Lipids are fats that are either absorbed from food or synthesized by the liver. Triglycerides (TGs) and cholesterol contribute most to disease, although all lipids are physiologically important. The primary function of TGs is to store energy in adipocytes and muscle cells; cholesterol is a ubiquitous constituent of cell membranes, steroids, bile acids, and signaling molecules. All lipids are hydrophobic and mostly insoluble in blood, so they require transport within hydrophilic, spherical structures called lipoproteins, which possess surface proteins (apoproteins, or apolipoproteins) that are cofactors and ligands for lipid-processing enzymes (see Table 1: Lipid Disorders: Major Apoproteins and Enzymes Important to Lipid Metabolism). Lipoproteins are classified by size and density (defined as the ratio of lipid to protein) and are important because high levels of low-density lipoproteins (LDL) and low levels of high-density lipoproteins (HDL) are major risk factors for atherosclerotic heart disease (see Arteriosclerosis).

Table 1

Major Apoproteins and Enzymes Important to Lipid Metabolism



Apo A-I
Major component of HDL particle

Apo A-II
Not known

Apo B-100
LDL receptor ligand

Apo C-II
Chylomicrons, VLDL, HDL
LPL cofactor

Apo E
Chylomicrons, remnants, VLDL, HDL
LDL receptor ligand

Not known


Within cells
Contributes to intracellular cholesterol transport to membrane

Mediates transfer of cholesteryl esters from HDL to VLDL

Esterifies free cholesterol for transport within HDL
ABCA1 = ATP-binding cassette transporter A1; apo = apoprotein; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LCAT = lecithin-cholesterol acyltransferase; LDL = low-density lipoprotein; LPL = lipoprotein lipase; Lp(a) = lipoprotein (a); VLDL = very-low-density lipoprotein.


Pathway defects in lipoprotein synthesis, processing, and clearance can lead to accumulation of atherogenic lipids in plasma and endothelium.

Exogenous (dietary) lipid metabolism: Over 95% of dietary lipids are TGs; the rest are phospholipids, free fatty acids (FFAs), cholesterol (present in foods as esterified cholesterol), and fat-soluble vitamins. Dietary TGs are digested in the stomach and duodenum into monoglycerides (MGs) and FFAs by gastric lipase, emulsification from vigorous stomach peristalsis, and pancreatic lipase. Dietary cholesterol esters are de-esterified into free cholesterol by these same mechanisms. MGs, FFAs, and free cholesterol are then solubilized in the intestine by bile acid micelles, which shuttle them to intestinal villi for absorption. Once absorbed into the enterocyte, they are reassembled into TGs and packaged with cholesterol into chylomicrons, the largest lipoproteins.

Chylomicrons transport dietary TGs and cholesterol from within enterocytes through lymphatics into the circulation. In the capillaries of adipose and muscle tissue, apoprotein C-II (apo C-II) on the chylomicron activates endothelial lipoprotein lipase (LPL) to convert 90% of chylomicron TG to fatty acids and glycerol, which are taken up by adipocytes and muscle cells for energy use or storage. Cholesterol-rich chylomicron remnants then circulate back to the liver, where they are cleared in a process mediated by apoprotein E (apo E).

Endogenous lipid metabolism: Lipoproteins synthesized by the liver transport endogenous TGs and cholesterol. Lipoproteins circulate through the blood continuously until the TGs they contain are taken up by peripheral tissues or the lipoproteins themselves are cleared by the liver. Factors that stimulate hepatic lipoprotein synthesis generally lead to elevated plasma cholesterol and TG levels.

Very-low-density lipoproteins (VLDL) contain apoprotein B-100 (apo B), are synthesized in the liver, and transport TGs and cholesterol to peripheral tissues. VLDL is the way the liver exports excess TGs derived from plasma FFA and chylomicron remnants; VLDL synthesis increases with increases in intrahepatic FFA, such as occur with high-fat diets and when excess adipose tissue releases FFAs directly into the circulation (eg, in obesity, uncontrolled diabetes mellitus). Apo C-II on the VLDL surface activates endothelial LPL to break down TGs into FFAs and glycerol, which are taken up by cells.

Intermediate-density lipoproteins (IDL) are the product of LPL processing of VLDL and chylomicrons. IDL are cholesterol-rich VLDL and chylomicron remnants that are either cleared by the liver or metabolized by hepatic lipase into LDL, which retains apo B.

Low-density lipoproteins (LDL), the products of VLDL and IDL metabolism, are the most cholesterol-rich of all lipoproteins. About 40 to 60% of all LDL are cleared by the liver in a process mediated by apo B and hepatic LDL receptors. The rest are taken up by either hepatic LDL or nonhepatic non-LDL (scavenger) receptors. Hepatic LDL receptors are down-regulated by delivery of cholesterol to the liver by chylomicrons and by increased dietary saturated fat; they can be up-regulated by decreased dietary fat and cholesterol. Nonhepatic scavenger receptors, most notably on macrophages, take up excess oxidized circulating LDL not processed by hepatic receptors. Monocytes rich in oxidized LDL migrate into the subendothelial space and become macrophages; these macrophages then take up more oxidized LDL and form foam cells within atherosclerotic plaques (see Arteriosclerosis: Pathophysiology). There are 2 forms of LDL: large, buoyant and small, dense LDL. Small, dense LDL is especially rich in cholesterol esters, associated with metabolic disturbances such as hypertriglyceridemia and insulin resistance, and especially atherogenic. The increased atherogenicity of small, dense LDL derives from less efficient hepatic LDL receptor binding, leading to prolonged circulation and exposure to endothelium and increased oxidation.

High-density lipoproteins (HDL) are initially cholesterol-free lipoproteins that are synthesized in both enterocytes and the liver. HDL metabolism is complex, but HDL’s overall role is to obtain cholesterol from peripheral tissues and other lipoproteins and transport it to where it is needed most—other cells, other lipoproteins (using cholesteryl ester transfer protein [CETP]), and the liver (for clearance). Its overall effect is anti-atherogenic. Efflux of free cholesterol from cells is mediated by ATP-binding cassette transporter A1 (ABCA1), which combines with apoprotein A-I (apo A-I) to produce nascent HDL. Free cholesterol in nascent HDL is then esterified by the enzyme lecithin-cholesterol acyl transferase (LCAT), producing mature HDL. Blood HDL levels may not completely represent reverse cholesterol transport.

Lipoprotein (a) [Lp(a)] is LDL that contains apoprotein (a), characterized by 5 cysteine-rich regions called kringles. One of these regions is homologous with plasminogen and is thought to competitively inhibit fibrinolysis and thus predispose to thrombus. The Lp(a) may also directly promote atherosclerosis. The metabolic pathways of Lp(a) production and clearance are not well characterized, but levels increase in patients with diabetic nephropathyDyslipidemia 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. In 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.


Dyslipidemias were traditionally classified by patterns of elevation in lipids and lipoproteins (Fredrickson phenotype—see 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.
Table 2

Lipoprotein Patterns (Fredrickson Phenotypes)

Elevated Lipoprotein(s)
Elevated Lipids



TGs and cholesterol

VLDL and chylomicron remnants
TGs and cholesterol


Chylomicrons and VLDL
TGs and cholesterol
LDL = low-density lipoprotein; TGs = triglycerides; VLDL = very-low-density lipoprotein.


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 (see Table 3: Lipid Disorders: Genetic (Primary) Dyslipidemias). 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 α (HDL) and β (LDL) bands on electrophoretic gels.
Table 3

Genetic (Primary) Dyslipidemias
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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, β-blockers, retinoids, highly active antiretroviral agents, estrogen and progestins, and glucocorticoids.

Diabetes 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.


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 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.

Lipid 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 (IDL), 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 MI; however, results obtained within 24 h after MI 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 IDL 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, IDL, and LDL) and may be more predictive of CAD risk than LDL alone.

Other 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 dyslipidemia—including measurements of fasting glucose, liver enzymes, creatinine, thyroid-stimulating hormone (TSH), and urinary protein—should 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

Diabetes mellitus

Cigarette use


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.

Indications for screening patients 240 mg/dL (> 6.2 mmol/L) or known dyslipidemia in a parent. If 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.


Risk assessment by explicit criteria

Lifestyle changes (eg, exercise, dietary modification)

For high LDL cholesterol, statins, sometimes bile acid sequestrants, ezetimibe

, and
other measures

For high TG or low HDL cholesterol, niacin

, fibrates, and sometimes other measures

General principles: Treatment is indicated for all patients with cardiovascular disease (secondary prevention) and for some without (primary prevention). The National Institutes of Health’s National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) guidelines are the most common reference for deciding which adults should be treated (see Table 4: Lipid Disorders: National Cholesterol Education Program Adult Treatment Panel III Approach to Dyslipidemias and Table 5: Lipid Disorders: NCEP Adult Treatment Panel III Guidelines for Treatment of Hyperlipidemia). The guidelines focus primarily on reducing elevated LDL cholesterol levels and secondarily on treating high TGs, low HDL, and metabolic syndrome (see Obesity and the Metabolic Syndrome: Metabolic Syndrome). An alternate treatment guide (the Sheffield table) uses TC:HDL ratios combined with presence of CAD risk factors to predict cardiovascular risk, but this approach probably leads to undertreatment.

Table 4

National Cholesterol Education Program Adult Treatment Panel III Approach to Dyslipidemias

1. Measure fasting lipoproteins (in mg/dL):

TC (mmol/L)

< 200 (< 5.17)

200–239 (5.17–6.18)
Borderline high

≥ 240 (≥ 6.20)

LDL cholesterol

< 100 (< 2.58)

100–129 (2.58–3.33)
Near optimal/above optimal

130–159 (3.36–4.11)
Borderline high

160–189 (4.13–4.88)

≥ 190 (≥ 4.91)
Very high

HDL cholesterol

< 40 (< 1.03)

≥ 60 (≥ 1.55)


< 150 ( 20% (see step #4 and see Table 6: Lipid Disorders: Framingham Risk Tables for Men and Table 7: Lipid Disorders: Framingham Risk Tables for Women)

3. Identify major CAD risk factors

Cigarette smoking

Hypertension (BP ≥ 140/90 or on antihypertensive drug)

Low HDL (≤ 40 mg/dL [1.03 mmol/L])

Family history of premature CAD (CAD in a male 1st-degree relative < 55 or in a female 1st-degree relative 20%)
LDL ≥ 100 mg/dL (≥ 2.58 mmol/L)
LDL ≥ 100 mg/dL (≥ 2.58 mmol/L)

Drug therapy optional if LDL is < 100 mg/dL [< 2.58 mmol/L])
< 100 mg/dL

< 70 mg/dL optional

Moderate high

≥ 2 risk factors with 10-yr risk 10 to 20%*
LDL ≥ 130 mg/dL (≥ 3.36 mmol/L)
LDL ≥ 130 mg/dL (≥ 3.36 mmol/L)
< 130 mg/dL < 100 mg/dL optional


≥ 2 risk factors with 10-yr risk < 10%*
LDL ≥ 130 mg/dL (≥ 3.36 mmol/L)
LDL ≥ 160 mg/dL (≥ 4.13 mmol/L)
< 130 mg/dL < 100 mg/dL optional


0–1 risk factor
LDL ≥ 160 mg/dL (≥ 4.13 mmol/L)
LDL ≥ 190 mg/dL (≥ 4.91 mmol/L)

Drug therapy optional if LDL is 160–189 mg/dL [4.13–4.88 mmol/L])
< 160 mg/dL
*For 10-yr risk, see Framingham risk tables (see Table 6: Lipid Disorders: Framingham Risk Tables for Men and Table 7: Lipid Disorders: Framingham Risk Tables for Women).
CAD = coronary artery disease; LDL = low-density lipoprotein; NCEP = National Cholesterol Education Program.
Data from the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Institutes of Health, National Heart, Lung, and Blood Institute, 2001 and from Grundy SM, Cleeman JI, Merz CNB, et al: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110:227–239, 2004.

Treatment of children is controversial; dietary changes may be difficult to implement, and no data suggest that lowering lipid levels in childhood effectively prevents heart disease in adulthood. Moreover, the safety and effectiveness of long-term lipid-lowering treatment are questionable. Nevertheless, the American Academy of Pediatrics (AAP) recommends treatment for some children who have elevated LDL cholesterol levels.

Treatment options depend on the specific lipid abnormality, although different lipid abnormalities often coexist. In some patients, a single abnormality may require several therapies; in others, a single treatment may be adequate for several abnormalities. Treatment should always include treatment of hypertension and diabetes, smoking cessation, and in patients with a 10-yr risk of MI or death from CAD of ≥ 10% (as determined from the Framingham tables—see Table 6: Lipid Disorders: Framingham Risk Tables for Men and Table 7: Lipid Disorders: Framingham Risk Tables for Women), low-dose daily aspirin

. In
general, treatment options for men and women are the same.
Table 6

Framingham Risk Tables for Men
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Table 7

Framingham Risk Tables for Women
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Clinical Calculator

Clinical Calculator

Elevated LDL cholesterol: In adults, ATPIII guidelines recommend treatment for those with any of the following:

Elevated LDL cholesterol levels and a history of CAD

Conditions that confer a risk of future cardiac events similar to that of CAD itself (CAD equivalents, defined as diabetes mellitus, abdominal aortic aneurysm, peripheral arterial disease, and symptomatic carotid artery disease)

≥ 2 CAD risk factors

ATPIII guidelines recommend that these patients have LDL cholesterol levels lowered to < 100 mg/dL, but accumulating evidence suggests that this target may be too high and a target LDL cholesterol 110 mg/dL. Drug therapy is recommended for children > 8 yr and with either of the following:

Poor response to dietary therapy, LDL cholesterol ≥ 190 mg/dL, and no family history of premature cardiovascular disease

LDL cholesterol ≥ 160 mg/dL and a family history of premature cardiovascular disease or ≥ 2 risk factors for premature cardiovascular disease

Childhood risk factors besides family history and diabetes include cigarette smoking, hypertension, low HDL cholesterol ( 200 mg/dL [> 5.2 mmol/L]) and those at high cardiovascular risk, drug therapy should accompany diet and exercise from the start.

Statins are the drugs and possibly treatment of choice for LDL cholesterol reduction; they demonstrably reduce cardiovascular mortality. Statins inhibit hydroxymethylglutaryl CoA reductase, a key enzyme in cholesterol synthesis, leading to up-regulation of LDL receptors and increased LDL clearance. They reduce LDL cholesterol by up to 60% and produce small increases in HDL and modest decreases in TGs. Statins also appear to decrease intra-arterial inflammation, systemic inflammation, or both by stimulating production of endothelial nitric oxide and may have other beneficial effects. Adverse effects are uncommon but include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation has also been reported. Adverse effects are more common among older patients, patients with several disorders, and patients taking several drugs. In some patients, changing from one statin to another or lowering the dose relieves the problem. Muscle toxicity seems to be most common when some of the statins are used with drugs that inhibit cytochrome P3A4 (eg, macrolide antibiotics, azole antifungals, cyclosporine

) and with fibrates, especially

. Properties of statins differ slightly by drug, and the choice of drug should be
based on patient characteristics, LDL cholesterol level, and provider discretion (see Table 8: Lipid Disorders: Lipid–Lowering Drugs).

Bile acid sequestrants block intestinal bile acid reabsorption, forcing up-regulation of hepatic LDL receptors to recruit circulating cholesterol for bile synthesis. They are proved to reduce cardiovascular mortality. Bile acid sequestrants are usually used with statins or with nicotinic acid (see Lipid Disorders: Low HDL) to augment LDL cholesterol reduction and are the drugs of choice for children and women who are or are planning to become pregnant. Bile acid sequestrants are safe, but their use is limited by adverse effects of bloating, nausea, cramping, and constipation. They may also increase TGs, so their use is contraindicated in patients with hypertriglyceridemia. Cholestyramine

and colestipol

, but not colesevelam

, interfere with absorption of other drugs—notably thiazides, β-blockers, warfarin

, digoxin

and thyroxine—an effect that can be decreased by administration 4 h before or 1 h after other drugs.

Cholesterol absorption inhibitors, such as ezetimibe

, inhibit intestinal absorption of
cholesterol and phytosterol. Ezetimibe

usually lowers LDL cholesterol by 15 to 20% and
causes small increases in HDL and a mild decrease in TGs. Ezetimibe

can be used as
monotherapy in patients intolerant to statins or added to statins for patients on maximum doses with persistent LDL cholesterol elevation. Adverse effects are infrequent.

Dietary supplements that lower LDL cholesterol levels include fiber supplements and commercially available margarines and other products containing plant sterols (sitosterol and campesterol) or stanols. The latter reduce LDL cholesterol by up to 10% without affecting HDL or TGs by competitively displacing cholesterol from intestinal micelles.

Procedural approaches are reserved for patients with severe hyperlipidemia (LDL cholesterol > 300 mg/dL) that is refractory to conventional therapy, such as occurs with familial hypercholesterolemia. Options include LDL apheresis (in which LDL is removed by extracorporeal plasma exchange), ileal bypass (to block reabsorption of bile acids), liver transplantation (which transplants LDL receptors), and portocaval shunting (which decreases LDL production by unknown mechanisms). LDL apheresis is the procedure of choice in most instances when maximally tolerated therapy fails to lower LDL adequately. Apheresis is also the usual therapy in patients with the homozygous form of familial hypercholesterolemia who have limited or no response to drug therapy.

Future therapies to reduce LDL include peroxisome proliferator–activated receptor agonists that have thiazolidinedione-like and fibrate-like properties, LDL-receptor activators, LPL activators, and recombinant apo E. Cholesterol vaccination (to induce anti-LDL antibodies and hasten LDL clearance from serum) and gene transfer are conceptually appealing therapies that are under study but years away from being available for use.

Elevated TGs: Although it is unclear whether elevated TGs independently contribute to cardiovascular disease, they are associated with multiple metabolic abnormalities that contribute to CAD (eg, diabetes, metabolic syndrome). Consensus is emerging that lowering elevated TGs is beneficial (see Table 4: Lipid Disorders: National Cholesterol Education Program Adult Treatment Panel III Approach to Dyslipidemias). No target goals exist, but levels < 150 mg/dL (< 1.7 mmol/L) are generally considered desirable. No guidelines specifically address treatment of elevated TGs in children.

The overall treatment strategy is to first implement lifestyle changes, including exercise, weight loss, and avoidance of concentrated dietary sugar and alcohol. Intake of 2 to 4 servings/wk of marine fish high in ω-3 fatty acids may be effective, but the amount of ω-3 fatty acids is often lower than needed; supplements may be helpful. In patients with diabetes, glucose levels should be tightly controlled. If these measures are ineffective, lipid-lowering drugs should be considered. Patients with very high TGs should begin drug therapy at diagnosis to more quickly reduce the risk of acute pancreatitis.

Fibrates reduce TGs by about 50%. They appear to stimulate endothelial LPL, leading to increased fatty acid oxidation in the liver and muscle and decreased hepatic VLDL synthesis. They also increase HDL by up to 20%. Fibrates can cause GI adverse effects, including dyspepsia, abdominal pain, and elevated liver enzymes. They uncommonly cause cholelithiasis. Fibrates may potentiate muscle toxicity when used with statins and potentiate the effects of warfarin


Nicotinic acid may also be useful (see see Lipid Disorders: Low HDL).

Statins can be used in patients with TGs < 500 mg/dL if LDL cholesterol elevations are also present; statins may reduce both LDL cholesterol and TGs through reduction of VLDL. If only TGs are elevated, fibrates are the drug of choice.

Omega-3 fatty acids in high doses (1 to 6 g/day of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) can be effective in reducing TGs. The ω-3 fatty acids EPA and DHA are the active ingredients in marine fish oil or ω-3 capsules. Adverse effects include eructation and diarrhea. These may be decreased by giving the fish oil capsules with meals in divided doses (eg, bid or tid). Omega-3 fatty acids can be a useful adjunct to other therapies.

Low HDL: Treatment to increase HDL cholesterol levels may decrease risk of death, but data are limited. ATPIII guidelines define low HDL cholesterol as < 40 mg/dL [ 3 times the upper limit of normal. Muscle enzyme levels need not be checked regularly unless patients develop myalgias or other muscle symptoms. If statin-induced muscle damage is suspected, statin use is stopped and CK may be measured. When muscle symptoms subside, a lower dose or a different statin can be tried.

Elevated High-Density Lipoprotein Levels

Elevated high-density lipoprotein (HDL) level is HDL cholesterol > 80 mg/dL (> 2.1 mmol/L).

Elevated HDL cholesterol levels usually correlate with decreased cardiovascular risk; however, high HDL cholesterol levels caused by some genetic disorders may not protect against cardiovascular disease, probably because of accompanying lipid and metabolic abnormalities.

Primary causes are single or multiple genetic mutations that result in overproduction or decreased clearance of HDL. Secondary causes of high HDL cholesterol include all of the following:

Chronic alcoholism without cirrhosis

Primary biliary cirrhosis


Drugs (eg, corticosteroids, insulin

, phenytoin


The unexpected finding of high HDL cholesterol in patients not taking lipid-lowering drugs should prompt a diagnostic evaluation for a secondary cause with measurements of AST, ALT, and thyroid-stimulating hormone; a negative evaluation suggests a possible primary cause.

Cholesteryl ester transfer protein (CETP) deficiency is a rare autosomal recessive disorder caused by a CETP gene mutation. CETP facilitates transfer of cholesterol esters from HDL to other lipoproteins, and CETP deficiency affects low-density lipoprotein (LDL) cholesterol and slows HDL clearance. Affected patients display no symptoms or signs but have HDL cholesterol > 150 mg/dL. Protection from cardiovascular disorders has not been proved. No treatment is necessary.

Familial hyperalphalipoproteinemia is an autosomal dominant condition caused by various unidentified and known genetic mutations, including those that cause apoprotein A-I overproduction and apoprotein C-III variants. The disorder is usually diagnosed incidentally when plasma HDL cholesterol levels are > 80 mg/dL. Affected patients have no other symptoms or signs. No treatment is necessary.

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