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Hypertriglyceridemia
Updated: Jun 20, 2018
Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP
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OVERVIEW

Practice Essentials
Hypertriglyceridemia, a condition in which triglyceride levels are elevated, is a common
disorder in the United States. It is often caused or exacerbated by uncontrolled diabetes
mellitus, obesity, and sedentary habits, all of which are more prevalent in industrialized
societies than in developing nations. In epidemiologic and interventional studies,
hypertriglyceridemia is a risk factor for coronary artery disease (CAD).

Hyperlipoproteinemia is a metabolic disorder characterized by abnormally elevated

concentrations of specific lipoprotein particles in the plasma.

Hyperlipidemia (ie, elevated plasma cholesterol or triglyceride levels or both) is present in

all hyperlipoproteinemias. The primary form includes chylomicronemia,
hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia, mixed
hyperlipoproteinemia, and combined hyperlipoproteinemia. Other diseases, such as
diabetes mellitus, pancreatitis, renal disease, and hypothyroidism, cause the secondary
form.

Signs and symptoms

Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-

2000 mg/dL. Signs and symptoms may include the following:

GI: Pain in the mid-epigastric, chest, or back regions; nausea, vomiting

 Respiratory: Dyspnea

Dermatologic: Xanthomas

Ophthalmologic: Corneal arcus, xanthelasmas

See Clinical Presentation for more detail.

Diagnosis

On examination, findings may be normal, or they may include the following:

GI: Tenderness to palpation over mid-epigastric or upper right/left quadrants;

hepatomegaly

Dermatologic: Eruptive xanthomas on back (see the image below), buttocks, chest,
proximal extremities; palmar xanthomas in dysbetalipoproteinemia

Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute
pancreatitis.

Cardiovascular: Decreased pedal pulses or ankle/brachial index in presence of

peripheral vascular disease

Ophthalmologic: Corneal arcus, lipemia retinalis, xanthelasmas [1]

Neurologic: Memory loss, dementia, and depression in the presence of

 chylomicronemia syndrome

Testing

Laboratory studies used to evaluate hypertriglyceridemia include the following:

Lipid analysis

Chylomicron determination

Fasting blood glucose level

TSH level

Urinalysis

Liver function studies

Procedures

If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious

lesions will reveal accumulations of fat (not cholesterol). A biopsy of cutaneous lesions
suspected to be either planar or tuberous xanthomas will reveal cholesterol deposition.

See Workup for more detail.

Fredrickson classification

Hyperlipidemia has been defined by the Fredrickson classification, which is based on

beta-quantification, a process involving ultracentrifugation followed by electrophoresis. [2]
In this system, shown in Table 1, below, all categories except type IIa are forms of
hypertriglyceridemia.

Table 1. Fredrickson Classification of Hyperlipidemia (Open Table in a new window)

Type Serum Elevation Lipoprotein Elevation

I Cholesterol and triglycerides Chylomicrons

IIa Cholesterol LDL

 IIb Cholesterol and triglycerides LDL, VLDL

III Cholesterol and triglycerides IDL

IV Triglycerides VLDL

V Cholesterol and triglycerides VLDL, chylomicrons

IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-

density lipoprotein.

Source: Fredrickson DS, Lees RS. A system for phenotyping hyperlipidaemia.

Circulation. Mar 1965;31:321-7. [2]

Type I is a rare disorder characterized by severe elevations in chylomicrons and

extremely elevated triglycerides, always reaching well above 1000 mg/dL and not
infrequently rising as high as 10,000 mg/dL or more. It is caused by mutations of either the
lipoprotein lipase gene (LPL), which is critical for the metabolism of chylomicrons and very
low-density lipoprotein (VLDL), or the gene's cofactor, apolipoprotein (apo) C-II.

Counterintuitively, despite exceedingly high elevations of triglyceride and, in some cases,

of total cholesterol, these mutations do not appear to confer an increased risk of
atherosclerotic disease. This fact may have contributed to the unfounded belief that
hypertriglyceridemia is not a risk factor for atherosclerotic disease. Although chylomicrons
contain far less cholesterol than other triglyceride-rich lipoproteins do, when serum
triglyceride levels are severely elevated, cholesterol levels can also be quite high.

Type IIb is the classic mixed hyperlipidemia (high cholesterol and triglyceride levels),
caused by elevations in low-density lipoprotein (LDL) and VLDL.

Type III is known as dysbetalipoproteinemia, remnant removal disease, or broad-beta

disease due to an individual’s decreased ability to convert VLDL and intermediate-density
lipoprotein (IDL), a VLDL remnant, to LDL particles in the blood and because of a
decreased clearance of chylomicron remnants. [3] Typically, patients with this rare
condition have elevated total cholesterol (range, 300 600 mg/dL) and triglyceride levels
(usually >400 mg/dL; may exceed 1000 mg/dL), [2] and these individuals are easily
confused with patients with type IIb hyperlipidemia. Patients with type III hyperlipidemia
have elevations in IDL.

Dysbetalipoproteinemia is the result of 2 "hits." [3] First, most affected individuals are
homozygous for the apo E isoform, apo E2. Second, affected individuals usually have a
metabolic disorder such as diabetes, obesity, or hypothyroidism. Consequently, those who
are homozygous for apo E2 have a 1-2% risk of developing dysbetalipoproteinemia, and
they are at high risk for atherosclerotic cardiovascular and peripheral vascular disease. [3]
The condition responds well to treatment of the causative medical condition and to lipid-
lowering medications.

Type IV is characterized by abnormal elevations of VLDL, and triglyceride levels are

almost always less than 1000 mg/dL. Serum cholesterol levels are normal.

Type V is characterized by elevations of chylomicrons and VLDL. Triglyceride levels are

invariably greater than 1000 mg/dL, and total cholesterol levels are always elevated. The
LDL cholesterol level is usually low. Given the rarity of type I disease, when triglyceride
levels above 1000 mg/dL are noted, the most likely cause is type V hyperlipidemia.

Triglyceride levels greater than 1000 mg/dL increase the risk of acute pancreatitis, and
because triglycerides are so labile, levels of 500 mg/dL or greater must be the primary
focus of therapy. If a patient also has a high risk for a cardiovascular event, LDL-lowering
therapy should be considered.

Management

Nonpharmacotherapy

Nonpharmacologic management of hypertriglyceridemia is generally the initial treatment

for patients with this condition. This primarily involves lifestyle modifications such as diet,
exercise, weight reduction, smoking cessation, and limiting alcohol intake.

Pharmacotherapy

Medications used in the management of hypertriglyceridemia include the following:

Fibric acid derivatives (eg, gemfibrozil, fenofibrate)

Niacin (slow-release, immediate-release, extended-release formulations)

Omega-3 fatty acids (eg, omega-3-acid ethyl esters)

HMG-CoA reductase inhibitors (eg, atorvastatin, fluvastatin, pitavastatin, pravastatin,

lovastatin, simvastatin, rosuvastatin)

Surgical option

In general, surgical intervention is not necessary to treat hypertriglyceridemia.

Plasmapheresis can be used in the setting of severe hypertriglyceridemia to reduce
triglycerides in the acute setting. Ileal bypass surgery has been shown to improve all lipid
parameters but should be reserved for severe hypertriglyceridemia refractory to all
treatment.

See Treatment and Medication for more detail.

Pathophysiology
Triglycerides

Triglycerides are fats consisting of 3 fatty acids covalently bonded to a glycerol molecule.
These fats are synthesized by the liver or, in the case of those derived from dietary
sources, are ingested by the liver (as described below); the triglycerides are subsequently
transported throughout the circulation by triglyceride-rich lipoproteins.

By dry weight, triglycerides make up approximately 86%, 55%, and 23% of chylomicrons,
very low-density lipoproteins (VLDLs), and intermediate-density lipoproteins (IDLs),
respectively, [4] as represented in the image below. Triglycerides are present in low-
density lipoprotein (LDL) and high-density lipoprotein (HDL), but in much smaller
quantities of 10% or less.

The following image shows composition of triglyceride-rich proteins.

Composition of triglyceride (TG)-rich lipoproteins. IDL = intermediate-density lipoprotein; VLDL = very low-
density lipoprotein.

Triglyceride-rich lipoproteins come from 2 sources, often described as the endogenous

and exogenous pathways. In the exogenous pathway, dietary fats (triglycerides) are
hydrolyzed to free fatty acids (FFAs) and monoglycerides and are absorbed, with
cholesterol, by intestinal cells. They are then reesterified and combined with
apolipoproteins and phospholipids to form a nascent chylomicron, a process requiring
microsomal triglyceride transfer protein (MTP). The initial apolipoproteins are
apolipoprotein (apo) A, which are soluble and can transfer to HDL; and apo B48, a
structural apolipoprotein that is not removed during catabolism of the chylomicron.
Chylomicrons enter the plasma via the thoracic duct, where they acquire other soluble
apolipoproteins, including apo CI, apo CII, apo CIII, and apo E, from HDL.

VLDLs and apolipoproteins

VLDLs are produced by a process analogous to the exogenous pathway. Triglycerides

may derive from de novo FFA synthesis in the liver and are metabolized by lipoprotein
lipase to IDL, also called VLDL remnants. Lipoprotein lipase hydrolyzes triglycerides,
releasing FFAs, which are taken up by myocytes and hepatocytes. Some apo Cs,
phospholipids, and apo Es are lost, and triglycerides are transferred to HDL in exchange
for cholesterol esters. IDL is, thus, cholesterol-enriched and triglyceride-poor compared to
unmetabolized VLDL. As IDL is metabolized by hepatic lipase to LDL, the remaining
surface apolipoproteins are lost. [5, 3, 6]

Triglycerides may also derive from the uptake of remnant chylomicrons, VLDL, or FFAs
from the plasma. Precursor VLDL combines triglycerides, the structural or transmembrane
apo B100, and phospholipids, as well as cholesterol and some apo Cs and Es. The
formation of the immature VLDL requires microsomal transfer protein (MTP). Once
secreted into the plasma, VLDLs acquire more apo Cs and Es.

Apo Es

ApoEs are ligands that have greater affinity for the LDL receptor than does apo B100. In
fact, the LDL receptor is more accurately designated the B/E receptor. Apo E also binds
with high affinity to the LDL receptor-related protein, which takes up chylomicron
remnants, VLDL, and IDL. In addition, apo E binds to cell-surface heparan sulfate
proteoglycans (HSPGs), which assists in the hepatic uptake of remnant lipoproteins. [3]

The apo E gene has been cloned, sequenced, and mapped to chromosome 19.
Genetically altered apo E–deficient mice develop severe dyslipidemia with accelerated
atherosclerosis, whereas transgenic mice overexpressing apo E appear to be protected
from atherosclerosis. [7, 8] Apo E has 3 isoforms that are present in slightly varying
proportions, depending on race and geographic location. [5] Apo E3 is the most prevalent
allele and for that reason was considered the “wild type” allele from which apo E2 and apo
E4 were derived. Newer data, however, suggest that apoA4 was the earliest form of the
protein. [9]

Most animals, including primates, possess an apo E4 equivalent. [10] Compared with apo
E3, apo E2 has less affinity for the receptor, and apo E4 has more. The alleles differ in 2
amino acid positions, 112 and 158. Apo E2 is most commonly caused by cysteine
substituted for arginine at position 158 in apo E3. In apo E4, an arginine is substituted for
cysteine at position 112 in apo E3. The substitutions are recessive in that
dysbetalipoproteinemia requires the presence of 2 apo E-2 isoforms. [10] Other very rare
genetic variants of apo E exist, and several of these have been shown to have defective
binding to the LDL receptor and LDL receptor-like protein. These variants act in a
dominant fashion in that only 1 copy of apo E is necessary for susceptibility to
development of type III hyperlipidemia.

white populations, approximately 1% of these individuals are homozygous for apo E2

(“first hit”); however, only 10% of those will develop the condition. A “second hit” is
necessary, most commonly metabolic abnormalities that cause increases in VLDL. [3]
Other, less common genetic conditions can also predispose people to
dysbetalipoproteinemia.

More than 90% of patients with dysbetalipoproteinemia are homozygous for apo E2; the
remainder have a rare, usually dominant, defect in apo E2. In addition to the apoE2
homology or defect, and combined with a metabolic condition, other genetic factors have
been suggested that increase the likelihood of developing dysbetalipoproteinemia.
Polymorphisms in the apo A5, lipoprotein lipase and apo C3 have all been mentioned as
possible cofactors for the condition. [5]

Accumulation of IDL is caused by the poor affinity of apo E2 to LDL receptors, whereas
LDL uptake via apo B100 is unaffected. In fact, total cholesterol, LDL cholesterol, and apo
B are usually low compared with those with apo E3. HDL cholesterol levels may be
normal or decreased. The following 3 mechanisms have been postulated for the
hypocholesterolemic effect of apo E2 [11] :

Increased upregulation of LDL receptors due to decreased binding of lipoproteins

containing apo E2

Increased hepatic LDL uptake due to lower LDL receptor affinity of apo E2 and
consequent decreased competition with the apo B100 born by LDL (its sole
apolipoprotein)

Apo E2 interference with lipolysis of VLDL to LDL [3]

Chylomicron and VLDL metabolism

Any disturbance that causes increased synthesis of chylomicrons and/or VLDLs or

decreased metabolic breakdown causes elevations in triglyceride levels. That disturbance
may be as common as dietary indiscretion or as unusual as a genetic mutation of an
enzyme in the lipid metabolism pathway. Essentially, hypertriglyceridemia occurs through
1 of the following 3 processes [12] :

Abnormalities in hepatic VLDL production, and intestinal chylomicron synthesis

Dysfunctional lipoprotein lipase -mediated lipolysis

Impaired remnant clearance

As shown in the images below, chylomicrons and VLDLs are initially metabolized by
lipoprotein lipase, which hydrolyzes the triglycerides, releasing FFAs; these FFAs are
stored in fat and muscle. With normal lipoprotein lipase activity, the half-lives of
chylomicrons and VLDLs are about 10 minutes and 9 hours, respectively. Because of the
large size of unmetabolized chylomicrons, they are unlikely to be taken up by
macrophages, which are the precursors of foam cells. Foam cells promote fatty streak
formation, the precursor of atherosclerotic plaque. Lipoprotein lipase activity produces
chylomicron remnants that are small enough to take part in the atherosclerotic process.
Chylomicron remnants are taken up by the LDL receptor or the LDL receptor-related
protein. [13]

Lipoprotein lipase (LPL) releases free fatty acids (FFAs) from chylomicrons (chylo) and produces chylomicron
remnants that are small enough to take part in the atherosclerotic process. Chol = cholesterol; TGs, TGS =
triglycerides.
Once very low-density lipoprotein (VLDL) has been metabolized by lipoprotein lipase, VLDL remnants in the
form of intermediate-density lipoprotein (IDL) can be metabolized by hepatic lipase, producing low-density
lipoprotein (LDL), or they can be taken up by the LDL receptor via either apolipoprotein B (apo B) or apo E.
Chol = cholesterol; TGs = triglycerides.

VLDL remnants have 1 of 2 fates: they can be metabolized by hepatic lipase, which
further depletes triglycerides, producing LDL, or they can be taken up by the LDL receptor
via either apo B or apo E. VLDL remnants are not only triglyceride-poor, they are also
cholesterol enriched, having acquired cholesterol ester from HDL via the action of
cholesterol ester transfer protein (CETP), which facilitates the exchange of VLDL
triglycerides for cholesterol in HDL. This pathway may promote HDL's reverse cholesterol
transport activity, but only if VLDL and LDL return cholesterol to the liver. If these
lipoproteins are taken up by macrophages, the CETP transfer results in increased
atherogenesis.

Chylomicron remnants, VLDL, VLDL remnants, and LDL are all atherogenic.

Etiology
Hypertriglyceridemia has many causes, including familial and genetic syndromes,
metabolic disease, and drugs. Risks appear to include diet, stress, physical inactivity, and
smoking.

CHD risk factors

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)
identifies the 2 or more of the following as risk factors for coronary heart disease (CHD)
that can lead to the need for more aggressive intervention [13] :

Older age: In men, age 45 years or older, whereas in women, 55 years or older; the
incidence of CHD is higher in the elderly than the young and in men more than
women of the same age

Family history of premature CHD: Paternal or male primary relative with myocardial
infarction (MI) before age 55 years or sudden death, or in maternal or female
primary relative before age 65 years

Active tobacco use

Hypertension: Blood pressure higher than 140/90 mm Hg or current use of

antihypertensive agents

Low level of high-density lipoprotein (HDL) cholesterol: Lower than 40 mg/dL

Genetic causes

Abnormalities of the enzyme pathway for chylomicron metabolism are the best-
characterized genetic causes of hypertriglyceridemia. Lipoprotein lipase deficiency and
apo C-II deficiency are caused by homozygous autosomal recessive genes present at
conception.

Type I hyperlipoproteinemia is the best-characterized genetic cause of

hypertriglyceridemia and is caused by a deficiency or defect in either the enzyme
lipoprotein lipase or its cofactor, apo C-II. Lipoprotein lipase hydrolyzes triglycerides in
chylomicrons and very low-density lipoprotein (VLDL), releasing free fatty acids. The
enzyme is found in the endothelial cells of capillaries and can be released into the plasma
by heparin. Lipoprotein lipase is essential for the metabolism of chylomicrons and VLDL,
transforming them into their respective remnants. Apo C-II, an apolipoprotein present in
both chylomicrons and VLDL, acts as a cofactor in the action of lipoprotein lipase.

The above pathway is affected by other genetic disorders, particularly type 1 or type 2
diabetes, because lipoprotein lipase requires insulin for full activity. That is, a secondary
cause of hyperlipidemia, “second hit,” must be present for the dysbetalipoproteinemia to
develop. In addition, the patient may be taking medications, such as protease inhibitors or
tricyclic antidepressants, that exacerbate hyperlipidemia.

Two more recently described syndromes include mutations in ApoAV leading to a

truncated ApoAV devoid of a lipid-binding domain and glycosylphosphatidylinositol-
anchored HDL-binding protein 1 (GP1HBP1) causing decreased binding to LPL and
reduced hydrolysis of chylomicrons. [14]

Genetic predisposition for dysbetalipoproteinemia is present in approximately 1% of the

population, but only 1-2% of individuals with apolipoprotein (apo) E-2 actually develop this
condition. More than 90% of patients with dysbetalipoproteinemia are homozygous for
apo E2. Extremely rare forms are associated with other genetic mutations in the apo E
gene or the complete absence of apo E.

Familial combined hyperlipidemia and familial hypertriglyceridemia

Two triglyceride disorders, familial combined hyperlipidemia and familial

hypertriglyceridemia, are genetically controlled, but the mechanisms are not clearly
defined but are likely associated with overproduction and decreased of apo B–containing
particles.

Familial combined hyperlipidemia is an autosomal dominant disorder characterized by

patients and their first-degree relatives who may have either isolated triglyceride or low-
density lipoprotein (LDL) cholesterol elevations or both. Diagnosis of the disorder in a
particular patient requires a family history of premature coronary artery disease (CAD) in 1
or more first-degree relatives and a family history for elevated triglycerides with or without
elevated LDL cholesterol levels. The diagnosis is important for prognosis; 14% of patients
with premature CAD have familial combined hyperlipidemia. [15]

Familial hypertriglyceridemia is also an autosomal dominant trait. [16] These patients and
their families have isolated triglyceride elevations and may have an increased risk of
premature CAD.

Genetic susceptibility factor effects

Known genetic susceptibility factor effects account for approximately 10-15% of the trait
variances in blood lipid levels (LDL cholesterol, HDL cholesterol, triglycerides). [17]
Genome-wide association studies (GWAS) have identified several loci associated with
blood lipid traits, including hypertriglyceridemia. [18]

Hypertriglyceridemia is associated with several genes (in aggregate) including apoAV,

GCKR, LPL, and APOB. [19] Patients with single nucleotide polymorphisms (SNPs) 40
kilobases (kb) from TRIB1 (a gene known to be strongly associated with dyslipidemia)
have abnormal levels of triglycerides, as well as HDL cholesterol and LDL cholesterol. [20]
In a large study of Japanese and Korean individuals, investigators reported that genetic
variants of APOA5 (-1131T→C polymorphism [rs662799]) and BTN2A1 (C→T
polymorphism [rs6929846]) synergistically affect the prevalence of dyslipidemia in East
Asian populations and metabolic syndrome in Japanese individuals. [21]

Certain genetic variants can further predispose a patient with hypertriglyceridemia and
certain environmental factors to consequences, such as CAD and MI. For example, the
genetic variant R952QP of LRP8 (a gene at 1p31-32 that is associated with familial and
premature CAD as well as high-level platelet activation) is associated with high
triglyceride levels in patients who are have a history of being overweight, smoke, and
have premature CAD/MI. [22]

Metabolic causes

Uncontrolled diabetes mellitus, both type 1 and type 2, is one of the most common causes
of hypertriglyceridemia, and it is often severe in patients presenting with ketosis. Patients
with type 1 diabetes mellitus are insulin deficient, and lipoprotein lipase is largely
ineffective. Control of these patients' diabetes mellitus with insulin will restore lipoprotein
lipase function, reducing triglyceride levels and restoring diabetes mellitus control.

In patients with uncontrolled type 2 diabetes mellitus and hyperinsulinemia, triglycerides

are elevated for several reasons, including the following:

Lipoprotein lipase is less effective in the insulin-resistant state

Overproduction of VLDL by the liver is common in patients with diabetes who are
often overweight
 Diabetes mellitus is one of the conditions that leads to incomplete metabolism of
VLDL, causing increased remnant VLDL or IDL observed in dysbetalipoproteinemia
(see Dysbetalipoproteinemia).

Mild to moderate elevations in triglycerides are common in obese patients, largely

secondary to reduced efficacy of LPL and overproduction of VLDL.

Hypothyroidism commonly causes LDL cholesterol elevations, but it also may lead to
mixed hyperlipidemia or isolated triglyceride elevations. Reduced hepatic lipase activity
slows VLDL remnant catabolism. As with diabetes mellitus, untreated hypothyroidism may
cause dysbetalipoproteinemia in patients with homozygous apo E-2.

Nephrotic syndrome is thought to increase hepatic synthesis of VLDL and may also slow
catabolism of both LDL and VLDL. As in hypothyroidism, elevated LDL cholesterol levels
are more common in this condition, but mixed hyperlipidemia or isolated triglyceride
elevations may be observed. Higher levels of proteinuria are correlated with more severe
hyperlipidemia.

Drugs

Medications that can cause hypertriglyceridemia include the following:

High-dose thiazide diuretics or chlorthalidone

High-dose beta-adrenergic blocking agents, excluding those with intrinsic

sympathomimetic activity

Unopposed oral estrogen replacement therapy

Oral contraceptives with high estrogen content

Tamoxifen

Glucocorticoids

Oral isotretinoin

Antiretroviral therapy (including some protease inhibitors, nonnucleoside reverse

transcriptase inhibitors)

Atypical antipsychotics

Other causes

Excessive alcohol intake and high-carbohydrate diets (>60% of caloric intake) are
frequent causes of hypertriglyceridemia.
Acute pancreatitis may cause substantial elevations in triglycerides by unknown
mechanisms. However, much more frequently, severe hypertriglyceridemia causes acute
pancreatitis. In patients presenting with acute pancreatitis and triglycerides greater than
1000 mg/dL, it is prudent to not assume that the triglycerides are the cause of the
pancreatitis. Other causes, such as common bile duct obstruction and alcoholism, must
be considered as possible etiologies.

A study by Zhang et al indicated that obesity and uric acid elevation have a strong additive
interaction that increases the risk for nonalcoholic fatty liver disease and
hypertriglyceridemia. The interaction was reportedly responsible for 27% and 26% of the
expanded hypertriglyceridemia risk in men and women, respectively. [23]

In pregnant patients with a history of mildly to moderately elevated triglycerides in the

nonpregnant state, hypertriglyceridemia (sometimes severe) may occur. Such patients
should be monitored closely, particularly in the third trimester. In fact, simply looking for
laboratory notation of lipemic serum in routine blood tests during pregnancy will avoid
unexpected complications resulting from unrecognized and untreated hypertriglyceridemia
during pregnancy.

Epidemiology
United States statistics

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)
defined elevated triglycerides as 150 mg/dL and higher. [13] Using that criterion, the Third
National Health and Nutrition Examination Survey (NHANES) found that the prevalence of
hypertriglyceridemia in US adults aged 20 years and older was approximately 35% in men
and 25% in women. Triglyceride levels in black men and women were 21% and 14%,
respectively; 40% and 35% in Mexican American men and women, respectively; and in
37% and 25% in white American men and women, respectively. [24]

In black individuals, the frequency of the alleles for apolipoprotein (apo) E2 is 12%; apo
E3, 65%; and apoE4, 23%; in the white population, the frequencies are approximately
13%; 76%; and 11%, respectively. [10] The frequency of homology for apo E2 is 1.3%, but
because of the necessary "second hit," only about 5% of homologous individuals have
overt hyperlipidemia. [10]

Prevalence of severe hypertriglyceridemia, defined as triglycerides greater than 2000

mg/dL, is estimated to be to be 1.8 cases per 10,000 white adults, with a higher
prevalence in patients with diabetes or alcoholism. [13] The most severe form of
hypertriglyceridemia, lipoprotein lipase deficiency, occurs in approximately 1 case per 1
million; the frequency of apo C-II deficiency is even lower. The frequency of
dysbetalipoproteinemia is less than 5 persons per 5,000 in the overall population. [10]

International statistics

Hyperlipoproteinemia has a high frequency in developed countries. The worldwide

incidence of lipoprotein lipase deficiency is similar to that in the United States with the
exception of small populations—such as in Quebec, Canada, where the number is
significantly higher, probably due to the founder effect. Apo C-II deficiency is infrequent in
all populations studied to date.

Globally, the frequency of all 3 major apoE alleles varies by racial group. The incidence of
the apo E2 allele, however, is always far lower than that of the apo E3 allele. Frequencies
as low as 4.1% and 4.6% were found in Finland and in Singhalese of Indian descent,
respectively. [10] In addition to the US, the highest frequencies were found in New Zealand
(12.0%) and in Malaysian Singhalese (11.4%). Frequencies in other populations ranged
from 6.1% (Iceland) to 9.7 (Chinese Singhalese). [10]

Race-, sex-, and age-related demographics

As noted above, although the frequency of apo E2 varies somewhat by race, the
prevalence of dysbetalipoproteinemia appears to be similar among races. The racial
differences are a consequence not only of apo E2 frequency but also of the prevalence of
the metabolic abnormalities necessary to cause dysbetalipoproteinemia.

Nonhispanic blacks often have lower triglyceride levels, possibly related to an increase in
LPL activity. [25] Racial predisposition has not been described for lipoprotein lipase
deficiency or apo CII deficiency.

In the Prospective Cardiovascular Munster study (PROCAM), a large observational study,

mild hypertriglyceridemia (triglycerides >200 mg/dL) was more prevalent in men (18.6%)
than in women (4.2%). [26] Genetic mutations in both lipoprotein lipase and apo CII affect
males and females in equal numbers.

Dysbetalipoproteinemia primarily affects older adults and is rare in children and

premenopausal women. However, in the United States and some other Western
populations, the increasing incidence of childhood obesity and type 2 diabetes may
presage the emergence of dysbetalipoproteinemia in children. Estrogen improves the
clearance of very low-density lipoprotein (VLDL) remnants, and estrogen treatment
appears to improve dysbetalipoproteinemia in some postmenopausal women.

Triglycerides increase gradually in men until about age 50 years and then decline slightly.
In women, they continue to increase with age. Mild hypertriglyceridemia (triglycerides
>150 mg/dL) is slightly more prevalent in men beginning at age 30 years and women
starting at age 60 years. [14, 24]
The manifestations of lipoprotein lipase and apo C-II deficiency (severe
hypertriglyceridemia) are usually detected in childhood, although defective apo C-II
sometimes presents in early adulthood.

Prognosis
Patients with hyperlipidemia are at extremely high risk of developing premature coronary
artery disease (CAD) (30%). [27] If the disease is inadequately managed, the prognosis is
poor, especially if other cardiovascular risk factors are present. If the patient complies with
lipid-lowering therapy, dietary modification, and lifestyle modification and if therapy is
successful, outcome is improved significantly.

Cardiovascular disease

Hypertriglyceridemia is correlated with an increased risk of cardiovascular disease (CVD),

particularly in the setting of low high-density lipoprotein (HDL) cholesterol levels and/or
elevated low-density lipoprotein (LDL) cholesterol levels. When low HDL cholesterol levels
are controlled for, some studies demonstrate that elevated triglycerides do not correlate
with risk of CVD. Others suggest that high triglyceride levels are an independent risk
factor.

Because metabolism of the triglyceride-rich lipoproteins (chylomicrons, very low-density

lipoprotein [VLDL]) and metabolism of HDL are interdependent and because triglycerides
are very labile, the independent impact of hypertriglyceridemia on CVD risk is difficult to
confirm. However, randomized clinical trials using triglyceride-lowering medications have
demonstrated decreased coronary events in both the primary and secondary coronary
prevention populations.

An understanding of lipoprotein catabolism provides an explanation for the absence of

increased risk of CVD in patients with the most severe form of hypertriglyceridemia, type I
hyperlipoproteinemia. The atherogenicity correlated with elevated triglyceride levels is
thought to be secondary to increased levels of chylomicron and VLDL remnants.
Remnants are smaller, richer in cholesterol, and more readily taken up by macrophages,
which are converted to plaque-forming foam cells. The chylomicrons in patients with type I
disease cannot be converted to remnants and, therefore, should not be atherogenic.

Pancreatitis

Extreme elevations of triglycerides, usually well above 1000 mg/dL, may cause acute
pancreatitis and all the sequelae of that condition. (A study by Pedersen et al indicated
that even nonfasting mild to moderate hypertriglyceridemia [177 mg/dL or above] raises
the risk for acute pancreatitis; the investigators found, for example, the multivariable
adjusted hazard ratio for acute pancreatitis to be 2.3 for persons with triglyceride levels of
177-265 mg/dL. [28] ) However, many patients tolerate triglycerides of 4000 mg/dL or
higher without developing symptoms. [29]

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)
guidelines indicate that triglycerides are so labile that a level between 500 and 1000
mg/dL may in certain settings increase dramatically and should be a target of treatment
even before ensuring that the LDL goal is reached. [13] Thus, these guidelines stipulate
that if triglycerides are 500 mg/dL or greater, the initial management should be to lower
the triglycerides to prevent pancreatitis. Only when the triglyceride level is below 500
should LDL-lowering be addressed.

The risk of recurrent pancreatitis secondary to hypertriglyceridemia can be avoided

entirely by ensuring that levels are maintained well below 700 mg/dL. Because triglyceride
levels are so labile, simply moderating levels to less than 1000 mg/dL does not decrease
risk substantially, because the slightest metabolic imbalance or dietary indiscretion may
push levels several hundred points higher.

Chylomicronemia syndrome

The chylomicronemia syndrome [30, 31] is an often unrecognized and less severe condition
than pancreatitis that is usually caused by triglyceride levels greater than 1000 mg/dL.
Recurrent episodes of ill-defined abdominal pain that may be accompanied by nausea
and vomiting are the most common presenting symptom, but chest pain and dyspnea may
sometimes occur. A papular rash may be present on the trunk, thighs, and buttocks, which
resolves with treatment. Amylase and lipase are minimally, if at all, elevated. Symptoms
resolve when triglyceride levels decrease well below 1000 mg/dL.

Patient Education
Patients often do not understand that triglycerides are a blood lipid that may be analyzed
along with cholesterol. They should be informed about the risks of hypertriglyceridemia,
including the increased risk of a cardiovascular event and risk of pancreatitis if levels are
close to or above 1000 mg/dL.

Patients should be informed that triglycerides respond to the simple interventions of diet
control, exercise, and appropriate weight loss. A trained dietitian should provide thorough
diet instructions. Exercise counseling or monitoring may be helpful to treat the
dyslipidemia and reduce the risk of symptomatic cardiovascular disease.

In addition, the provider should stress the importance of alcohol intake of no more than 1
drink per day, provide instructions on the use of medications, and provide comprehensive
diabetes education to diabetic patients.

For patient education resources, Medscape Reference’s Cholesterol Center and Heart
Health Center, as well as High Cholesterol, Understanding Your Cholesterol level,
Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, and
Statins and Cholesterol.

Clinical Presentation