, frequent feedings and avoidance of fasting may be required. Administration of

uncooked cornstarch at bedtime or even an overnight intragastric

infusion of glucose may be necessary for some patients.

■ FURTHER READING

Cryer PE: Hypoglycemia in Diabetes, 3rd ed. Alexandria, VA, American

Diabetes Association, 2016.

Cryer PE: Hypoglycemia, in Williams Textbook of Endocrinology, 13th ed, S Melmed et al (eds). Philadelphia, Saunders, 2016,

pp. 1582–1607.

Lee AK et al: The association of severe hypoglycemia with incident

cardiovascular events and mortality in adults with type 2 diabetes.

Diabetes Care 41:104, 2018.

Russell SJ et al: Outpatient glycemic control with a bionic pancreas in

type 1 diabetes. N Engl J Med 371:313, 2014.

Salehi M et al: Hypoglycemia after gastric bypass surgery: Current

concepts and controversies. J Clin Endocrinol Metab 103:2815, 2018.

Lipoproteins are complexes of lipids and proteins that are essential for

transport of cholesterol, triglycerides (TGs), and fat-soluble vitamins

in the blood. Lipoproteins play essential roles in the absorption of

dietary cholesterol, long-chain fatty acids, and fat-soluble vitamins; the

transport of TGs, cholesterol, and fat-soluble vitamins from the liver

to peripheral tissues; and the transport of cholesterol from peripheral

tissues back to the liver and intestine for excretion. Disorders of lipoprotein metabolism can be primary (caused by genetic conditions)

or secondary (to other medical conditions or environmental exposures) and involve either a substantial increase or decrease in specific

circulating lipids or lipoproteins. Lipoprotein disorders can have a

number of clinical consequences, most notably premature atherosclerotic cardiovascular disease (ASCVD), and are therefore important to

appropriately diagnose and treat. This chapter reviews the etiology and

407 Disorders of Lipoprotein

Metabolism

Daniel J. Rader

pathophysiology of disorders of lipoprotein metabolism and clinical

approaches to their diagnosis and management.

LIPOPROTEIN STRUCTURE

AND METABOLISM

Lipoproteins contain an “oil droplet” core of hydrophobic lipids (TGs

and cholesteryl esters) surrounded by a shell of hydrophilic lipids

(phospholipids, unesterified cholesterol) and proteins (called apolipoproteins) that interact with body fluids (Fig. 407-1). The plasma

lipoproteins are divided into major classes based on their relative density: chylomicrons, very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and

high-density lipoproteins (HDLs). Each lipoprotein class comprises a

family of particles that vary in density, size, and protein composition.

Because lipid is less dense than water, the density of a lipoprotein particle is primarily determined by the amount of lipid per particle. Chylomicrons are the most lipid-rich and therefore least dense lipoprotein

particles, whereas HDLs have the least lipid and are therefore the most

dense. Lipoprotein particles vary widely in size, with the largest particles being the most lipid-rich (chylomicrons) and the smallest particles

being the most dense (HDL).

The proteins associated with lipoproteins, called apolipoproteins

(Table 407-1), are required for the assembly, structure, function, and

metabolism of lipoproteins. Apolipoproteins provide a structural basis

for lipoproteins, activate enzymes important in lipoprotein metabolism, and act as ligands for cell surface receptors. ApoB is the major

structural protein of chylomicrons, VLDLs, IDLs, and LDLs (collectively known as apoB-containing lipoproteins). One molecule of apoB,

either apoB-48 (chylomicrons) or apoB-100 (VLDL, IDL, or LDL), is

present on each lipoprotein particle. The human liver synthesizes the

full-length apoB-100 (one of the largest proteins in humans), whereas

the intestine makes the shorter apoB-48, which is derived from transcription of the same APOB gene after posttranscriptional mRNA

editing. HDLs lack apoB and have different apolipoproteins that define

this lipoprotein class, most importantly apoA-I, which is synthesized in

both the liver and intestine and is found on virtually all HDL particles.

ApoA-II is the second most abundant HDL apolipoprotein and is on

approximately two-thirds of the HDL particles. ApoC-II, apoC-III, and

apoA-V regulate the metabolism of TG-rich lipoproteins. ApoE plays a

critical role in the metabolism and clearance of TG-rich particles. Most

apolipoproteins, other than apoB, exchange actively among lipoprotein particles in the blood. Apolipoprotein(a) [apo(a)] is a distinctive

apolipoprotein that results in the formation of a lipoprotein known as

lipoprotein(a) [Lp(a)] and is discussed more below.

■ TRANSPORT OF INTESTINALLY DERIVED

DIETARY LIPIDS BY CHYLOMICRONS

The critical role of chylomicrons is the efficient transport of absorbed

dietary lipids from the intestine to tissues that require fatty acids

for energy or storage and then return of cholesterol to the liver

(Fig. 407-2). Dietary lipids are hydrolyzed by lipases within the

intestinal lumen and emulsified with bile acids to form micelles.

Dietary cholesterol, fatty acids, and fat-soluble vitamins are absorbed

in the proximal small intestine. Cholesterol and retinol are esterified

(by the addition of a fatty acid) in the enterocyte to form cholesteryl

esters and retinyl esters, respectively. Longer-chain fatty acids (>12

carbons) are incorporated into TGs and packaged with apoB-48,

phospholipids, cholesteryl esters, retinyl esters, and α-tocopherol

(vitamin E) in a process that requires the action of the microsomal TG

transfer protein (MTP) to form chylomicrons. Nascent chylomicrons

are secreted into the intestinal lymph and delivered via the thoracic

duct directly to the systemic circulation, where they are extensively

processed by peripheral tissues before reaching the liver. The particles

encounter lipoprotein lipase (LPL), which is anchored to the endothelial surfaces of capillaries in adipose tissue and heart and skeletal

muscle (Fig. 407-2). ApoC-II and apoA-V are apolipoproteins that are

transferred to circulating chylomicrons from HDL in the postprandial state; apoC-II acts as a required cofactor for LPL activation, and

apoA-V serves as a facilitator of LPL activity. The TGs in chylomicrons

3136 PART 12 Endocrinology and Metabolism

and have a higher ratio of cholesterol to TG (~1 mg of cholesterol for

every 5 mg of TG, whereas in chylomicrons, this ratio is closer to ~1:8).

After secretion by the liver into the plasma, the circulating TGs in

VLDL are hydrolyzed by LPL. After the relatively TG-depleted VLDL

remnants dissociate from LPL, they are referred to as IDLs, which contain roughly similar amounts of cholesterol and TG by mass. The liver

removes ~40–60% of IDL by receptor-mediated endocytosis via binding to apoE, which is acquired through transfer of this protein from

HDL. The remainder of IDL is further remodeled by hepatic lipase

(HL) to form LDL. During this process, phospholipids and TGs in the

particle are hydrolyzed, and most of the remaining apolipoproteins

except apoB-100 are transferred to other lipoproteins. LDL is primarily

a by-product of fatty acid energy transport by VLDL with little true

physiologic role; one exception is that LDL may be partially responsible for delivery of vitamin E to the retina and brain. LDL is ultimately

removed from the circulation by receptor-mediated endocytosis (primarily via the LDL receptor) in the liver, with a region of apoB-100

serving as the specific ligand for binding to the LDL receptor. It should

be noted that apoB-48 does not contain the LDL receptor-binding

ligand region, and therefore, clearance of apoB-48-containing chylomicron remnants is dependent on apoE-mediated clearance as noted

above. Some LDL particles are lipolytically processed to small dense

LDL particles that are believed to be especially atherogenic.

Lp(a) is a lipoprotein similar to LDL in lipid and protein composition, but it contains an additional distinctive protein called apo(a).

Apo(a) is synthesized in the liver and attached to apoB-100 by a disulfide linkage. The major site of clearance of Lp(a) is the liver, but the

uptake pathway is not known. Lp(a) is now established as causal factor

for ASCVD, and an elevated level of Lp(a) serves as an independent

risk factor and merits more aggressive therapy to reduce LDL cholesterol levels (see below).

■ HDL METABOLISM AND REVERSE CHOLESTEROL

TRANSPORT

All nucleated cells synthesize cholesterol, but only hepatocytes and

enterocytes can effectively excrete cholesterol from the body, into

either the bile or the gut lumen, respectively. In the liver, cholesterol is

secreted into the bile, either directly or after conversion to bile acids.

Cholesterol in peripheral cells is transported from the plasma membranes of peripheral cells to the liver and intestine by a process termed

reverse cholesterol transport that is facilitated by HDL (Fig. 407-3).

Nascent HDL particles are synthesized by the intestine and the liver.

Newly secreted apoA-I rapidly acquires phospholipids and unesterified

cholesterol from its site of synthesis (intestine or liver) via cellular

efflux promoted by the membrane protein ATP-binding cassette protein A1 (ABCA1). This process results in the formation of discoidal

HDL particles, which then recruit additional unesterified cholesterol

from cells or circulating lipoproteins. Within the HDL particle, the

cholesterol is esterified to cholesteryl ester (CE) through the addition

of a fatty acid by lecithin-cholesterol acyltransferase (LCAT), a plasma

enzyme associated with HDL; the hydrophobic CE forms the core

Density, g/mL

1.20

5 10

Diameter, nm

1.10

1.02

1.06

20 40 60 80 1000

1.006

0.95

HDL

LDL

IDL

VLDL

Chylomicron

remnants

Chylomicron

FIGURE 407-1 The density and size distribution of the major classes of lipoprotein

particles. Lipoproteins are classified by density and size, which are inversely

related. HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL,

low-density lipoprotein; VLDL, very-low-density lipoprotein.

are hydrolyzed by LPL, and free fatty acids are released and taken up

by adjacent myocytes or adipocytes and are either oxidized to generate

energy or reesterified and stored as TG. Some of the released free fatty

acids bind albumin before entering cells and are transported to other

tissues, especially the liver. The chylomicron particle progressively

shrinks in size as the hydrophobic TG core is hydrolyzed and the excess

hydrophilic lipids (cholesterol and phospholipids) and apolipoproteins

on the particle surface are transferred to HDL, ultimately creating

chylomicron remnants.

Chylomicron remnants contain apoB-48, which lacks the region

in apoB-100 that binds to the LDL receptor. Nevertheless, they are

rapidly removed from the circulation by the liver through a process

that critically requires apoE as a ligand for receptors in the liver. Few,

if any, chylomicrons or chylomicron remnants are generally present in

the blood after a 12-h fast, except in patients with certain disorders of

lipoprotein metabolism.

■ TRANSPORT OF HEPATICALLY DERIVED

LIPIDS BY VLDL AND LDL

Another key role of lipoproteins is the transport of hepatic lipids from

the liver to the periphery (Fig. 407-2) to provide an energy source

during fasting. During the fasting state, lipolysis of adipose TGs generates fatty acids that are transported to the liver, and the liver is also

capable of synthesizing fatty acids through de novo lipogenesis. These

fatty acids are esterified by the liver into TGs, which are packaged into

VLDL particles along with apoB-100, phospholipids, cholesteryl esters,

and vitamin E in a process that also requires MTP. VLDL thus resemble

chylomicrons in that they are “triglyceride-rich lipoproteins,” but they

contain apoB-100 rather than apoB-48, are smaller and less buoyant,

TABLE 407-1 Major Apolipoproteins

APOLIPOPROTEIN PRIMARY SOURCE LIPOPROTEIN ASSOCIATION FUNCTION

ApoA-I Intestine, liver HDL, chylomicrons Core structural protein for HDL, promotes cellular lipid efflux via ABCA1,

activates LCAT

ApoA-II Liver HDL, chylomicrons Structural protein for HDL

ApoA-V Liver VLDL, chylomicrons Promotes LPL-mediated triglyceride lipolysis

Apo(a) Liver Lp(a) Structural protein for Lp(a)

ApoB-48 Intestine Chylomicrons, chylomicron remnants Core structural protein for chylomicrons

ApoB-100 Liver VLDL, IDL, LDL, Lp(a) Core structural protein for VLDL, LDL, IDL, Lp(a); ligand for binding to

LDL receptor

ApoC-II Liver Chylomicrons, VLDL, HDL Cofactor for LPL

ApoC-III Liver, intestine Chylomicrons, VLDL, HDL Inhibits LPL activity and lipoprotein binding to receptors

ApoE Liver Chylomicron remnants, IDL, HDL Ligand for binding to LDL receptor and other receptors

Abbreviations: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; Lp(a),

lipoprotein(a); LPL, lipoprotein lipase; VLDL, very-low-density lipoprotein.

3137 Disorders of Lipoprotein Metabolism CHAPTER 407

Small

intestines

Exogenous Endogenous

Bile acids + cholesterol

Peripheral

tissues

Liver

ApoE

ApoB-48

LDLR

ApoC’s

Dietary lipids

LDL

Chylomicron VLDL IDL Chylomicron

remnant

Capillaries

LPL

FFA

Muscle Adipose

ApoB-100

HL

Capillaries

LPL

FFA

Muscle Adipose

FIGURE 407-2 The exogenous and endogenous lipoprotein metabolic pathways. The exogenous

pathway transports dietary lipids to the periphery and the liver. The endogenous pathway transports

hepatic lipids to the periphery. FFA, free fatty acid; HL, hepatic lipase; IDL, intermediate-density

lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPL, lipoprotein

lipase; VLDL, very-low-density lipoprotein.

of the mature HDL particle. As HDL acquires more CE, it becomes

spherical, and additional apolipoproteins and lipids are transferred

to the particles from the surfaces of chylomicrons and VLDLs during

lipolysis.

HDL cholesterol in the blood is transported to hepatocytes by two

major pathways. HDL CE can be “selectively” taken up by hepatocytes

via the scavenger receptor class B1 (SR-B1), a cell surface

HDL receptor that mediates the selective transfer of CE

from HDL with subsequent dissociation and “recycling”

of the HDL particle. In addition, HDL CE can be transferred to apoB-containing lipoproteins in exchange for

TG by the cholesteryl ester transfer protein (CETP).

The CE esters are then removed from the circulation

by LDL receptor–mediated endocytosis. HDL-derived

CE taken up by the hepatocyte through these pathways

is hydrolyzed, and much of the cholesterol is ultimately

excreted directly into the bile or converted to bile acids

with excretion to bile, providing a biliary route into

the intestinal lumen. There is also evidence that, under

certain conditions, HDL cholesterol can be transported

directly into the intestinal lumen without requiring a

transhepatobiliary route, a process known as transintenstinal cholesterol excretion.

HDL particles undergo extensive remodeling within

the plasma compartment by a variety of lipid transfer

proteins and lipases. The phospholipid transfer protein

(PLTP) transfers phospholipids from other lipoproteins

to HDL or among different classes of HDL particles

and is a regulator of HDL metabolism. After CETP- and

PLTP-mediated lipid exchange, the TG-enriched HDL

becomes a much better substrate for HL, which hydrolyzes the TGs and phospholipids to generate smaller

HDL particles. A related enzyme called endothelial lipase

(EL) hydrolyzes HDL phospholipids, generating smaller

HDL particles that are catabolized faster. Remodeling of

HDL influences the metabolism, function, and plasma

concentrations of HDL.

SCREENING

Dyslipidemia is an important causal factor in ASCVD,

and treatment has been proven to substantially reduce

cardiovascular risk. Therefore, all adults (and many

children) should be actively screened for plasma lipids. A lipid panel

should be measured, preferably after an overnight fast. In most

clinical laboratories, the total cholesterol and TGs in the plasma are

measured enzymatically, and then after precipitation of apoB-containing lipoproteins, the cholesterol in the supernatant is measured to

determine the HDL cholesterol (HDL-C). The LDL cholesterol (LDLC) is then estimated using the following equation (the

Friedewald formula):

LDL-C = total cholesterol – (TG/5) – HDL-C

(The VLDL cholesterol content is estimated by

dividing the plasma TG by 5, reflecting the ratio of TG

to cholesterol in VLDL particles.) This formula is reasonably accurate if test results are obtained on fasting

plasma and if the TG level does not exceed ~200 mg/

dL; by convention, it cannot be used if the TG level

is >400 mg/dL. LDL-C can be directly measured by a

number of methods. The non-HDL-C can be easily

calculated by subtracting the HDL-C from the total

cholesterol. It has the advantage of incorporating the

cholesterol contained within VLDL and IDL, which

in most cases is also atherogenic and associated with

increased ASCVD risk. There is increasing evidence

that measurement of plasma apoB levels may provide

a better assessment of cardiovascular risk than the

LDL-C level, and even the non-HDL-C level, and is

recommended by some experts. While this has not

yet become standard clinical practice, the data supporting the use of apoB as a risk marker and guide to

therapeutic intervention are quite strong. There is also

increasing interest in Lp(a), an independent ASCVD

risk factor that is highly heritable and may be helpful

Small

intestines

Liver

LDL

LDLR

SR-BI

Mature HDL

Peripheral cells Chylomicrons

LCAT

CETP

Nascent

HDL

IDL

ApoA-I

CETP

ApoA-I

Free

cholesterol

Macrophage

VLDL

FIGURE 407-3 High-density lipoprotein (HDL) metabolism and reverse cholesterol transport. The HDL

pathway transports excess cholesterol from the periphery back to the liver for excretion in the bile.

The liver and the intestine produce nascent HDLs. Free cholesterol is acquired from macrophages and

other peripheral cells and esterified by lecithin-cholesterol acyltransferase (LCAT), forming mature

HDLs. HDL cholesterol can be selectively taken up by the liver via SR-BI (scavenger receptor class BI).

Alternatively, HDL cholesteryl ester can be transferred by cholesteryl ester transfer protein (CETP)

from HDLs to very-low-density lipoproteins (VLDLs) and chylomicrons, which can then be taken up

by the liver. IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density

lipoprotein receptor.

3138 PART 12 Endocrinology and Metabolism

in risk stratification. In patients with evidence of dyslipidemia, further evaluation and treatment are based on evidence of preexisting

ASCVD and clinical assessment of cardiovascular risk using risk

calculators such as the American Heart Association (AHA)/American

College of Cardiology (ACC) risk calculator as well as, in some cases,

based on additional approaches to risk assessment such as apoB and

Lp(a) (see “Approach to the Patient” for more detailed discussion).

DISORDERS ASSOCIATED WITH ELEVATED

APOB-CONTAINING LIPOPROTEINS

Disorders of lipoprotein metabolism that cause elevated levels of

apoB-containing lipoproteins are among the most common and

clinically important of the dyslipoproteinemias. They are generally

characterized by increased plasma levels of total cholesterol, accompanied by increased TGs, LDL-C, or both. Many patients with hyperlipidemia have some combination of genetic predisposition (often

polygenic) and medical or environmental contribution (medical

condition, diet, lifestyle, or drug). Many, but not all, patients with

hyperlipidemia are at increased risk for ASCVD, which is the primary

reason for making the diagnosis, as intervention can substantially

reduce this risk. In addition, patients with severe hypertriglyceridemia may be at risk for acute pancreatitis and require intervention

to reduce this risk.

Although hundreds of proteins influence lipoprotein metabolism,

and genetic variants in most of the genes that encode them interact

with each other and the environment to produce dyslipidemia, there

are a limited number of discrete “nodes” or pathways that regulate lipoprotein metabolism and are dysfunctional in specific dyslipidemias.

These include (1) lipolysis of TG-rich lipoproteins by LPL; (2) receptormediated uptake of apoB-containing lipoproteins by the liver; (3)

cellular cholesterol metabolism in the hepatocyte and the enterocyte;

(4) assembly and secretion of VLDLs by the liver; and (5) neutral lipid

transfer and phospholipid hydrolysis in the plasma. Primary genetic

disorders of lipoprotein metabolism caused by single-gene mutations

(Table 407-2) have taught us a great deal about the physiologic roles of

specific proteins in these pathways in humans and are clinically important to diagnose and treat.

■ SEVERE HYPERTRIGLYCERIDEMIA

Severe hypertriglyceridemia (HTG) is defined by fasting TG levels

>500 mg/dL and is usually accompanied by moderately elevated total

cholesterol levels and reduced levels of HDL-C, usually without important elevation in LDL-C or apoB. It is medically important because

it is associated with risk of acute pancreatitis and, in some cases, is

also associated with increased risk of ASCVD. Severe HTG is usually

caused by impaired lipolysis of TGs in TG-rich lipoproteins (TRLs)

by the enzyme LPL. LPL is synthesized by adipocytes, skeletal myocytes, and cardiomyocytes, and its posttranslational maturation and

folding require the action of lipase maturation factor 1 (LMF1). After

secretion, it is transported from the subendothelial to the vascular

endothelial surfaces by GPIHPB1, which docks it to the endothelial

surface. ApoC-II is a required cofactor for LPL, and apoA-V promotes

LPL activity, and both are transported to the bound LPL on the TRLs.

Single-gene Mendelian disorders that reduce LPL activity have been

described (Table 407-3) as reviewed below; the majority of patients

with severe HTG have a polygenic predisposition to secondary factors

like obesity or insulin resistance.

Primary (Genetic) Causes of Severe Hypertriglyceridemia • FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS) LPL is required

for the hydrolysis of TGs in chylomicrons and VLDLs. Genetic deficiency or inactivity of LPL results in impaired lipolysis and profound

elevations in plasma TGs, mostly in chylomicrons. While chylomicronemia predominates, in fact, these patients often have elevated

plasma levels of VLDL as well. The fasting plasma is turbid, and if

left undisturbed for several hours, the chylomicrons float to the top

and form a creamy supernatant layer. Fasting TG levels are >500 mg/

dL and usually >1000 mg/dL. Because chylomicrons contain cholesterol, fasting total cholesterol levels are also elevated. There are five

genes in which mutations can result in FCS (Table 407-2). FCS has

an estimated frequency of ~1 in 200,000–300,000, although its true

prevalence is unknown. The most common molecular cause of FCS

involves mutations in the LPL gene. LPL deficiency has autosomal

recessive inheritance (loss-of-function mutations in both alleles).

Heterozygotes with LPL mutations often have moderate elevations in

plasma TG levels and increased risk for coronary heart disease (CHD).

FCS can also be caused by mutations in genes that affect LPL processing or activity. For example, apoC-II is a required cofactor for LPL.

APOC2 deficiency due to loss-of-function mutations in both APOC2

alleles results in functional lack of LPL activity and severe hyperchylomicronemia that is indistinguishable from LPL deficiency. It is also

recessive in inheritance pattern and much rarer than LPL deficiency.

Another apolipoprotein, apoA-V, facilitates the association of TRLs

with LPL and promotes hydrolysis of the TGs. Individuals harboring

loss-of-function mutations in both APOA5 alleles causing APOA5

deficiency develop a form of FCS. GPIHBP1 is required for transport

and tethering of LPL to the endothelial luminal surface. Homozygosity

for mutations in GPIHBP1 that interfere with its synthesis or folding

cause FCS. Autoantibodies to GPIHBP1 have also been reported to

cause severe hyperchylomicronemia. Finally, LMF1 is required for

appropriate processing and folding of LPL, and bialleleic loss-of-function

mutations can cause FCS.

FCS can present in childhood or adulthood with severe abdominal

pain due to acute pancreatitis. In this setting, the diagnosis should be

suspected if a fasting TG level is >500 mg/dL. Eruptive xanthomas,

which are small, yellowish-white papules, may appear in clusters on

the back, buttocks, and extensor surfaces of the arms and legs. On

funduscopic examination, the retinal blood vessels may be opalescent

(lipemia retinalis). Hepatosplenomegaly is sometimes noted as a result

of uptake of circulating chylomicrons by reticuloendothelial cells in the

liver and spleen. Premature ASCVD is not generally a feature of FCS.

The diagnosis of FCS is a clinical diagnosis based on persistence

and severity of HTG, with a history of acute pancreatitis or eruptive

xanthomas increasing the suspicion. While LPL activity can be measured in “postheparin plasma” obtained after an IV heparin injection

to release the endothelial-bound LPL, this assay is not widely available.

Genetic testing of a panel of candidate FCS genes can be used to confirm the diagnosis but is not required for making the clinical diagnosis.

Because of the risk of pancreatitis, it is important to consider the

diagnosis and institute therapeutic interventions in FCS. The goal is

to prevent pancreatitis by reducing fasting TG levels to <500 mg/dL.

Consultation with a registered dietician familiar with this disorder

is essential. Dietary fat intake should be markedly restricted (to as

little as 15 g/d), often with fat-soluble vitamin supplementation. Strict

adherence to dietary fat restriction can be successful at controlling the

chylomicronemia; fish oils or fibrates (such as fenofibrate) may be tried

but are unlikely to be effective. A new therapeutic approach involving

the silencing of APOC3 with an antisense oligonucleotide is approved

in Europe for patients with FCS. In patients with APOC2 deficiency,

apoC-II can be provided exogenously by infusing fresh-frozen plasma

to resolve the chylomicronemia in the setting of severe acute pancreatitis. Management of patients with FCS is particularly challenging during

pregnancy when VLDL production is increased.

FAMILIAL PARTIAL LIPODYSTROPHY (FPLD) FPLD is a genetic condition in which the generation of adipose tissue in certain fat depots

is impaired and in others is excessive. FPLD is an underrecognized

monogenic cause of severe HTG, which is likely due to both increased

lipid synthesis and VLDL production, as well as reduced LPL-mediated

clearance of TRLs. FPLD is typically a dominantly inherited disorder

caused by mutations in several different genes, including lamin A/C

(LMNA), PPARγ (PPARG), perilipin (PLIN1), AKT2, and ADRA2A

(Table 407-2). FPLD is characterized by loss of subcutaneous fat in

the extremities and buttocks, often accompanied by increased visceral

fat. Because of the reduced or absent subcutaneous fat in the arms and

legs, patients are often described as having a “muscular” appearance. In

addition to severe HTG, FPLD patients usually have insulin resistance,

often quite severe, accompanied by type 2 diabetes and hepatosteatosis.

3139 Disorders of Lipoprotein Metabolism CHAPTER 407

Pancreatitis secondary to HTG can be a complication; in addition,

ASCVD risk is increased in FPLD patients. The diagnosis of FPLD is

a clinical diagnosis based on the constellation of metabolic findings

accompanied by the distinctive distribution of adipose tissue. Genetic

testing of a panel of candidate FPLD genes can be used to confirm the

diagnosis but is not required for making the clinical diagnosis. Because

FPLD is a dominant disorder, the finding of a causal mutation should

lead to family-based screening.

The dyslipidemia of FPLD can be difficult to manage clinically.

Patients should be treated aggressively not only to reduce TG levels but

also with statins and, if necessary, additional LDL-lowering therapies

to reduce atherogenic lipoproteins. The insulin-resistant diabetes often

requires aggressive management as well. Some patients have progression of fatty liver disease to nonalcoholic steatohepatitis and fibrosis.

A different group of very rare patients have congenital generalized

lipodystrophy, a recessive disorder caused by mutations in the AGPAT2

TABLE 407-2 Primary Dyslipoproteinemias Caused by Known Single-Gene Mutations

GENETIC DISORDER GENES MUTATED

LIPOPROTEINS

AFFECTED CLINICAL FINDINGS

GENETIC

TRANSMISSION ESTIMATED PREVALENCE

Severe Hypertriglyceridemia

Familial chylomicronemia

syndrome (FCS)

Biallelic LoF mutations

in: LPL, APOC2, APOA5,

GPIHBP1, LMF1

Elevated: Chylomicrons,

VLDL

Reduced: HDL

Pancreatitis,

eruptive xanthomas,

hepatosplenomegaly

AR ~1/200,000–300,000

Familial partial lipodystrophy

(FPLD)

Heterozygous LoF mutations

in: LMNA, PPARG, PLIN1,

AKT2, ADRA2A

Elevated: Chylomicrons,

VLDL, LDL

Reduced: HDL

Insulin resistance, fatty liver

disease, pancreatitis, central

obesity, lack of subcutaneous

adipose in extremities

AD <1/1,000,000

Hypercholesterolemia

Familial

hypercholesterolemia (FH)

Heterozygous LoF mutations

in LDLR

Elevated: LDL Tendon xanthomas,

premature atherosclerotic

cardiovascular disease

(ASCVD)

AD ~1/250

Familial defective apoB-100

(FDB)

Heterozygous LoF receptor

binding region mutations in

APOB

Elevated: LDL Tendon xanthomas, premature

ASCVD

AD ~1/1500

Autosomal dominant

hypercholesterolemia (ADH),

type 3

Heterozygous GoF mutations

in PCSK9

Elevated: LDL Tendon xanthomas, premature

ASCVD

AD <1/1,000,000

Autosomal recessive

hypercholesterolemia (ARH)

Biallelic LoF mutations in

LDLRAP1

Elevated: LDL Tendon xanthomas, premature

ASCVD

AR <1/1,000,000

Sitosterolemia Biallelic LoF mutations in

ABCG5, ABCG8

Elevated: LDL Tendon xanthomas, premature

ASCVD

AR <1/1,000,000

Lysosomal acid lipase

deficiency

Biallelic LoF mutations in

LIPA

Elevated: LDL

Reduced: HDL

Fatty liver disease,

micronodular cirrhosis

AR <1/1,000,000

Mixed Dyslipidemia

Familial

dysbetalipoproteinemia

(FDBL)

Biallelic carriers of the

APOE2 variant

Elevated: Chylomicron

remnants, IDL

Palmar and tuberoeruptive

xanthomas, premature ASCVD

AR ~1/10,000

Hepatic lipase deficiency Biallelic LoF mutations in

LIPC

Elevated: Chylomicron

remnants, IDL, HDL

Premature ASCVD AR <1/1,000,000

Hypolipidemic Syndromes

Abetalipoproteinemia Biallelic LoF mutations in

MTTP

Absent: LDL

Reduced: TG, HDL

Spinocerebellar degeneration,

retinal degeneration

AR <1/1,000,000

Familial

hypobetalipoproteinemia

Heterozygous truncating

mutations in APOB

Reduced: LDL Fatty liver, reduced risk of

ASCVD

AD <1/1,000,000

Familial PCSK9 deficiency Heterozygous LoF mutations

in PCSK9

Reduced: LDL Reduced risk of ASCVD AD ~1/1,000

Familial combined

hypolipidemia

Heterozygous LoF mutations

in ANGPTL3

Reduced: TG, LDL, HDL Reduced risk of ASCVD AD <1/1,000,000

Primary Low HDL Cholesterol Syndromes

ApoA-I deletions/mutations Heterozygous structural

mutations in APOA1

Reduced: HDL Variable depending on

mutation: premature ASCVD,

systemic amyloidosis

AD <1/1,000,000

Tangier disease Biallelic LoF mutations in

ABCA1

Nearly absent: HDL

Reduced: LDL

Elevated: TG

Peripheral neuropathy,

hepatosplenomegaly

AR <1/1,000,000

Familial LCAT deficiency

(FLD); fish eye disease (FED)

Biallelic LoF mutations in

LCAT

Markedly reduced: HDL Corneal opacities (both FLD

and FED), progressive chronic

kidney disease (FLD only)

AR <1/1,000,000

Abbreviations: AD, autosomal dominant; apo, apolipoprotein; AR, autosomal recessive; ARH, autosomal recessive hypercholesterolemia; CHD, coronary heart disease; GoF,

gain of function; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LoF, loss of

function; LPL, lipoprotein lipase; PVD, peripheral vascular disease; TG, triglyceride; VLDL, very-low density lipoprotein.

3140 PART 12 Endocrinology and Metabolism

and BSCL2 genes. These patients have nearly complete absence of

subcutaneous fat, accompanied by profound leptin deficiency, insulin

resistance, severe HTG, and accumulation of TGs in multiple tissues

including the liver. Patients with generalized lipodystrophy can be

effectively treated with recombinant leptin administration, which often

manages the multiple metabolic issues in these patients.

Multifactorial Severe Hypertriglyceridemia Most patients with

severe HTG do not have a single-gene mutation but instead have a

multifactorial etiology that includes genetics and environment. The

prevalence of this phenotype is ~1 in 1000. HTG often runs in families,

and the term familial HTG has been employed; however, except for the

genes in which mutations cause FCS or FPLD, reviewed above, no other

classic Mendelian causes of HTG have been identified to date. Instead,

extensive human genetic studies have clearly established a polygenic

basis to this phenotype that consists of two categories: (1) rare heterozygous variants in the five genes discussed earlier that cause FCS in the

homozygous state, and (2) a high burden of common variants that have

small individual effects at raising TGs. Patients who inherit some combination of rare and common TG-raising alleles often have environmental

factors that exacerbate their HTG. These “secondary” factors are reviewed

in detail below, but the quantitatively most important factors promoting

HTG include obesity, type 2 diabetes, insulin resistance, and alcohol

use. Multifactorial HTG is characterized by elevated fasting TGs but

average to below average LDL-C levels and low HDL-C levels; apoB levels are not generally elevated. This condition is not generally associated

with a significantly increased risk of ASCVD. However, if the HTG is

exacerbated by environmental factors, medical conditions, or drugs, the

TGs can rise to a level at which acute pancreatitis is a risk. Indeed, management of patients with this condition is mostly focused on reduction

of TGs to prevent pancreatitis. It is important to consider and rule out

secondary causes of the HTG. Patients who are at high risk for ASCVD

due to other risk factors should be treated with statin therapy. In patients

who are otherwise not at high risk for ASCVD, lipid-lowering drug

therapy can frequently be avoided with appropriate dietary and lifestyle

changes. Patients with plasma TG levels >500 mg/dL after a trial of diet

and exercise should be considered for drug therapy with a fibrate or fish

oil to reduce TGs in order to prevent pancreatitis. These patients should

also be carefully evaluated for ASCVD risk and may be candidates for

statin therapy to further reduce cholesterol and cardiovascular risk.

■ HYPERCHOLESTEROLEMIA (ELEVATED LDL-C)

Elevated LDL-C is common and is medically important because it is

associated with risk of premature ASCVD. Elevated LDL-C is often

caused by impaired uptake of LDL by the liver. As discussed above,

the LDL receptor is the major receptor responsible for uptake of LDL,

and most causes of elevated LDL-C converge on reduced expression

or activity of the LDL receptor in the liver. One major environmental

factor that reduces LDL receptor activity is a diet high in saturated and

trans fats. Other medical conditions that reduce LDL receptor activity

include hypothyroidism and estrogen deficiency. Single-gene Mendelian disorders involving several genes that influence LDL clearance

should be considered in patients with LDL-C levels >190 mg/dL (Table

407-2). However, the majority of patients with elevated LDL-C have a

polygenic predisposition exacerbated by secondary factors like a diet

high in saturated and trans fats.

Primary (Genetic) Causes of Elevated LDL-C • FAMILIAL

HYPERCHOLESTEROLEMIA (FH) FH is an autosomal dominant disorder characterized by elevated plasma levels of LDL-C usually with

relatively normal TG levels. FH is caused by mutations that lead to

reduced function of the LDL receptor, with the most common being

mutations in the LDLR gene itself. The reduction in LDL receptor

activity in the liver results in a reduced rate of clearance of LDL from

the circulation. The plasma level of LDL increases to a level such that

the rate of LDL production equals the rate of LDL clearance by residual

LDL receptor as well as non-LDL receptor mechanisms. Individuals

with two mutated LDLR alleles (homozygotes or compound heterozygotes) have much higher LDL-C levels than those with one mutant

allele, causing a condition known as homozygous FH.

Although mutations in LDLR are the most common cause of FH

(and originally the term FH was used specifically for patients with

LDLR mutations), mutations in at least two other genes, APOB and

PCSK9, can also cause FH. ApoB-100 is the critical structural protein

in LDL and contains a domain that serves as the ligand for binding to

the LDL receptor. Mutations in the LDL receptor–binding domain of

apoB-100 reduce the affinity of apoB/LDL binding to the LDL receptor,

such that LDL is removed from the circulation at a reduced rate. This

condition has also been termed familial defective apoB (FDB). Of note,

truncating mutations in APOB cause low LDL-C levels (see below).

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted

protein that binds to the LDL receptor and targets it for lysosomal

degradation. Normally, after LDL binds to the LDL receptor, it is internalized along with the receptor, and in the low pH of the endosome, the

LDL receptor dissociates from the LDL and recycles to the cell surface.

When circulating PCSK9 binds the receptor, the complex is internalized and the receptor is directed to the lysosome, rather than to the cell

surface, reducing the number of active LDL receptors. Gain-of-function

TABLE 407-3 Secondary Causes of Altered Lipid and Lipoprotein Levels

LDL-C HDL-C LP(a) ELEVATED

 TG ELEVATED ELEVATED REDUCED ELEVATED REDUCED

High-carbohydrate diet

Alcohol

Obesity

Insulin resistance

Type 2 diabetes

Lipodystrophy

Chronic kidney disease

Nephrotic syndrome

Viral hepatitis

Sepsis

Cushing’s syndrome

Acromegaly

Glycogen storage disease

Pregnancy

Drugs: estrogen, glucocorticoids,

isotretinoin, bexarotene, other

retinoids, beta blockers, bile acid

binding resins

Hypothyroidism

Cholestasis

Nephrotic syndrome

Cushing’s syndrome

Acute intermittent

porphyria

Drugs: corticosteroids,

cyclosporin, sirolimus,

carbamazepine

Vegan diet

Malabsorption

Malnutrition

Severe liver disease

Gaucher’s disease

Chronic infectious

disease

Hyperthyroidism

High-fat diet

Alcohol

Exercise

Drugs: estrogen

Hypertriglyceridemia

Vegan diet

Malabsorption

Malnutrition

Sedentary lifestyle

Smoking

Obesity

Gaucher’s disease

LAL deficiency

Drugs: anabolic steroids,

testosterone, beta

blockers

Chronic kidney disease

Nephrotic syndrome

Inflammation

Menopause

Orchidectomy

Hypothyroidism

Acromegaly

Drugs: growth hormone,

isotretinoin

Abbreviations: HDL-C, high-density lipoprotein cholesterol; LAL, lysosomal acid lipase; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); TG, triglyceride.

3141 Disorders of Lipoprotein Metabolism CHAPTER 407

mutations in PCSK9 that enhance the activity of PCSK9 cause a form

of FH, also known as ADH type 3. Of note, loss-of-function mutations

in PCSK9 reduce LDL-C levels (see below).

The population frequency of heterozygous FH was originally estimated to be 1 in 500 individuals, but recent data suggest it may be as

high as ~1 in 250 individuals, making it one of the most common singlegene disorders in humans. FH has a much higher prevalence in certain

founder populations, such as South African Afrikaners, Christian

Lebanese, French Canadians, and Lancaster County Amish. Heterozygous FH is characterized by elevated plasma levels of LDL-C (usually

>190 mg/dL) and relatively normal levels of TGs. Patients with FH

have hypercholesterolemia from birth, and FH diagnosis is often based

on detection of hypercholesterolemia on routine lipid screening; this

serves as the basis for the recommendation to screen children between

the ages of 9 and 11. A family history of hypercholesterolemia or premature ASCVD should prompt targeted screening. Inheritance of FH

is dominant, meaning that the condition is inherited from one parent,

and ~50% of the patient’s siblings and children can be expected to

have FH. For this reason, family-based “cascade screening” can be very

effective in identifying additional persons with FH. Physical findings

in some, but not all, patients with FH may include corneal arcus and/or

tendon xanthomas, particularly involving the dorsum of the hands and

the Achilles tendons. Untreated heterozygous FH is associated with

a markedly increased risk of cardiovascular disease; untreated men

with heterozygous FH have an ~50% chance of having a myocardial

infarction before age 60 years, and women with heterozygous FH are at

substantially increased risk as well. The age of onset of cardiovascular

disease is highly variable and depends on the specific molecular defect,

the level of LDL-C, and coexisting cardiovascular risk factors.

The diagnosis of FH is generally a clinical diagnosis based on hypercholesterolemia with LDL-C >190 mg/dL in the absence of a secondary

etiology and ideally with a family history of hypercholesterolemia and/

or premature ASCVD. Secondary causes of significant hypercholesterolemia such as hypothyroidism, nephrotic syndrome, and obstructive

liver disease should be excluded. Sequencing of an FH gene panel

(LDLR, APOB, PCSK9) to confirm the diagnosis is widely available and

worthy of consideration; persons with molecularly confirmed FH are at

higher risk of ASCVD and therefore may benefit from more aggressive

treatment, and the finding of a specific causal variant has implications

for family-based cascade screening.

FH patients should be actively treated to lower plasma levels of LDLC, preferably starting in childhood. Initiation of a diet low in saturated

and trans fats is recommended, but heterozygous FH patients almost

always require pharmacologic therapy for effective control of their

LDL-C levels. Statins are the initial drug class of choice, and usually

“high-intensity” statin therapy is needed. Many FH patients cannot

achieve adequate control of their LDL-C levels even with high-intensity statin therapy, and a cholesterol absorption inhibitor (ezetimibe),

a PCSK9 inhibitor, an ACL inhibitor (bempedoic acid), and a bile

acid sequestrant are other classes of drugs that can be added to statins

(Table 407-4). Some patients with severe heterozygous FH cannot

be adequately managed using existing therapies and are candidates

for LDL apheresis, a physical method of purging the blood of LDL in

which the LDL particles are selectively removed from the circulation.

Other novel approaches for these patients are under development.

Homozygous FH (HoFH) is caused by loss-of-function mutations in

both alleles of the LDL receptor or double heterozygosity for mutations

in two FH genes. Patients with HoFH have been classified into those

with virtually no detectable LDL receptor activity (receptor negative)

and patients with markedly reduced but detectable LDL receptor

activity (receptor defective). Untreated LDL-C levels in patients with

HoFH range from ~400 to >1000 mg/dL, with receptor-defective

patients at the lower end and receptor-negative patients at the higher

end of the range. TGs are usually relatively normal. Some patients with

HoFH, particularly receptor-negative patients, present in childhood

with cutaneous planar xanthomas on the hands, wrists, elbows, knees,

heels, or buttocks. The devastating consequence of HoFH is accelerated

ASCVD, which often presents in childhood or early adulthood. Atherosclerosis often develops first in the aortic root, where it can cause

aortic valvular or supravalvular stenosis, and typically extends into the

coronary ostia, which become stenotic. Symptoms can be atypical, and

sudden death is not uncommon. Untreated, receptor-negative patients

with HoFH rarely survive beyond the second decade; patients with

receptor-defective LDL receptor defects have a better prognosis but

almost invariably develop clinically apparent atherosclerotic vascular

disease by age 30 and often much sooner.

HoFH should be suspected in a child or young adult with LDL

>400 mg/dL without secondary cause. Cutaneous xanthomas, evidence of ASCVD, and/or hypercholesterolemia in both parents all are

supportive of the diagnosis. While the diagnosis is usually made on

clinical grounds, genetic testing should be performed to identify specific causal variants. Patients with HoFH must be treated aggressively

to delay the onset and progression of CVD. Although receptor-negative

patients have no response to statins and PCSK9 inhibitors, receptordefective patients can have modest responses to these medicines, and

they should be tried in patients with HoFH. Two drugs that reduce the

hepatic production of VLDL and thus LDL, a small-molecule inhibitor of the microsomal TG transfer protein (MTP) and an antisense

oligonucleotide to apoB, and an antibody that inhibits ANGPLT3 are

approved for the treatment of patients with HoFH and should be considered in patients who have insufficient response to statins and PCSK9

inhibitors. LDL apheresis should be considered in HoFH patients who

have persistently elevated LDL-C levels despite drug therapy. Liver

transplantation is effective in decreasing plasma LDL-C levels in this

disorder and is sometimes used as a last resort. Liver-directed gene

therapy is under development for HoFH, as are other new therapeutic

approaches intended to address the remaining unmet medical need.

FH is an autosomal dominant disorder. There are a few rare conditions that cause an FH-like phenotype in an autosomal recessive

manner and should be considered in patients with severe hypercholesterolemia who do not report a family history of hypercholesterolemia

or premature CHD.

AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA (ARH) ARH is a

very rare autosomal recessive disorder that was originally reported in

individuals of Sardinian descent. The disease is caused by mutations in

the gene LDLRAP1 encoding the protein LDLR adaptor protein (also

called the ARH protein), which is required for LDL receptor–mediated

endocytosis in the liver. LDLRAP1 binds to the cytoplasmic domain of

the LDL receptor and links the receptor to the endocytic machinery. In

the absence of LDLRAP1, LDL binds to the extracellular domain of the

LDL receptor, but the lipoprotein-receptor complex fails to be internalized. ARH, like HoFH, is characterized by hypercholesterolemia, tendon

xanthomas, and premature coronary artery disease (CAD). The levels of

plasma LDL-C tend to be intermediate between the levels present in FH

homozygotes and FH heterozygotes, and CAD is not usually symptomatic until the third decade. LDL receptor function in cultured fibroblasts

is normal or only modestly reduced in ARH, whereas LDL receptor

function in the liver is negligible. Unlike FH homozygotes, the hyperlipidemia responds to treatment with statins, but these patients often require

additional therapy to lower plasma LDL-C to acceptable levels.

SITOSTEROLEMIA Sitosterolemia is a rare autosomal recessive disease

that is caused by biallelic loss-of-function mutations in either of two

members of the ATP-binding cassette (ABC) half transporter family,

ABCG5 and ABCG8. These genes are expressed in both enterocytes

and hepatocytes. The proteins heterodimerize to form a functional

complex that transports plant sterols such as sitosterol and campesterol, and animal sterols, predominantly cholesterol, across the apical

biliary membrane of hepatocytes into the bile and across the apical

luminal membrane of enterocytes into the gut lumen, thus reducing

their (re)absorption and promoting their excretion. In normal individuals, <5% of dietary plant sterols are absorbed by the proximal

small intestine. The small amounts of plant sterols that enter the

circulation are preferentially excreted into the bile, and thus, levels of

plant sterols are kept very low in tissues. In sitosterolemia, the intestinal absorption of sterols is increased and biliary and fecal excretion of

the sterols is reduced, resulting in increased plasma and tissue levels

of both plant sterols and cholesterol. The increase in hepatic sterol

3142 PART 12 Endocrinology and Metabolism

levels results in transcriptional suppression of the expression of the

LDL receptor, resulting in reduced uptake of LDL and substantially

increased LDL-C levels. In addition to the clinical picture of severe

hypercholesterolemia, often accompanied by tendon xanthomas and

premature ASCVD, these patients also have anisocytosis and poikilocytosis of erythrocytes and megathrombocytes due to the incorporation of plant sterols into cell membranes. Episodes of hemolysis and

splenomegaly are a distinctive clinical feature of this disease compared

to other genetic forms of hypercholesterolemia and can be a clue to

the diagnosis. Sitosterolemia should be suspected in a patient with

severe hypercholesterolemia without a family history of such or who

fails to respond to statin therapy. Sitosterolemia can be diagnosed by

a laboratory finding of a substantial increase in plasma sitosterol and/

or other plant sterols and should be confirmed by gene sequencing of

ABCG5 and ABCG8. It is important to make the diagnosis, because

diet, bile acid sequestrants, and cholesterol-absorption inhibitors are

the most effective agents to reduce LDL-C and plasma plant sterol

levels in these patients. Of note, heterozygosity for mutations in

ABCG5 or ABCG8 is now recognized to cause a moderate form of

hypercholesterolemia.

LYSOSOMAL ACID LIPASE DEFICIENCY (LALD) LALD, also known

as cholesteryl ester storage disease, is an autosomal recessive disorder

caused by loss-of-function variants in both alleles of the gene LIPA

encoding the enzyme lysosomal acid lipase (LAL). LAL is responsible

for hydrolyzing neutral lipids, particularly TGs and CEs, after delivery

to the lysosome by cell surface receptors such as the LDL receptor. It

is particularly important in the liver, which clears large amounts of

lipoproteins from the circulation. LALD is characterized by elevated

LDL-C, usually in association with low HDL-C and with variably elevated TG levels, together with progressive fatty liver ultimately leading

to hepatic fibrosis. Genetic deficiency of LAL results in accumulation

TABLE 407-4 Drugs Used to Treat Dyslipidemia

DRUG

MAJOR

INDICATIONS STARTING DOSE MAXIMAL DOSE MECHANISM ADVERSE EFFECTS

LDL-Lowering Drugs

HMG-CoA reductase

inhibitors (statins)

Elevated LDL-C;

increased CV risk

↓ Inhibition of cholesterol

synthesis → ↑ Hepatic LDL

receptors

Myalgias and myopathy,

↑ transaminases, ↑

diabetes risk

Lovastatin 20–40 mg daily 80 mg daily

Pravastatin 40–80 mg daily 80 mg daily

Simvastatin 20–40 mg daily 80 mg daily

Fluvastatin 20–40 mg daily 80 mg daily

Atorvastatin 20–40 mg daily 80 mg daily

Rosuvastatin 5–20 mg daily 40 mg daily

Pitavastatin 1–2 mg daily 4 mg daily

Cholesterol absorption

inhibitor

Elevated LDL-C ↓ Cholesterol absorption→ ↑ LDL

receptors

Elevated transaminases

Ezetimibe 10 mg daily 10 mg daily

Bile acid sequestrants Elevated LDL-C ↑ Bile acid excretion → ↑ LDL

receptors

Bloating, constipation,

elevated triglycerides

Cholestyramine 4 g daily 32 g daily

Colestipol 5 g daily 40 g daily

Colesevelam 3750 mg daily 4375 mg daily

PCSK9 inhibitors

Evolocumab (Ab)

Alirocumab (Ab)

Elevated LDL-C 140 mg SC every 2 weeks

75 mg SC every 2 weeks

420 mg SC every 1 month

(HoFH)

150 mg SC every 2 weeks

↓ PCSK9 activity due to Ab

inhibition → ↑ LDL receptors

Injection site reactions

Inclisiran (siRNA) 300 mg SC every 6 months 300 mg SC every 6 months ↓ PCSK9 synthesis due to siRNA

silencing → ↑ LDL receptors

Injection site reactions

ATP citrate lyase inhibitor

Bempedoic acid

Elevated LDL-C 180 mg daily 180 mg daily ↓ Inhibition of cholesterol

synthesis → ↑ LDL receptors

↑ uric acid and gout

Tendon rupture

MTP inhibitor

Lomitapide

HoFH 5 mg daily 60 mg daily MTP inhibition → ↓ VLDL assembly

and secretion

Nausea, diarrhea,

increased hepatic fat

ApoB inhibitor (ASO)

Mipomersen

HoFH 200 mg SC weekly 200 mg SC weekly ↓ ApoB synthesis due to ASO

silencing → ↓ ApoB/VLDL

secretion

Injection site reactions, flulike symptoms, increased

hepatic fat

ANGPTL3 inhibitor (Ab)

Evinacumab

HoFH 15 mg/kg IV q 4 weeks 15 mg/kg IV q 4 weeks ↓ ANGPTL3 activity due to Ab

inhibition → ↑ LPL activity, ↑ LDL

catabolism

Reduced HDL-C levels

TG-Lowering Drugs

Fibric acid derivatives

(fibrates)

Gemfibrozil

Fenofibrate

Elevated TG 600 mg bid

40–160 mg daily

depending on product

600 mg bid

40–160 mg daily

depending on product

↑ LPL, ↓ VLDL synthesis Dyspepsia, myalgia,

gallstones, elevated

transaminases

Omega-3 fatty acids

Acid ethyl esters

Elevated TG 4 g daily 4 g daily ↑ TG catabolism Dyspepsia, fishy odor to

breath

Icosapent ethyl 4 g daily 4 g daily

Abbreviations: Ab, antibody; GI, gastrointestinal; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL, low-density lipoprotein;

LDL-C, LDL cholesterol; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very-low-density lipoprotein.

3143 Disorders of Lipoprotein Metabolism CHAPTER 407

of neutral lipid in the hepatocytes, leading to hepatosplenomegaly,

microvesicular steatosis, and ultimately fibrosis and end-stage liver disease. The most severe form of this disorder, Wolman’s disease, presents

in infancy and is rapidly fatal. The etiology of the elevated LDL-C

levels is primarily due to impaired LDL receptor–mediated clearance

of LDL. LALD should be suspected in nonobese patients with elevated

LDL-C, low HDL-C, and evidence of fatty liver in the absence of overt

insulin resistance. The diagnosis can be made with a dried blood spot

assay of LAL activity and confirmed by DNA genotyping for the most

common mutation, followed if necessary by sequencing of the gene to

find the second mutation. Liver biopsy is required to assess the degree

of inflammation and fibrosis. LALD is underdiagnosed; it is critically

important to suspect it and make the diagnosis because enzyme

replacement therapy with sebelipase alfa is now available and is highly

effective in treating this condition.

The above conditions primarily cause elevations in LDL due to

impaired catabolism of LDL from the blood. There are a few forms of

primary dyslipidemia that impair the catabolism of “remnant” TRLs

(after their processing by LPL) and therefore cause elevations in both

cholesterol and TGs due to remnant accumulation.

Multifactorial Hypercholesterolemia Most patients with elevated LDL-C do not have a single-gene disorder, as described above,

but instead have a multifactorial etiology that includes genetics and

environment. Genetic variation contributes substantially to elevated

LDL-C levels in the general population. It has been estimated that

at least 50% of variation in LDL-C is genetically determined. Many

patients with elevated LDL-C have polygenic hypercholesterolemia due

to multiple common genetic variants exerting modest LDL-raising

effects. Individuals at the tail of the highest burden of polygenic risk

score for LDL-C often have LDL-C levels that are similar to those with

FH. In patients who are genetically predisposed to higher LDL-C levels,

diet plays a key exacerbating role; indeed, increased saturated and trans

fats in the diet shift the entire distribution of LDL-C levels in the population to the right. As described in more detail below, patients with elevated LDL-C should be carefully assessed for their risk of ASCVD and

managed with lifestyle modification and LDL-lowering medications as

needed to reduce LDL-C and risk of ASCVD.

■ MIXED HYPERLIPIDEMIA (ELEVATED TG AND LDL-C)

Mixed hyperlipidemia can be defined as fasting TGs >150 mg/dL

and evidence of elevated cholesterol-containing lipoproteins (such as

LDL-C >130 mg/dL or non-HDL-C >160 mg/dL). It is one of the most

common types of lipid disorders seen in clinical practice, due both to

genetic predisposition and influence of medical conditions and environmental factors (see below). It is generally associated with elevated

risk of ASCVD, and therefore, patients with mixed hyperlipidemia

should be carefully evaluated and managed to reduce this risk.

Primary (Genetic) Causes of Mixed Hyperlipidemia • FAMILIAL

DYSBETALIPOPROTEINEMIA (FDBL) FDBL (also known as type III

hyperlipoproteinemia) is a recessive disorder characterized by a mixed

hyperlipidemia due to the accumulation of remnant lipoprotein particles (chylomicron remnants and VLDL remnants, or IDL). ApoE

is present in multiple copies on chylomicron remnants and IDL and

mediates their removal via hepatic lipoprotein receptors (Fig. 407-2).

The APOE gene is polymorphic in sequence, resulting in the expression

of three common isoforms: apoE3, which is the most common (~78%

global allele frequency [AF]), apoE4 (~14% global AF), and apoE2

(~8% global AF). The apoE4 allele, which has an arginine instead of a

cysteine at position 112, is widely known for being the major genetic

risk factor for Alzheimer’s disease. It is associated with slightly higher

LDL-C levels and increased ASCVD risk but is not associated with

FDBL. The apoE2 allele, which has a cysteine at position 158 instead of

an arginine, is the cause of FDBL when present on both alleles. ApoE2

has a lower affinity for the LDL receptor; therefore, chylomicron remnants and IDL containing apoE2 are removed from plasma at a slower

rate, leading to their accumulation in blood.

Approximately 0.5% of the general population are apoE2/E2

homozygotes, but only a small minority of these individuals actually

develop hyperlipidemia characteristic of FDBL (which has a prevalence of ~1 in 10,000). Thus, an additional, sometimes identifiable,

factor precipitates the development of overt dysbetalipoproteinemia

in apoE2/E2 homozygotes. The most common precipitating factors

are a high-fat diet, sedentary lifestyle, obesity, alcohol use, menopause,

diabetes mellitus, hypothyroidism, renal disease, HIV infection, or

certain drugs. Certain dominant-negative mutations in apoE can cause

a dominant form of FDBL where the hyperlipidemia is fully manifest in

the heterozygous state, but these mutations are very rare.

Patients with FDBL usually present in adulthood with hyperlipidemia, xanthomas, or premature coronary or peripheral vascular

disease. In FDBL, in contrast to other disorders of elevated TGs, the

plasma levels of cholesterol and TG are often elevated to a similar

degree, and the level of HDL-C is usually normal. Two distinctive types

of xanthomas, tuberoeruptive and palmar, are seen in FDBL patients.

Tuberoeruptive xanthomas begin as clusters of small papules on the

elbows, knees, or buttocks and can grow to the size of small grapes.

Palmar xanthomas (alternatively called xanthomata striata palmaris)

are orange-yellow discolorations of the creases in the palms and wrists.

Both of these xanthoma types are virtually pathognomonic for FDBL.

Subjects with FDBL have premature ASCVD and tend to have more

peripheral vascular disease than is typically seen in FH.

The definitive diagnosis of FDBL can be made either by the documentation of very high levels of remnant lipoproteins or by identification of the apoE2/E2 genotype. A variety of methods are used to identify

remnant lipoproteins in the plasma, including “β-quantification” by

ultracentrifugation (ratio of directly measured VLDL cholesterol to

total plasma TG >0.30), lipoprotein electrophoresis (broad β band),

or nuclear magnetic resonance lipoprotein profiling. The Friedewald

formula for calculation of LDL-C is not valid in FDBL because the

VLDL particles are depleted in TG and enriched in cholesterol. The

plasma levels of LDL-C are actually low in this disorder due to defective metabolism of VLDL to LDL. DNA-based apoE genotyping can be

performed to confirm homozygosity for apoE2, which is diagnostic for

FDBL. However, absence of the apoE2/E2 genotype does not strictly

rule out the diagnosis of FDBL, because other mutations in apoE can

(rarely) cause this condition.

Because FDBL is associated with increased risk of premature

ASCVD, it should be treated aggressively. Other metabolic conditions

that can exacerbate the hyperlipidemia (see above) should be managed.

Patients with FDBL are typically diet-responsive and can respond

favorably to low-cholesterol, low-fat diets and weight reduction.

Alcohol intake should be curtailed. Pharmacologic therapy is often

required, and statins are the first line in management. In the event of

statin intolerance or insufficient control of hyperlipidemia, cholesterol

absorption inhibitors, PCSK9 inhibitors, and fibrates are also effective

in the treatment of FDBL.

HEPATIC LIPASE DEFICIENCY Hepatic lipase (HL; gene name LIPC)

is a member of the same gene family as LPL and hydrolyzes TGs and

phospholipids in remnant lipoproteins and HDL. Hydrolysis of lipids

in remnant particles by HL contributes to their hepatic uptake via an

apoE-mediated process. HL deficiency is a very rare autosomal recessive disorder caused by biallelic loss-of-function mutations in LIPC.

It is characterized by elevated plasma levels of cholesterol and TGs

(mixed hyperlipidemia) due to the accumulation of lipoprotein remnants, accompanied by elevated plasma level of HDL-C. The diagnosis

is confirmed by confirmation of pathogenic mutations in both alleles

of LIPC. Due to the small number of patients with HL deficiency, the

association of this genetic defect with ASCVD is not entirely clear,

although anecdotally, patients with HL deficiency who have premature

CVD have been described. As with FDBL, statin therapy is recommended to reduce remnant lipoproteins and cardiovascular risk.

FAMILIAL COMBINED HYPERLIPIDEMIA (FCHL) FCHL is one of the

most common familial lipid disorders; it is estimated to occur in ~1

in 100–200 individuals. FCHL is characterized by elevations in plasma

levels of TGs (VLDL) and LDL-C (including especially a small dense

3144 PART 12 Endocrinology and Metabolism

form of LDL) and reduced plasma levels of HDL-C. This disorder is

an important contributor to premature CHD; ~20% of patients who

develop CHD under age 60 have FCHL. FCHL can manifest in childhood but is usually not fully expressed until adulthood. The disease

clusters in families, and affected family members typically have one

of three possible phenotypes: (1) elevated plasma levels of LDL-C, (2)

elevated plasma levels of TGs due to elevation in VLDL, or (3) elevated

plasma levels of both LDL-C and TG. The lipoprotein profile can

switch among these three phenotypes in the same individual over time

and may depend on factors such as diet, exercise, weight, and insulin

sensitivity. Patients with FCHL have substantially elevated plasma levels of apoB, often disproportionately high relative to the plasma LDL-C

concentration, indicating the presence of small dense LDL particles,

which are characteristic of this syndrome.

Individuals with this phenotype generally share the same metabolic

defect, namely overproduction of VLDL and apoB by the liver. The

molecular etiology of this condition remains poorly understood, and

no single gene has been identified in which mutations convincingly

cause this disorder in a simple Mendelian fashion. It is likely that defects

in a combination of genes can cause the condition, suggesting that a

more appropriate term for the disorder might be polygenic combined

hyperlipidemia.

The presence of a mixed dyslipidemia (plasma TG levels between

150 and 500 mg/dL and total cholesterol levels between 200

and 400 mg/dL, usually with HDL-C levels <40 mg/dL in men and

<50 mg/dL in women) and a family history of mixed dyslipidemia and/

or premature CHD suggests the diagnosis. Measurement of plasma

apoB levels can help support the diagnosis if they are substantially

elevated, particularly relative to the LDL-C level. Individuals with this

disorder should be treated aggressively due to significantly increased

risk of premature CHD, often disproportionate to the LDL-C level.

Decreased dietary intake of simple carbohydrates, increased aerobic

exercise, and weight loss can all have beneficial effects on the lipid

profile. Patients with type 2 diabetes should be aggressively treated to

maintain good glucose control. Virtually all patients with FCHL merit

lipid-lowering drug therapy to reduce apoB-containing lipoprotein

levels and lower the risk of ASCVD. High-intensity statins are first

line, but many patients with FCHL require combination therapy that

includes ezetimibe, a PCSK9 inhibitor, and/or bempedoic acid.

■ SECONDARY CONTRIBUTORS TO ELEVATED

LEVELS OF APOB-CONTAINING LIPOPROTEINS

There are many “secondary” factors that contribute to dyslipidemia

(Table 407-3), often acting in concert with polygenic predisposition

as reviewed above. Some primarily affect TGs, some primarily affect

LDL-C, and some influence both, with a great deal of variability. Here

the major secondary contributors are reviewed.

Secondary Factors That Primarily Elevate TG Levels • HIGHCARBOHYDRATE DIET Dietary carbohydrates are utilized as a substrate for fatty acid synthesis in the liver. Some of the newly synthesized

fatty acids are esterified, forming TGs, and secreted in VLDL. Thus,

excessive intake of calories as carbohydrates, which is frequent in

Western societies, leads to increased hepatic VLDL-TG secretion and

elevated TG levels. Reduction in carbohydrate consumption can have

a substantial effect in reducing TG levels, although replacing carbohydrates with saturated fat can elevate LDL-C levels.

OBESITY, INSULIN RESISTANCE, AND TYPE 2 DIABETES (See also

Chaps. 401–403) Obesity, insulin resistance, and type 2 diabetes mellitus are the most frequent contributors to dyslipidemia, primarily by

influencing TGs. The increase in adipocyte mass and accompanying

decreased insulin sensitivity associated with obesity have multiple

effects on lipid metabolism, with one of the major effects being excessive

hepatic VLDL production. More free fatty acids are delivered from the

expanded and insulin-resistant adipose tissue to the liver, where they are

reesterified in hepatocytes to form TGs, which are packaged into VLDLs

for secretion into the circulation. In addition, the increased insulin levels promote increased fatty acid synthesis in the liver. In insulin-resistant

patients who progress to type 2 diabetes mellitus, dyslipidemia remains

common, even when the patient is under relatively good glycemic control. In addition to increased VLDL production, insulin resistance can

also result in decreased LPL activity, resulting in reduced catabolism of

chylomicrons and VLDLs and more severe HTG. This may be due in

part to the effects of tissue insulin resistance leading to reduced transcription of LPL in skeletal muscle and adipose, as well as to increased

production of the LPL inhibitor apoC-III by the liver. This reduction in

LPL activity often exacerbates the effects of increased VLDL production

and contributes to the dyslipidemia seen in these patients. The dyslipidemia in this setting is almost invariable associated with low HDL-C

levels as well. A cluster of metabolic risk factors are often found together,

including obesity, insulin resistance, hypertension, high TGs, and low

HDL-C (the so-called “metabolic syndrome,” Chap. 408).

ALCOHOL CONSUMPTION Excessive alcohol consumption inhibits

hepatic oxidation of free fatty acids, thus promoting hepatic TG synthesis and VLDL secretion and leading to increased plasma TG levels.

Regular alcohol use also raises plasma levels of HDL-C and should be

considered in patients with the relatively unusual combination of elevated TGs and normal or elevated HDL-C. A careful history of alcohol

use should be taken in patients with elevated TGs. Reduction in alcohol

consumption can often have a substantial effect in reducing TG levels.

CHRONIC KIDNEY DISEASE (See also Chap. 311) Chronic kidney

disease (CKD) is often associated with mild HTG (150–400 mg/dL)

due to the accumulation of VLDLs and remnant lipoproteins in the

circulation. TG lipolysis and remnant clearance are both reduced in

patients with renal failure. Because the risk of ASCVD is increased in

CKD, patients should usually be treated with lipid-lowering agents,

particularly statins.

ESTROGEN AND OTHER DRUGS Many drugs have an impact on lipid

metabolism and can result in significant alterations in the lipoprotein

profile (Table 407-3). Estrogens often elevate TG levels, and TG levels

can also increase during pregnancy. In women with HTG, plasma TG

levels should be monitored when birth control pills or postmenopausal

estrogen therapy is initiated and during pregnancy. Use of low-dose

preparations of estrogen or the estrogen patch can minimize the effect

of exogenous estrogen on lipids. Isotretinoin therapy for acne can

cause substantial elevations in TGs, and TG levels should be checked

at baseline and after initiation of therapy. Bexarotene therapy for cutaneous T-cell lymphoma often causes substantial increases in TGs, and

patients should be monitored accordingly.

Secondary Factors That Elevate LDL-C Levels • DIET HIGH

IN SATURATED AND TRANS FATS Dietary saturated and trans fats

act to downregulate LDL receptor expression in the liver, leading to

elevation in LDL-C levels and increased ASCVD risk. A careful dietary

history should be taken in individuals with elevated LDL-C with a

focus on sources of saturated and trans fats. Reduction in consumption

of saturated and trans fats can sometimes have a substantial effect in

reducing LDL-C levels and is a cornerstone of the initial nonpharmacologic management of hypercholesterolemia.

HYPOTHYROIDISM (See also Chap. 382) Hypothyroidism is the most

important secondary factor causing elevated LDL-C levels. It causes

elevated plasma LDL-C levels due to downregulation of the hepatic

LDL receptor, which is normally increased by the action of thyroid

hormone. Because hypothyroidism is often subtle and therefore easily overlooked, all patients presenting with elevated plasma levels of

LDL-C, especially if there has been an unexplained increase in LDL-C,

should be screened for hypothyroidism by measuring thyroid-stimulating hormone (TSH). Thyroid replacement therapy usually reduces

LDL-C levels; if not, the patient probably has a primary lipoprotein

disorder and may require lipid-lowering drug therapy with a statin.

LIVER DISORDERS (See also Chap. 336) Cholestasis is almost invariably associated with hypercholesterolemia due to elevated LDL-C

levels and sometimes particles called Lp-X. A major pathway by which

cholesterol is excreted from the body is via secretion into bile, either

directly or after conversion to bile acids, and cholestasis blocks this

3145 Disorders of Lipoprotein Metabolism CHAPTER 407

critical excretory pathway. The increase in hepatocellular cholesterol

results in downregulation of the LDL receptor, leading to increased

plasma LDL-C levels. In severe cholestasis, excess free cholesterol,

coupled with phospholipids, is shed into the plasma as a constituent

of a lamellar particle called Lp-X. These unusual particles, which are

not lipoproteins, lack apoB, and have an aqueous and not neutral lipid

core, are rich in free cholesterol, and can deposit in the skin, producing

xanthomas sometimes seen in patients with cholestasis. Some liver

disorders can affect plasma lipid levels in other ways. Viral hepatitis

can increase TGs, and liver failure can result in reduction in plasma

cholesterol and TGs.

NEPHROTIC SYNDROME (See also Chap. 311) Nephrotic syndrome

is a classic cause of excessive VLDL production leading to elevation

in both TGs and LDL-C. The molecular mechanism of VLDL overproduction remains poorly understood but has been attributed to

the effects of hypoalbuminemia leading to increased hepatic protein

synthesis. Effective treatment of the underlying renal disease may

normalize the lipid profile, but many patients with chronic nephrotic

syndrome require lipid-lowering drug therapy with statins and sometimes additional drugs.

CUSHING’S SYNDROME (See also Chap. 386) Endogenous glucocorticoid excess in Cushing’s syndrome is associated with increased VLDL

synthesis and secretion leading to dyslipidemia characterized by HTG

and elevated LDL-C. Treatment of the underlying cause is often sufficient to manage the dyslipidemia, but sometimes lipid-lowering drug

therapy is needed.

IMMUNOSUPPRESSIVE THERAPY AND CORTICOSTEROIDS Several

of the immunosuppressants used after solid organ transplantation,

including cyclosporin and sirolimus, can cause substantial elevation

in LDL-C and TG levels. These patients can present a difficult clinical management problem. Chronic corticosteroid use, whether after

transplant or in other inflammatory conditions, can also result in

elevations in LDL-C and TG levels, sometimes producing a substantial

mixed dyslipidemia. When the immunosuppressant or steroid must be

continued, which is often the case, drug therapy with statins may be

indicated in certain patients, with careful attention to the potential for

untoward muscle-related side effects.

■ DISORDERS ASSOCIATED WITH REDUCED

APOB-CONTAINING LIPOPROTEINS

Plasma concentrations of LDL-C <60 mg/dL are unusual. Although

in some cases, LDL-C levels in this range may be reflective of malnutrition or serious chronic illness, LDL-C <60 mg/dL in an otherwise

healthy individual suggests an inherited condition. The major inherited causes of low LDL-C are reviewed here and listed in Table 407-2.

Abetalipoproteinemia The synthesis and secretion of apoB-containing lipoproteins in the enterocytes of the proximal small bowel

and in the hepatocytes of the liver involve a complex series of events

that coordinate the coupling of various lipids with apoB-48 and apoB100, respectively. Abetalipoproteinemia is a rare autosomal recessive

disease caused by loss-of-function mutations in the gene encoding

microsomal TG transfer protein (MTP; gene name MTTP), a protein

that transfers lipids to nascent chylomicrons and VLDLs in the intestine and liver, respectively. Plasma levels of cholesterol and TG are

extremely low in this disorder, and chylomicrons, VLDLs, LDLs, and

apoB are undetectable in plasma. The parents of patients with abetalipoproteinemia (obligate heterozygotes) have normal plasma lipid and

apoB levels. Abetalipoproteinemia usually presents in early childhood

with diarrhea and failure to thrive due to fat malabsorption. The initial

neurologic manifestations are loss of deep tendon reflexes, followed by

decreased distal lower extremity vibratory and proprioceptive sense,

dysmetria, ataxia, and the development of a spastic gait, often by the

third or fourth decade. Patients with abetalipoproteinemia also develop

a progressive pigmented retinopathy presenting with decreased night

and color vision, followed by reductions in daytime visual acuity and

ultimately progressing to near-blindness. The presence of spinocerebellar degeneration and pigmented retinopathy in this disease has

resulted in some patients with abetalipoproteinemia being misdiagnosed as having Friedreich’s ataxia.

Most of the clinical manifestations of abetalipoproteinemia result

from defects in the absorption and transport of fat-soluble vitamins.

Vitamin E and retinyl esters are normally transported from enterocytes

to the liver by chylomicrons, and vitamin E is dependent on VLDL for

transport out of the liver and into the circulation. As a consequence

of the inability of these patients to secrete apoB-containing particles,

patients with abetalipoproteinemia are markedly deficient in vitamin

E and are also mildly to moderately deficient in vitamins A and K.

Patients with abetalipoproteinemia should be referred to specialized

centers for confirmation of the diagnosis and appropriate therapy.

Treatment consists of a low-fat, high-caloric, vitamin-enriched diet

accompanied by large supplemental doses of vitamin E. It is imperative

that treatment be initiated as soon as possible to prevent development

of neurologic sequelae, which can progress even with high-dose vitamin

E therapy. New therapies for this serious, albeit rare, disease are needed.

The discovery that genetic loss of MTP causes absent LDL-C led to the

development of an MTP inhibitor to treat homozygous FH (see below).

Familial Hypobetalipoproteinemia (FHBL) FHBL generally

refers to a condition of low total cholesterol, LDL-C, and apoB due

to mutations in the APOB gene. Most of the mutations causing FHBL

result in a truncated apoB protein, resulting in impaired assembly and

secretion of chylomicrons from enterocytes and VLDL from the liver.

Any secreted VLDL particles containing a truncated apoB protein are

cleared from the circulation at an accelerated rate, which also contributes to the low levels of LDL-C and apoB. Individuals heterozygous

for these mutations usually have LDL-C levels <60–80 mg/dL and

also tend to have low levels of plasma TG. Many FHBL patients have

elevated levels of hepatic fat (due to reduced VLDL export) and sometimes have increased levels of liver transaminases, although it appears

that these patients infrequently develop associated hepatic inflammation and fibrosis.

Truncating mutations in both apoB alleles cause homozygous FHBL,

an extremely rare disorder resembling abetalipoproteinemia with nearly

undetectable LDL-C and apoB. The neurologic defects in homozygous

hypobetalipoproteinemia are similar to those seen in abetalipoproteinemia, but tend to be less severe. Homozygous hypobetalipoproteinemia

can be distinguished from abetalipoproteinemia by examining the

inheritance pattern of the plasma LDL-C level. The levels of LDL-C

and apoB are normal in the parents of patients with abetalipoproteinemia, a classic recessive condition, and low in those of patients with

homozygous hypobetalipoproteinemia, a co-dominant condition. The

discovery that truncating mutations in apoB reduce LDL-C led to the

development of an antisense oligonucleotide to treat HoFH (see below).

Familial PCSK9 Deficiency Another inherited cause of low

LDL-C results from loss-of-function mutations in PCSK9. PCSK9 is

a secreted protein that binds to the extracellular domain of the LDL

receptor in the liver and promotes the degradation of the receptor. Heterozygosity for nonsense mutations in PCSK9 that interfere with the synthesis of the protein are associated with increased hepatic LDL receptor

activity and reduced plasma levels of LDL-C. Such mutations are more

frequent in individuals of African descent. Individuals who are heterozygous for a loss-of-function mutation in PCSK9 have an ~30–40%

reduction in plasma levels of LDL-C and have a substantial protection

from CHD relative to those without a PCSK9 mutation, presumably due

to having lower plasma cholesterol levels since birth. Homozygotes for

these nonsense mutations have been reported and have extremely low

LDL-C levels (<20 mg/dL) but appear otherwise healthy. A sequence

variation of somewhat higher frequency (R46L) is found predominantly in individuals of European descent. This mutation impairs, but

does not completely destroy, PCSK9 function. As a consequence, the

plasma levels of LDL-C in individuals carrying this mutation are more

modestly reduced (~15–20%); individuals with these mutations have a

45% reduction in CHD risk. The discovery of this condition led to the

development of therapies that antagonize or silence PCSK9, thus reducing LDL-C levels and risk of CHD (see below).