HYPERLIPIDEMIA

Christine N. Papadea, Ph.D.

Objectives

To review or introduce the following topics:

1. Plasma lipids in the assessment of the risk of coronary heart disease.

2. Composition, classification, and primary functions of plasma lipoproteins and
their apolipoproteins.
3. Metabolic pathways of lipoproteins.
4. Familial (primary) and acquired (secondary) disorders of lipid metabolism.
5. Clinical laboratory methods for measuring blood lipids.

References

1. Harrison’s Principles of Internal Medicine, 15th ed., pp. 2245-2257.

2. Kumar, Cotran, Robbins, Basic Pathology, 6th ed., pp. 182-184; 282-289.
3. Laposata. Laboratory Medicine, Clinical Pathology in the Practice of Medicine. 2002: pp. 64-65;
232-239.
4. Chait and Brunzell, In: Besser and Thorner, Clinical Endocrinology, 2nd ed., chapter 6.
5. Schaefer EJ. Overview of the Diagnosis and Treatment of Lipid Disorders. Monograph. Genzyme
Corporation, 1993.
6. Rifai et al., In: Tietz Textbook of Clinical Chemistry, 3rd ed., chapter 25.
7. Williams Textbook of Endocrinology, 9th ed., chapter 23.
8. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
National Cholesterol Education Program. National Heart, Lung, and Blood Institute. NIH
publication no. 02-5215. Sept. 2002. www.nhlbi.nih.gov.

Key Words, Definitions, and Abbreviations

1. Atherosclerotic vascular disease.

2. Lipoproteins. Complex micellar particles consisting of proteins and lipids
including triglycerides (TGs), phospholipids, cholesterol, and cholesterol esters.
Lipoproteins can be separated into 5 major classes on the basis of their densities
and physical-chemical properties:
• Chylomicrons
• VLDL, very low density
• IDL, intermediate density
• LDL, low density
• HDL, high density
A sixth type, Lipoprotein (a) [Lp(a)], is thought to have atherogenic properties,
but its function is not well understood.
2. Hyperlipidemia. Condition in which one or both of the major plasma lipids–
cholesterol (free and esterified) and TGs – is/are elevated.
9. Lipoprotein phenotype. A laboratory description of hyperlipidemias based on the
levels and distribution patterns of lipoproteins, and the appearance of the
patient’s plasma. Different clinical syndromes, which may be inherited and/or
acquired, are associated with each of the 6 types: I, IIa, IIb, III, IV, V.
4. Apolipoproteins. Specialized protein monolayers on the surface of lipoproteins.
5. Enzymes in lipoprotein metabolism (figures 1-4, below):

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• LPL, lipoprotein lipase. Bound to capillary walls of most tissues where it is

activated for the hydrolysis of TGs in chylomicrons, VLDL, and IDL. Circulates
with LDL.
• HTGL, hepatic triglyceride lipase. Secreted by hepatocytes. Circulates with
LDL. Promotes the conversion of VLDL remnants and IDL to LDL.
• LCAT, lecithin cholesterol acyl transferase. Circulates in the plasma with
HDL. Catalyzes the esterification of cholesterol. May have a role in the
metabolism of chylomicrons and VLDL.
• CETP, cholesteryl ester transfer protein. Circulates with HDL.Transfers
cholesterol esters from HDL to triglyceride-rich remnants, e.g., VLDL and IDL.
• HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Determines the rate of intracellular cholesterol synthesis in the LDL receptor
pathway.
6. Adult Treatment Panel III (ATP III): recently (2001-2002) updated evidence-
based report of the National Cholesterol Education Program (NCEP) that
provides the scientific rationale for recommendations for intensive cholesterol-
lowering therapy. ATP III builds on the earlier ATP I and ATP II guidelines for
primary prevention and management of coronary heart disease (CHD) in
individuals with elevated LDL cholesterol. It focuses on primary prevention in
people with multiple CHD risk factors, including the metabolic syndrome, and
emphasizes LDL as the primary target of cholesterol-lowering therapy.

I. Clinical Perspective
A. Coronary Heart Disease (CHD)
CHD, atherosclerotic vascular disease, and stroke are the leading causes of
death in the US. Most cases of CHD can be attributed to abnormalities in the
concentrations and metabolism of plasma lipids. Elevated lipids in most individuals
are the result of lifestyle: excess weight, sedentary, and a fat-rich diet, all modifiable
risk factors of CHD. Only a small percentage of lipid disorders are attributable
to gene defects.
Since the introduction of the National Cholesterol Education Program in 1986,
increased public awareness and control of modifiable risk factors have contributed to
declining deaths due to heart disease and stroke. Numerous studies indicate that
blood levels of certain lipids and lipoproteins are strong indicators of the risk of
developing CHD.
B. Factors that increase the risk for CHD and/or stroke:
• Elevated plasma lipids and lipoproteins.
• Cigarette smoking
• High-fat diet
• Physical inactivity
• Genetics- family history of premature CHD
• Gender and age: men >45 yrs., women >55 yrs.
• Diabetes
• Hypertension
• Potential adjuncts to risk assessment. These are substances not associated
with hyperlipidemias but recognized as contributing to vascular damage when
elevated, e.g, homocysteine and C-reactive protein.

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II. Lipoproteins and Apolipoproteins

A. Lipoproteins
Macromolecular complexes synthesized in the liver and intestine.
Function: Transport hydrophobic lipids in plasma.
Structure:
Core, non-polar lipids are “passengers,” being inactive in the metabolism
of the particle.
Triglycerides
Cholesterol esters
Surface, polar lipids
Free (unesterified) cholesterol
Phospholipids
Apolipoproteins
The composition of the circulating lipoproteins is not static! A continuous
exchange of components occurs between the different types of
particles.

Figure 1 (from Ref. 5)

B. Apolipoproteins (Table 1)
Specialized proteins embedded in a monolayer on the phospholipid surface.
Functions: Regulate lipid transport and lipoprotein metabolism.
1. Provide the interface between plasma and core components.
2. Activate enzymes in the lipoprotein metabolic pathways.
3. Stabilize the particle.
4. Promote the uptake of lipoproteins into cells via specific cell-surface
receptors.
Clinical use: Biochemical markers for increased risk of CHD (Table 2).

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Table 1. Properties of the Major Apolipoproteins.

Main Functions Lipoprotein Carrier Particle(s)

Apo A-I LCAT co-factor. Structural for HDL; HDL; Chylomicrons.
ligand for HDL receptor.
Apo A-II Unknown. HDL; Chylomicrons.
Apo B-100 Assembly of lipoproteins (VLDL and VLDL; IDL; LDL.
LDL) of hepatic origin. Ligand for LDL
to the apo B receptors on hepatic and
other tissues.
Apo B-48 Assembly and secretion with Chylomicrons.
chylomicrons by the intestine.
Apo C-I Modulates hepatic uptake of VLDL and Chylomicrons; VLDL; HDL;
IDL. IDL.
Apo C-II Activates LPL.
Apo C-III Inhibits LPL.

Apo (a) Uncertain. Lp(a)

Structurally similar to plasminogen.
Apo E Uptake of chylomicrons, VLDL, IDL Chylomicrons; VLDL; IDL.
remnants and LDL. Ligand for B/E
receptor.

Table 2. Apolipoproteins as Markers for Risk of Developing CHD

Level Associated with Increased Risk

Apo A-I Decreased
Apo B-100 Increased
Apo (a) Increased
Apo E Decreased

C. Properties and Metabolism of Lipoproteins (Table 25.5).

Lipoproteins differ in size, density, relative proportions of cholesterol, TGs,
phospholipids, and apolipoproteins and other physical-chemical properties
1. Chylomicrons
Source: Exogenous; intestinal absorption of fat in the diet.
Comprised mainly of TGs, ~80%.
High concentrations of triglyceride-rich particles impart a cloudy or
creamy appearance to plasma (see Figure 6).
Principal function: transports exogenous TGs.
Apolipoproteins: B-48; Apo C-II, activates LPL which hydrolyzes TGs
to fatty acids and remnants.
2. VLDL
Synthesized in the liver.
Comprised mainly of TGs>>cholesterol.
Function: transport of TGs synthesized in the liver.
Apolipoproteins: Apo B-100, Apo C-I, -II and -III, and Apo E.
Metabolism of VLDL is mediated by LPL to produce IDL, TGs, and
LDL, thus VLDL is atherogenic.

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3. IDL (VLDL remnants)
Source: derived from VLDL.
Components: TGs> cholesterol or phosphopholipids.
Function: precursor of LDL.
Apolipoproteins: Apo-B-100 > Apo-E.
Can enter the liver or can be metabolized by the action of LPL to LDL,
TGs, fatty acids and glycerol.
4. LDL
Source: IDL.
Function: transports cholesterol into hepatic and other tissues via LDL-
receptors.
Primary component: ~60% cholesterol >> phospholipids, proteins, and
TGs.
Apolipoprotein: Apo B-100. Mediates removal of LDL through Apo B
receptors found on nearly all cells.
The liver contains 70% of the body’s LDL receptors and is the main
target of interventions designed to lower plasma cholesterol.
Elevated LDL levels are associated with atherosclerotic lesions and
risk of CHD. Half-life of plasma LDL is controlled by LDL receptors.
5. HDL
Source: Released as disc-like (nascent) particles from the liver and
intestine. Secretion is dependent on the synthesis of Apo A-I.
Primary function: Shuttles cholesterol from the peripheral tissues back
to the liver in “reverse cholesterol transport.”
Nascent HDL discs absorb cholesterol esters (LCAT-mediated) and
form spherical particles.
Components: Approx. 50% protein >phospholipids >cholesterol >TGs
Apolipoproteins: the Apo-A’s; Apo-E.
6. Lipoprotein (a), Lp(a)
Synthesized in the liver. Structure is similar to LDL.
Apolipoproteins: Apo(a) and Apo B-100.
Apo(a) structure has >75% homology to plasminogen, an important
factor in blood clotting. Apo(a) may compete with plasminogen for
binding sites thereby hindering clot lysis and increasing the risk of
myocardial infarction.
Independent risk factor for CHD.

(from Ref. 6)

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III. Metabolism of Lipids: Four Pathways
• Exogenous Pathway. Transport of dietary lipid from the intestine to the liver.
• Endogenous Pathway. Transport of lipoproteins synthesized in the hepatocytes
to peripheral tissues.
• Low-Density Receptor Pathway.
• Reverse Cholesterol Transport. Cholesterol carried by HDL from peripheral
tissues to the liver.

A. Exogenous
1. Dietary fat. Hydrolysis of TGs from chylomicrons and VLDL mediated by LPL.
2. Free fatty acids, glycerol, monoglycerides.
3. Repackaged as chylomicrons with apolipoproteins.
4. Apolipoproteins activate LPL for the hydrolysis of TGs.
5. Hepatic receptors for Apo-B and Apo-E bind and remove chylomicrons.
6. TGs-depleted remnant is removed by the liver.

Figure 2. (from Ref. 4)

B. Endogenous
1. Hepatic synthesis of TGs and cholesterol.
2. Packaged and released as nascent TGs-rich VLDL with Apo-B100, -C, -E.
3. TGs VLDL IDL.
4. IDL particles removed by hepatic cells
5. LPL-mediated hydrolysis of TGs leads to the formation of LDL.
6. Hepatic LDL receptors bind Apo-B 100 on LDL particles.

Figure 3. (from Ref. 4)

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C. LDL Receptor (LDL R) Pathway
1. Apo-B and Apo-E receptors expressed by hepatic cells and comprise the
primary mechanism of regulating cholesterol homeostasis.
2. LDL particles are internalized and degraded.
Proteins → amino acids.
Cholesterol esters → free cholesterol.
3. Free cholesterol available for cholesterol utilization in cell membranes;
steroids, bile salts. Can accumulate as atheromas.
4. LDL Receptors are synthesized or inhibited, depending on free cholesterol in
the cytoplasm. Intracellular cholesterol feedback:

↑ Free Cholesterol ↓ LDL R

Mediated by HMG Co-A reductase

5. Hepatic cells and tissues in the steroid-producing cells are primarily involved
in this mechanism.

D. Reverse Cholesterol Transport

1. Nascent HDL particles from liver and intestine pick up free cholesterol.
2. Release of HDL is dependent on Apo A-I synthesis (liver and intestine).
3. Free cholesterol is converted to esterified cholesterol within the HDL.
4. Chol. esters transferred to LDL particles which acquire Apo-E in the plasma.
5. LDL and VLDL transport cholesterol to the liver. Mediated by Apo-E.

Figure 4 (from ref. 4)

IV. Pathophysiology
Genetic and acquired forms of hyperlipidemia can occur due to defects in the
endogenous pathway at 5 main sites:
• Increased production of VLDL particles, leading to hypertriglyceridemia.
• Impaired LPL-hydrolysis of TGs, leading to hypertriglyceridemia.
• Defective cellular internalization of lipoproteins, leading to defective removal of
remnants and increased cholesterol and TGs.
• Defective LDL receptors, leading to increased LDL and hypercholesterolemia.
• Defective Apo-B100 impairs binding by LDL-receptor, leading to
hypercholesterolemia.

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V. Secondary Dyslipidemias Caused by:
A. Diabetes:
Proposed mechanism: Normally, secretion of insulin stimulates LPL activity and
fatty acid esterification; insufficient insulin is associated with decreased LPL
activity.
Type 1. Excess production of VLDL and deficiency of LPL. Incr. TGs due to
elevated VLDL (overproduction) and chylomicrons, especially in diabetic
ketoacidosis.
Type 2. Reduced insulin or insulin resistance; obesity. incr. TGs and decr. HDL.
B. Hypothyroidism: Proposed mechanism: Decreased thyroxine down-regulates
LDL-receptors, leading to increased cholesterol.
C. Nephrotic syndrome:
Elevated cholesterol and TGs due to incr. LDL and VLDL.
D. Alcohol abuse with liver disease: increased TGs in VLDL.
E. Drugs that raise LDL-C or cause other dyslipidemias- corticosteroids, anabolic
steroids, progestins, protease inhibitors (Rx in HIV infections).

VI. Metabolic Syndrome

Defined by the ATP III as multiple interrelated factors that increase the risk of
CHD.
Root causes are: obesity; physical inactivity, and genetic factors.
Associated with the following factors:
• insulin resistance (impaired responsiveness of tissues to the normal
action of insulin)
• prothrombotic state
• proinflammatory state
• elevated blood pressure
• atherogenic hyperlipidemia
The individual contribution of each factor to CHD risk is difficult to assess, but
taken together, this syndrome substantially increases the risk regardless of
the LDL-cholesterol level. It is considered to be equally important as cigarette
smoking in contributing to premature CHD.

VII. Clinical Management Issues

• Elevated LDL cholesterol (>100 mg/dL): ATP III guidelines emphasize
more intensive management for lower LDL-cholesterol goal.
• Elevated TGs: Considered by the ATP III to be an independent risk factor
for CHD.
• Primary hyperlipidemias with incr. TGs: Hyperchylomicronemia (types I
and V) and hypertriglyceridemia (IV) are associated with recurrent bouts
of pancreatitis.
• In addition to LDL, elevated Lp(a) and VLDL are atherogenic
• Multiple risks factors: obesity, physical inactivity, cigarette smoking,
excess alcohol, high fat or carb. diet, diabetes, renal failure, drugs.

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VIII. Table 3. Summary of Primary Lipoprotein Disorders. References: 1,7,and 8.

Disorder/ Type/ Metabolic defect Increased Plasma Lipids Clinical Features of
o o
Genetic Defect Population components (mg/dL) after a 12 1 and 2
Frequency hr. fast.

Familial Lipoprotein Lipase I Low or absent LPL. Apo B-48. TGs>10,000. 1°: manifests at early
Deficiency. very rare Impaired removal of TGs. T. cholesterol, mild age; eruptive
Hyperchylomicronemia. Chylomicrons incr. xanthomas.
Singe gene (marked incr.) 2°: pancreatitis
hepatosplenomegaly;
insulinopenic diabetes.
Hypercholesterolemia, IIa LDL
isolated. Three disease Expression: Single gene defects:
forms: Homozygotes, Xanthomas on
1) Familial hyper- rare 1) Defective LDL T. Cholesterol, tendons;eyelids;
cholesterolemia, receptor. > 500. elbows. High risk
heterozygous or Heterozygotes, of CHD.
homozygous. Single T. Cholesterol, 275-
gene. 500.
2) Secondary to defective common 2) Mutant Apo-B100 has Polygenic:
Apo-B. Single gene low affinity for No xanthomas.
receptor. Polygenic form: Affected by diet and
3) Polygenic. Multifactorial. T. cholesterol, inactivity.
Unclear genetic or common 3) Over-production and 250-350. hypothyroid;
metabolic pathogenesis impaired removal. nephrotic syndr;
biliary obstruction.
Familial Combined IIb Incr. VLDL VLDL and LDL; TGs, 250-750. No xanthomas.
Hyperlipidemia. common Manifestations: Apo B100 T.Cholesterol, 250- Obesity; glucose
Two manifestations. Gene 1) Overproduction of 500 resistance.
mutation(s) obscure. hepatic (large) VLDL Incr. risk of
particles. atherosclerosis due to
2) Overproduction of VLDL and LDL.
Apo-B 100 on small
VLDL particles.
Dysbetalipoproteinemia III Apo-E low or absent. Chylomicron TGs 500-1700. Arcus cornea; palmar
rare Defective removal of remnants, T. Cholesterol, 250- xanthomas. Obesity;
Single gene. VLDL. VLDL, and IDL 750. insulinopenic diabetes;
Confirm by Apo-E hypothyroid;
phenotyping. hyperuricemia.
Premature CHD.
Hypertriglyceridemia IV Hepatic VLDL with VLDL TGs 250-750. Obesity; insulinopenic
Gene mutation(s) common abnormally high TGs diabetes; hypothyroid;
obscure. content. estrogen/pregnancy;
nephrotic; alcohol
abuse.
Familial Apo C II deficiency. V LPL, functional Chylomicrons TGs >750. Eruptive xanthomas.
A form of hyper- rare. deficiency. Incr. and VLDL T. cholesterol, Obesity, insulinopenic
chylomicronemia. synthesis/decr. removal 250-350. diabetes;uremia;
Single gene. of chylomicrons and pancreatitis;
VLDL. alcohol abuse.
(Pheno)types refer to the original Frederickson classification of hyperliproteinemias based on descriptions
that included the appearance of the serum, the patterns on liprotein electrophoresis, and the correlation
with various clinical presentations.
Estimates of population frequency: Very Rare, 1/106; Rare, 1/104 ; Common 1/102 to 1/103.

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IX. Laboratory Diagnosis of Hyperlipidemias

A. ATP III-Recommended Limits for Lipids in Adult Fasting Blood (ref. 8)

Plasma or Serum Lipids Optimal, Borderline High risk for

mg/dL High, mg/dL CHD, mg/dL
Total cholesterol < 200 200-239 >240

TGs < 150 150-199 > 200

LDL cholesterol (LDL-C) < 100 130- 159 >160

HDL cholesterol (HDL-C) > 60 < 40

B. ATP III-Recommendations for Screening and Detection:

1. Preferred
• Fasting (12-14 hours) venous blood. Capillary blood not recommended.
• Lipoprotein profile
♦ Total Cholesterol
♦ LDL-C
♦ HDL-C
♦ TGs
• Adults > 20 y.o., fasting lipoprotein profile at least once/5 yrs.

2. Secondary Option
• Non-fasting total cholesterol and HDL-C.
• Proceed to fasting lipid profile if total cholesterol >200 mg/dL or HDL-C
<40 mg/dL.

C. Lipids Measured in the Clinical Laboratory (MUSC Medical Center)

Components measured directly (•) or calculated ():
• Total cholesterol
• TGs
• HDL-C cholesterol
• LDL-C (can also be calculated)
 VLDL = (TGs/5)
 LDL-C: estimation using the Friedewald formula
LDL-C = (Total Cholesterol) - (HDL-C) - (TGs/5)

Limitations of the formula:

1. Estimate of LDL cholesterol based on multiple components.
2. Cannot use if blood sample is non-fasting.
3. Cannot use if TGs >400 mg/dL.

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D. Other tests for lipid measurements
1. Lipoprotein electrophoresis: proteins in an electrophoretic field have
characteristic migration distances related to the amount of protein in the
particles. The major lipoproteins have been named according to their
migration rates: alpha lipoprotein (HDL) is fastest, followed by pre-beta
(VLDL), then by beta lipoprotein (LDL). IDL migrates between pre-beta and
beta, and chylomicrons remain at the origin or point of application.
An agarose gel is typically used in clinical laboratories and a lipid-staining dye
is applied to visualize the positions of the lipoproteins.

Figure 5. Patterns of Lipoproteins in Serum after Electrophoresis on an Agarose Gel.

C, serum containing a mixture of lipoproteins to mark the electrophoretic positions.
N, normal serum. IIa, IIb, III, IV, I, and V: patterns in six hyperlipidemia phenotypes.
Chyl, chylomicrons; α, alpha; β, beta. (-) cathode; (+) anode.

2. Chilled plasma or serum: visual inspection of plasma in a test tube that has
been allowed to stand refrigerated overnight.

1 2 3 4

Figure 6. Photo of four chilled plasma samples. 1. Clear, normal lipids; 2. Chylomicrons above cloudy
plasma; 3. Cloudy ; 4. Clear.

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Figure 7. Laboratory Results in Six Types of Hyperliproteinemia.

(from: Gotto AM, Robertson AL, Epstein, SE, DeBakey, ME,McCollum CH,
Atherosclerosis. A SCOPE Monograph. The Upjohn Co. 1977.)

3. Specialized tests, seldom available in hospital clinical laboratories:

• Apolipoproteins
♦ Apo A (HDL particles)
♦ Apo B (LDL particles)
♦ Apo E
• Lp(a)
• Analytical ultracentrifugal method. The “gold standard” or classical
reference method which defines the lipoproteins in terms of their
flotation rates by ultracentrifugation. Is time-consuming and requires
special equipment; not used in clinical laboratories.

X. Summary
Cholesterol and TGs in blood are transported in lipoproteins, complex particles of
lipids with various specific proteins called apolipoproteins. The five major classes of
lipoproteins and their features include: 1) chylomicrons, transport dietary fat from the
intestine to the liver, adipose and peripheral tissues; 2) VLDL, transport endogenous
triglycerides from the liver to the tissues; 3) IDL, atherogenic products of VLDL
metabolism; 4) LDL, the cholesterol-rich end-products of VLDL which transport
cholesterol from the liver to peripheral tissues; and 5) HDL, disc-like particles secreted
by liver into the circulation to bring cholesterol from the tissues to the liver. These
various particles are in a dynamic state exchanging lipids and proteins from one to
another. The functionality of apolipoproteins B and E and their receptors are important
in determining the rate of clearance of lipoproteins from the plasma. Lp(a), one of the

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apo B-containing lipoproteins, comprises the sixth class of lipoproteins and is
synthesized in the liver. While its metabolism is not well understood, the structural
similarity of Lp(a) to plasminogen may explain its coronary atherogenic properties and
role in cardiovascular disease.
Hyperlipidemias result from derangements in the synthesis and/or metabolism of
lipoproteins and can increase the risk of CHD, pancreatitis, and vascular disease.
These disorders have been classified into six types based on the levels of cholesterol
and triglycerides, the electrophoretic distribution of the lipoproteins, and the
appearance of plasma. While this classification helps to correlate laboratory findings
and clinical disease syndromes, the six types do not correspond to specific diseases. In
fact, different patients with the same condition may manifest as different types. The
hyperlipidemias may result from rare genetic defects or, more often, from secondary
disorders such as diabetes, hypothyroidism, obesity, alcoholism, and renal disease.
Primary and secondary causes can co-exist, and a genetic cause can be worsened by
the presence of a secondary disorder.
The rare familial hyperchylomicronemia disorders (types I and V) are due to LPL
deficiencies and are further characterized by elevated TGs, xanthomas, and
pancreatitis. Familial hypercholesterolemia (type IIa) with the hallmarks of xanthomas
and markedly elevated cholesterol, is due to the impaired removal of LDL because of
functionally defective LDL receptors, a reduced number of LDL receptors, or defective
Apo B. One of the more common as well as complex disorders, familial combined
hyperlipidemia (type IIb), is characterized by moderately elevated TGs and cholesterol
and involves “polygenic” factors, which means that the genetic and/or metabolic
pathogenesis is not clear. The rare familial dysbetalipoproteinemia (type III) is
characterized by cholesterol deposits in the palmar creases, by increased VLDL and
IDL which are not cleared due to defective apo E, and by triglycerides and cholesterol
being moderately elevated at approximately equal levels. Familial hypertriglyceridemia
(type IV) is due to the overproduction and decreased metabolism of VLDL, however the
underlying defect is not clear.
Although screening adults for hypercholesterolemia is important for public
awareness and education of CHD risk and prevention, lipid profile testing is essential for
individuals who have: 1) a family history of premature CHD or hyperlipidemia; 2)
xanthomata ; 3) a diagnosis of diabetes, hypothyroidism, chronic renal failure,
hypertension, chronic abdominal pain, or liver disease; 4) been using certain drugs such
as progestins and steroids ; 5) life-style risk factors including cigarette smoking, obesity,
and inactivity. The diagnosis of primary hyperlipidemia is supported when secondary
causes ( primarily 3-5, above) can be excluded and if there is a family history to support
the former.
Familial, pathological, and epidemiological studies have demonstrated the strong
relationship between the increased risk of CHD and the accumulation of LDL
cholesterol. Increased TGs are now considered to be an independent risk factor and
also are a recognized cause of pancreatitis. The NCEP Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) recently issued
revised guidelines calling for more intensive (compared with ATP I and II) goals:
lowering LDL-C to <100 mg/dL, lowering TGs to <150 mg/dL, increasing HDL-C to >60
mg/dL, and emphasizing primary prevention of CHD in individuals with multiple risk
factors or with diabetes. The metabolic syndrome, increasingly common in the US, is
characterized by several metabolic risk factors in one individual: 1) abdominal obesity,
2) atherogenic dyslipidemia, 3) hypertension, 4) insulin resistance, 5) prothrombotic
state and 6) proinflammatory states. The ATP III places increased emphasis on the
metabolic syndrome as an enhancer of the risk for CHD at any LDL-cholesterol level.

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With the increasing awareness of hyperlipidemia as a health risk factor, the trend
towards risk-reduction and the introduction of effective treatments for hyperlipidemia
have resulted in a steady increase of lipid profile testing to include total cholesterol,
LDL-C, HDL-C, and TGs. Patients should be fasting and in a steady state of
metabolism and activity to obtain the most representative test results. However, when a
patient is hospitalized for a major coronary event or procedure, a lipid profile should be
measured on admission or within 24 hours. The results can be used for treatment
decisions and to motivate the patient (avoid the “treatment gap”) to follow risk-lowering
interventions. Although a diagnosis can be inferred for most patients from their history,
clinical presentation, and fasting blood lipid profile, specialized laboratory tests may be
needed to confirm rare familial hyperlipidemias.

Case Studies and Study Questions:

1. Hx and P.E.: A 39 y.o. man visited an optician for reading glasses. The optician
noticed that the man had arcus cornea bilaterally and recommended that he consult
his family physician. The physician found tendon xanthomata arising from the
Achilles tendons. The patient’s blood pressure was normal; he was not a smoker
and was less than 10 pounds over ideal weight. His father had died of a heart attack
at age 42. An ECG at rest was normal but ischemic changes developed on exercise
stress.
Lab results: Fasting basic metabolic chemistries (Na, K, Cl, CO2, glucose, urea,
creatinine, and calcium) were within reference limits; total cholesterol, 507 mg/dL;
triglycerides, 114 mg/dL.

2. Hx and P.E.: A 45 y.o. man was referred by his family physician to a dermatologist
because of extensive yellowish papules on his elbows. The dermatologist
recognized these as eruptive xanthomata and also noticed there were yellow fatty
streaks in the palmar creases. After an overnight fast, blood was drawn for lipid
profile and lipoprotein electrophoresis. Lab results: total cholesterol, 396 mg/dL;
triglycerides, 403 mg/dL; the lipoprotein electrophoresis pattern showed a densely
stained “broad” band (confluent pre-beta and beta zones).

Study questions for each case:

1. What additional information would you obtain after seeing the concentrations of
cholesterol and triglycerides?

2. Based on the information you have at this time, what is the most likely diagnosis?

3. What levels of HDL cholesterol and LDL cholesterol would you expect in each
case?

4. The broad pre-beta and beta staining, seen in the serum electrophoresis of case 2,
is due to an increased production of ______________particles?

5. For each case, what mechanisms or metabolic defects would you use to explain the
physical and laboratory findings?

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