Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density

lipoprotein level that contributes to the development of atherosclerosis. Causes may be primary (genetic)
or secondary. Diagnosis is by measuring plasma levels of total cholesterol, TGs, and individual
lipoproteins. Treatment is dietary changes, exercise, and lipid-lowering drugs.
There is no natural cutoff between normal and abnormal lipid levels because lipid measurements are
continuous. A linear relation probably exists between lipid levels and cardiovascular risk, so many people
with "normal cholesterol levels benefit from achieving still lower levels. Consequently, there are no
numeric definitions of dyslipidemia; the term is applied to lipid levels for which treatment has proven
beneficial. Proof of benefit is strongest for lowering elevated low-density lipoprotein (LDL) levels. n the
overall population, evidence is less strong for a benefit from lowering elevated TG and increasing low
high-density lipoprotein (HDL) levels, in part because elevated TG and low HDL levels are more
predictive of cardiovascular risk in women than in men.
HDL levels do not always predict cardiovascular risk. For example, high HDL levels caused by some
genetic disorders may not protect against cardiovascular disorders, and low HDL levels caused by some
genetic disorders may not increase the risk of cardiovascular disorders. Although HDL levels predict
cardiovascular risk in the overall population, the increased risk may be caused by other factors, such as
accompanying lipid and metabolic abnormalities, rather than the HDL level itself.
CIassification
Dyslipidemias were traditionally classified by patterns of elevation in lipids and lipoproteins (Fredrickson
phenotypesee Table 2: Lipid Disorders: Lipoprotein Patterns (Fredrickson Phenotypes) ). A more practical
system categorizes dyslipidemias as primary or secondary and characterizes them by increases in
cholesterol only (pure or isolated hypercholesterolemia), increases in TGs only (pure or isolated
hypertriglyceridemia), or increases in both cholesterol and TGs (mixed or combined hyperlipidemias).
This system does not take into account specific lipoprotein abnormalities (eg, low HDL or high LDL) that
may contribute to disease despite normal cholesterol and TG levels.
TabIe 2

Lipoprotein Patterns
(Fredrickson Phenotypes)
Phenotype E|evated L|poprote|n(s} E|evated L|p|ds
I Chylomicrons TGs
IIa LDL Cholesterol
IIb LDL and VLDL TGs and
cholesterol
III VLDL and
chylomicron
TGs and
cholesterol
remnants
IV VLDL TGs
V Chylomicrons and
VLDL
TGs and
cholesterol
LDL = low-density lipoprotein; TGs = triglycerides;
VLDL = very-low-density lipoprotein.

tioIogy
Primary (genetic) causes and secondary (lifestyle and other) causes contribute to dyslipidemias in varying
degrees. For example, in familial combined hyperlipidemia, expression may occur only in the presence of
significant secondary causes.
Primary causes: Primary causes are single or multiple gene mutations that result in either
overproduction or defective clearance of TG and LDL cholesterol, or in underproduction or excessive
clearance of HDL. Primary disorders, the most common cause of dyslipidemia in children, do not cause a
large percentage of cases in adults. The names of many reflect an old nomenclature in which lipoproteins
were detected and distinguished by how they separated into d (HDL) and (LDL) bands on
electrophoretic gels.
Secondary causes: Secondary causes contribute to most cases of dyslipidemia in adults. The most
important secondary cause in developed countries is a sedentary lifestyle with excessive dietary intake of
saturated fat, cholesterol, and trans fats. Trans fats are polyunsaturated or monounsaturated fatty acids
to which hydrogen atoms have been added; they are commonly used in many processed foods and are
as atherogenic as saturated fat. Other common secondary causes include diabetes mellitus, alcohol
overuse, chronic kidney disease, hypothyroidism, primary biliary cirrhosis and other cholestatic liver
diseases, and drugs, such as thiazides, -blockers, retinoids, highly active antiretroviral agents, estrogen
and progestins, and glucocorticoids.
iabetes is an especially significant secondary cause because patients tend to have an atherogenic
combination of high TGs; high small, dense LDL fractions; and low HDL (diabetic dyslipidemia,
hypertriglyceridemic hyperapo B). Patients with type 2 diabetes are especially at risk. The combination
may be a consequence of obesity, poor control of diabetes, or both, which may increase circulating free
fatty acids (FFAs), leading to increased hepatic very-low-density lipoprotein (VLDL) production. TG-rich
VLDL then transfers TG and cholesterol to LDL and HDL, promoting formation of TG-rich, small, dense
LDL and clearance of TG-rich HDL. Diabetic dyslipidemia is often exacerbated by the increased caloric
intake and physical inactivity that characterize the lifestyles of some patients with type 2 diabetes.
Women with diabetes may be at special risk of cardiac disease from this form.
Symptoms and Signs
Dyslipidemia itself usually causes no symptoms but can lead to symptomatic vascular disease, including
coronary artery disease (CAD) and peripheral arterial disease. High levels of TGs (> 1000 mg/dL [> 11.3
mmol/L]) can cause acute pancreatitis. High levels of LDL can cause eyelid xanthelasmas; arcus
corneae; and tendinous xanthomas at the Achilles, elbow, and knee tendons and over
metacarpophalangeal joints. Patients with the homozygous form of familial hypercholesterolemia may
have the above findings plus planar or cutaneous xanthomas. Patients with severe elevations of TGs can
have eruptive xanthomas over the trunk, back, elbows, buttocks, knees, hands, and feet. Patients with the
rare dysbetalipoproteinemia can have palmar and tuberous xanthomas.
Severe hypertriglyceridemia (> 2000 mg/dL [> 22.6 mmol/L]) can give retinal arteries and veins a creamy
white appearance (lipemia retinalis). Extremely high lipid levels also give a lactescent (milky) appearance
to blood plasma. Symptoms can include paresthesias, dypsnea, and confusion.
iagnosis
O Serum lipid profile (measured total cholesterol, TG, and HDL cholesterol and calculated LDL cholesterol and
VLDL)
Dyslipidemia is suspected in patients with characteristic physical findings or complications of dyslipidemia
(eg, atherosclerotic disease). Primary lipid disorders are suspected when patients have physical signs of
dyslipidemia, onset of premature atherosclerotic disease (at <60 yr), a family history of atherosclerotic
disease, or serum cholesterol > 240 mg/dL (> 6.2 mmol/L). Dyslipidemia is diagnosed by measuring
serum lipids. Routine measurements (lipid profile) include total cholesterol (TC), TGs, HDL cholesterol,
and LDL cholesterol.
ipid profile measurement: TC, TGs, and HDL cholesterol are measured directly; TC and TG values
reflect cholesterol and TGs in all circulating lipoproteins, including chylomicrons, VLDL, intermediate-
density lipoprotein (DL), LDL, and HDL. TC values vary by 10% and TGs by up to 25% day-to-day even
in the absence of a disorder. TC and HDL cholesterol can be measured in the nonfasting state, but most
patients should have all lipids measured while fasting for maximum accuracy and consistency.
Testing should be postponed until after resolution of acute illness, because TGs increase and cholesterol
levels decrease in inflammatory states. Lipid profiles can vary for about 30 days after an acute M;
however, results obtained within 24 h after M are usually reliable enough to guide initial lipid-lowering
therapy.
LDL cholesterol values are most often calculated as the amount of cholesterol not contained in HDL and
VLDL. VLDL is estimated by TG 5 because the cholesterol concentration in VLDL particles is
usually
1
/
5
of the total lipid in the particle. Thus, LDL cholesterol = TC ~[HDL cholesterol + (TGs 5)]
(Friedewald formula). This calculation is valid only when TGs are< 400 mg/dL and patients are fasting,
because eating increases TGs. The calculated LDL cholesterol value incorporates measures of all non-
HDL, nonchylomicron cholesterol, including that in DL and lipoprotein (a) [Lp(a)]. LDL can also be
measured directly using plasma ultracentrifugation, which separates chylomicrons and VLDL fractions
from HDL and LDL, and by an immunoassay method. Direct measurement may be useful in some
patients with elevated TGs, but these direct measurements are not routinely necessary. The role of apo B
testing is under study because values reflect all non-HDL cholesterol (in VLDL, VLDL remnants, DL, and
LDL) and may be more predictive of CAD risk than LDL alone.
ther tests: Patients with premature atherosclerotic cardiovascular disease, cardiovascular disease with
normal or near-normal lipid levels, or high LDL levels refractory to drug therapy should probably have
Lp(a) levels measured. Lp(a) levels may also be directly measured in patients with borderline high LDL
cholesterol levels to determine whether drug therapy is warranted. C-reactive protein and homocysteine
measurement may be considered in the same populations.
Secondary causes: Tests for secondary causes of dyslipidemiaincluding measurements of fasting
glucose, liver enzymes, creatinine, thyroid-stimulating hormone (TSH), and urinary proteinshould be
done in most patients with newly diagnosed dyslipidemia and when a component of the lipid profile has
inexplicably changed for the worse.
Screening: A fasting lipid profile (TC, TGs, HDL cholesterol, and calculated LDL cholesterol) should be
obtained in all adults < 20 yr and should be repeated every 5 yr. Lipid measurement should be
accompanied by assessment of other cardiovascular risk factors, defined as
O Diabetes mellitus
O Cigarette use
O Hypertension
O Family history of CAD in a male 1st-degree relative before age 55 or a female 1st-degree relative before age 65
A definite age after which patients no longer require screening has not been established, but evidence
supports screening of patients into their 80s, especially in the presence of atherosclerotic cardiovascular
disease.
ndications for screening patients < 20 yr are atherosclerotic risk factors, such as diabetes, hypertension,
cigarette smoking, and obesity; premature CAD in a parent, grandparent, or sibling; or a cholesterol
level > 240 mg/dL (> 6.2 mmol/L) or known dyslipidemia in a parent. f information on relatives is
unavailable, as in the case of adopted children, screening is at the discretion of the health care
practitioner.
Patients with an extensive family history of heart disease should also be screened by measuring Lp(a)
levels.




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