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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. 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.
Classification
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.
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Table 2
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| Lipoprotein Patterns (Fredrickson Phenotypes) |
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Phenotype
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Elevated Lipoprotein(s)
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Elevated Lipids
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I
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Chylomicrons
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TGs
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IIa
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LDL
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Cholesterol
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IIb
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LDL and VLDL
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TGs and cholesterol
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III
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VLDL and chylomicron remnants
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TGs and cholesterol
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IV
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VLDL
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TGs
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V
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Chylomicrons and VLDL
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TGs and cholesterol
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LDL = low-density lipoprotein; TGs = triglycerides; VLDL = very-low-density lipoprotein.
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Etiology
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.
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Table 3
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| Genetic (Primary) Dyslipidemias |
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Disorder
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Genetic Defect/Mechanism
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Inheritance
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Prevalence
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Clinical Features
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Treatment
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Familial hypercholesterolemia
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LDL receptor defect
Diminished LDL clearance
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Codominant or complex with multiple genes
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Common among French Canadians, Christian Lebanese, and Afrikaners
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Diet
Lipid-lowering drugs
LDL apheresis (for homozygotes)
Liver transplantation (for homozygotes)
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Heterozygotes: 1/500
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Tendon xanthomas, arcus senilis, premature CAD (ages 30–50), responsible for about 5% of MIs in people < 60 yr
TC: 250–500 mg/dL (7–13 mmol/L)
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Homozygotes: 1/1 million
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Planter and tendon xanthomas and premature CAD (before age 18)
TC > 500 mg/dL (> 13 mmol/L)
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Familial defective apo B-100
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Apo B (LDL receptor–binding region defect)
Diminished LDL clearance
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Dominant
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1/700
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Xanthomas, arcus senilis, premature CAD
TC: 250–500 mg/dL (7–13 mmol/L)
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Diet
Lipid-lowering drugs
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Polygenic hypercholesterolemia
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Unknown, possibly multiple defects and mechanisms
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Variable
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Common
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Premature CAD
TC: 250–350 mg/dL (6.5–9.0 mmol/L)
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Diet
Lipid-lowering drugs
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LPL deficiency
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Endothelial LPL defect
Diminished chylomicron clearance
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Recessive
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Rare but present worldwide
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Failure to thrive (in infants), xanthomas, hepatosplenomegaly, pancreatitis
TG: > 750 mg/dL (> 8.5 mmol/L)
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Diet: Total fat restriction with fat-soluble vitamin supplementation and medium-chain TG supplementation
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Apo C-II deficiency
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Apo C-II (causing functional LPL deficiency)
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Recessive
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< 1/1 million
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Pancreatitis (in some adults), metabolic syndrome (often present)
TG: > 750 mg/dL (> 8.5 mmol/L)
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Diet: Total fat restriction with fat-soluble vitamin supplementation and medium-chain TG supplementation
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Familial hypertriglyceridemia
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Unknown, possibly multiple defects and mechanisms
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Dominant
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1/100
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Usually no symptoms or findings; occasionally hyperuricemia, sometimes early atherosclerosis
TG: 200–500 mg/dL (2.3–5.7 mmol/L), possibly higher depending on diet and alcohol use
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Diet
Weight loss
Lipid-lowering drugs
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Familial combined hyperlipidemia
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Unknown, possibly multiple defects and mechanisms
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Dominant
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1/50 to 1/100
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Premature CAD, responsible for about 15% of MIs in people < 60 yr
Apo B: Disproportionately elevated
TC: 250–500 mg/dL (6.5–13.0 mmol/L)
TG: 250–750 mg/dL (2.8–8.5 mmol/L)
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Diet
Weight loss
Lipid-lowering drugs
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Familial dysbetalipoproteinemia
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Apo E (usually e2/e2 homozygotes)
Diminished chylomicron and VLDL clearance
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Recessive (more common) or dominant (less common)
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1/5000
Present worldwide
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Xanthomas (especially palmar), yellow palmar creases, premature CAD
TC: 250–500 mg/dL (6.5–13.0 mmol/L)
TG: 250–500 mg/dL (2.8–5.6 mmol/L)
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Diet
Lipid-lowering drugs
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Primary hypoalphalipoproteinemia (familial or nonfamilial)
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Unknown, possibly apo A-I, C-III, or A-IV
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Dominant
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About 5%
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Premature CAD
HDL: 15–35 mg/dL
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Exercise
HDL-elevating drugs
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Familial apo A/apo C-III deficiency/mutations
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Apo A or apo C-III
Increased HDL catabolism
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Unknown
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Rare
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Corneal opacities, xanthomas, premature CAD (in some people)
HDL: 15–30 mg/dL
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Nonspecific
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Familial LCAT deficiency
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LCAT gene
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Recessive
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Extremely rare
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Corneal opacities, anemia, renal failure
HDL: < 10 mg/dL
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Fat restriction
Renal transplantation
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Fisheye disease (partial LCAT deficiency)
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LCAT gene
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Recessive
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Extremely rare
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Corneal opacities
HDL: < 10 mg/dL
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Nonspecific
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Tangier disease
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ABCA1 gene
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Recessive
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Rare
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Premature CAD (in some people), peripheral neuropathy, hemolytic anemia, corneal opacities, hepatosplenomegaly, orange tonsils
HDL: < 5 mg/dL
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Low-fat diet
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Familial HDL deficiency
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ABCA1 gene
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Dominant
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Rare
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Premature CAD
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Low-fat diet
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Hepatic lipase deficiency
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Hepatic lipase
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Recessive
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Extremely rare
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Premature CAD
TC: 250–1500 mg/dL
TG: 395–8200 mg/dL
HDL: Variable
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Empiric: Diet, lipid-lowering drugs
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Cerebrotendinous xanthomatosis
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Hepatic mitochondrial 27-hydroxylase defect
Blockage of bile acid synthesis and conversion of cholesterol to cholestanol, which accumulates
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Recessive
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Rare
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Cataracts, premature CAD, neuropathy, ataxia
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Chenodeoxycholic acid
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Sitosterolemia
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ABCG5 and ABCG8 genes
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Recessive
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Rare
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Tendon xanthomas, premature CAD
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Fat restriction
Bile acid sequestrants
Ezetimibe
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Cholesteryl ester storage disease and Wolman's disease
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Lysosomal esterase deficiency
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Recessive
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Rare
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Premature CAD
Accumulation of cholesteryl esters and TG in lysosomes in the liver, spleen, and lymph nodes
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Possibly statins
Bone marrow transplantation (experimental)
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ABCA1 = ATP-binding cassette transporter A1; ABCG5 and 8 = ATP-binding cassette subfamily G members 5 and 8; apo = apoprotein; CAD = coronary artery disease; HDL = high-density lipoprotein; LCAT = lecithin-cholesterol acyltransferase; LDL = low-density lipoprotein; LPL = lipoprotein lipase; TC = total cholesterol; TG = triglyceride; VLDL = very-low-density lipoprotein.
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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.
Diagnosis
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.
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
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 < 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. 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.
Treatment
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.
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Table 4
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| National Cholesterol Education Program Adult Treatment Panel III Approach to Dyslipidemias |
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1. Measure fasting lipoproteins (in mg/dL):
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|
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TC (mmol/L)
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|
|
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Desirable
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Borderline high
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High
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LDL cholesterol
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Optimal
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Near optimal/above optimal
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Borderline high
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High
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Very high
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HDL cholesterol
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Low
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High
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TG
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Desirable
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Borderline high
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High
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Very high
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2. Identify CAD or CAD equivalents (if present, see Table 5: Lipid Disorders: NCEP Adult Treatment Panel III Guidelines for Treatment of Hyperlipidemia)
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|
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Other atherosclerotic disease:
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Peripheral arterial disease
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Abdominal aortic aneurysm
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Symptomatic carotid artery disease
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|
|
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3. Identify major CAD risk factors
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Hypertension (BP ≥ 140/90 or on antihypertensive drug)
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Low HDL (≤ 40 mg/dL [1.03 mmol/L])
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Family history of premature CAD (CAD in a male 1st-degree relative < 55 or in a female 1st-degree relative < 65)
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Age (men ≥ 45, women ≥ 55)
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4. If ≥ 2 major risk factors are present without CAD or CAD equivalent, assess 10-yr risk of MI or CAD death using Framingham risk tables (see Table 6: Lipid Disorders: Framingham Risk Tables for Men and Table 7: Lipid Disorders: Framingham Risk Tables for Women).
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CAD = coronary artery disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TC = total cholesterol; TG = triglyceride.
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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.
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Table 5
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| NCEP Adult Treatment Panel III Guidelines for Treatment of Hyperlipidemia |
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Risk Category
|
Begin Lifestyle Changes If
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Consider Drug Therapy If
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LDL Goal
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High
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CAD or CAD equivalents (10-yr risk > 20%)
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LDL ≥ 100 mg/dL (≥ 2.58 mmol/L)
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LDL ≥ 100 mg/dL (≥ 2.58 mmol/L)
Drug therapy optional if LDL is < 100 mg/dL [< 2.58 mmol/L])
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< 100 mg/dL
< 70 mg/dL optional
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Moderate high
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≥ 2 risk factors with 10-yr risk 10 to 20%*
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LDL ≥ 130 mg/dL (≥ 3.36 mmol/L)
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LDL ≥ 130 mg/dL (≥ 3.36 mmol/L)
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< 130 mg/dL < 100 mg/dL optional
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Moderate
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≥ 2 risk factors with 10-yr risk < 10%*
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LDL ≥ 130 mg/dL (≥ 3.36 mmol/L)
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LDL ≥ 160 mg/dL (≥ 4.13 mmol/L)
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< 130 mg/dL < 100 mg/dL optional
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Lower
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0–1 risk factor
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LDL ≥ 160 mg/dL (≥ 4.13 mmol/L)
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LDL ≥ 190 mg/dL (≥ 4.91 mmol/L)
Drug therapy optional if LDL is 160–189 mg/dL [4.13–4.88 mmol/L])
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< 160 mg/dL
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*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).
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CAD = coronary artery disease; LDL = low-density lipoprotein; NCEP = National Cholesterol Education Program.
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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.
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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.
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Table 6
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| | |
| Framingham Risk Tables for Men |
|
Point Score
|
|
Age
|
20–34
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35–39
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40–44
|
45–49
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50–54
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55–59
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60–64
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65–69
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70–74
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75–79
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Age points
|
−9
|
−4
|
0
|
3
|
6
|
8
|
10
|
11
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12
|
13
|
|
TC
|
|
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0
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0
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0
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0
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0
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0
|
0
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0
|
0
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0
|
|
|
4
|
4
|
3
|
3
|
2
|
2
|
1
|
1
|
0
|
0
|
|
|
7
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7
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5
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5
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3
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3
|
1
|
1
|
0
|
0
|
|
|
9
|
9
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6
|
6
|
4
|
4
|
2
|
2
|
1
|
1
|
|
|
11
|
11
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8
|
8
|
5
|
5
|
3
|
3
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1
|
1
|
|
Smoking status
|
|
Nonsmoker
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0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
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0
|
|
Smoker
|
8
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8
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5
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5
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3
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3
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1
|
1
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1
|
1
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HDL
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|
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−1
|
|
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0
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|
|
1
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|
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2
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Systolic BP
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|
|
Untreated 0; treated 0
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|
|
Untreated 0; treated 1
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|
|
Untreated 1; treated 2
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|
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Untreated 1; treated 2
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|
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Untreated 2; treated 3
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|
Points for 10-yr risk of MI or CAD death (%): < 0 points =
< 1%; 0–4 points = 1%; 5–6 points = 2%; 7 points = 3%; 8 points = 4%; 9 points = 5%; 10 points = 6%; 11 points = 8%; 12 points = 10%; 13 points = 12%; 14 points = 16%; 15 points = 20%; 16 points = 25%; >17 points =
≥ 30%.
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CAD = coronary artery disease; HDL = high-density lipoprotein; TC = total cholesterol.
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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.
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|
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Table 7
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| | |
| Framingham Risk Tables for Women |
|
Point Score
|
|
Age
|
20–34
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35–39
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40–44
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45–49
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50–54
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55–59
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60–64
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65–69
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70–74
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75–79
|
|
Age points
|
−7
|
−3
|
0
|
3
|
6
|
8
|
10
|
12
|
14
|
16
|
|
TC
|
|
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
|
|
4
|
4
|
3
|
3
|
2
|
2
|
1
|
1
|
1
|
1
|
|
|
8
|
8
|
6
|
6
|
4
|
4
|
2
|
2
|
1
|
1
|
|
|
11
|
11
|
8
|
8
|
5
|
5
|
3
|
3
|
2
|
2
|
|
|
13
|
13
|
10
|
10
|
7
|
7
|
4
|
4
|
2
|
2
|
|
Smoking status
|
|
Nonsmoker
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
|
Smoker
|
9
|
9
|
7
|
7
|
4
|
4
|
2
|
2
|
1
|
1
|
|
HDL
|
|
|
−1
|
|
|
0
|
|
|
1
|
|
|
2
|
|
Systolic BP
|
|
|
Untreated 0; treated 0
|
|
|
Untreated 1; treated 3
|
|
|
Untreated 2; treated 4
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|
|
Untreated 3; treated 5
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|
|
Untreated 4; treated 6
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|
Points for 10-yr risk of MI or CAD death (%): < 9 points =
< 1%; 9–12 points = 1%; 13–14 points = 2%; 15 points = 3%; 16 points = 4%; 17 points = 5%; 18 points = 6%; 19 points = 8%; 20 points = 11%; 21 points = 14%; 22 points = 17%; 23 points = 22%; 24 points = 27%; ≥ 25 points =
≥ 30%.
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CAD = coronary artery disease; HDL = high density lipoprotein; TC = total cholesterol.
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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.
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Clinical Calculator
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Elevated LDL cholesterol:
In adults, ATPIII guidelines recommend treatment for those with any of the following:
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 < 70 mg/dL is an option for patients at very high risk (eg, patients with known CAD and diabetes, other poorly controlled risk factors, metabolic syndrome, or acute coronary syndrome). When drugs are used, a dose providing at least a 30 to 40% decrease in LDL cholesterol is desirable (see Table 8: Lipid Disorders: Lipid–Lowering Drugs).
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Table 8
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| Lipid–Lowering Drugs |
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Drugs
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Adult Doses
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Comments
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Statins
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Lower LDL-C (primary), increase HDL-C, lower TGs (secondary)
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Atorvastatin
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10–80 mg po once/day
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No renal excretion, long half-life
Dose necessary to achieve recommended 30–40% reduction of LDL-C: 10 mg
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Fluvastatin
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Immediate release: 20–80 mg po once/day at bedtime
Extended release: 80 mg once/day
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Least potent, no renal excretion
Dose necessary to achieve recommended 30–40% reduction of LDL-C: 40–80 mg
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Lovastatin
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Immediate release: 20–80 mg po once/day at dinner
Extended release: 20–60 mg po once/day
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Dose necessary to achieve recommended 30–40% reduction of LDL-C: 40 mg
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Pravastatin
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10–80 mg po once/day
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Dose necessary to achieve recommended 30–40% reduction of LDL-C: 40 mg
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Rosuvastatin
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5–40 mg po once/day
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Most potent, long half-life
Dose necessary to achieve recommended 30–40% reduction of LDL-C: 5–10 mg
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Simvastatin
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5–80 mg po once/day in the evening
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Dose necessary to achieve recommended 30–40% reduction of LDL-C: 20–40 mg
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Nicotinic acid (niacin)
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Immediate-release: 500 mg bid–1000 mg po tid
Extended-release: 500–2000 mg po once/day at bedtime
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Increases HDL; lowers TGs (low doses), LDL-C (higher doses), and Lp(a) (secondary)
Frequent adverse effects: Flushing, impaired glucose tolerance, increased uric acid
Aspirin and administration with food minimize flushing
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Bile acid sequestrants
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Lower LDL-C (primary), slightly increase HDL (secondary), may increase TGs
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Cholestyramine
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4 g po 1–6 times/day with meals
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—
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Colesevelam
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2.4–4.5 g po once/day with a meal
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—
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Colestipol
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5–30 g po once/day with a meal
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—
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Fibrates
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Lower TGs and VLDL, increase HDL, may increase LDL-C (in patients with high TGs)
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Bezafibrate
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200 mg po tid or 400 mg po once/day
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Decreased dose required in renal insufficiency
Not available in US
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Ciprofibrate
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100–200 mg po once/day
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Not available in US
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Fenofibrate
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67–201 mg po once/day
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Decreased dose required in renal insufficiency
May be safest fibrate for use with statins
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Gemfibrozil
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600 mg po bid
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Decreased dose required in renal insufficiency
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Cholesterol absorption inhibitor
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Lowers LDL-C (primary), minimally increases HDL-C
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Ezetimibe
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10 mg po once/day
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—
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Dietary supplements
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Omega-3 acid ethyl esters
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3–4 g po once/day (4 capsules)
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Lower TGs only
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Combination products
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Combined effects of the 2 drugs
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Ezetimibe + simvastatin
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Ezetimibe 10 mg + simvastatin 10, 20, 40, or 80 mg po once/day
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Not recommended as initial therapy
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Niacin extended release + lovastatin
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Niacin 500 mg + lovastatin 20 mg po once/day
Niacin 2000 mg + lovastatin 40 mg po once/day
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Niacin extended release + simvastatin
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Niacin 500 mg + simvastatin mg po once/day at bedtime (starting dose) or niacin 750 or 1000 mg + simvastatin 20 mg po once/day at bedtime
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HDL = high-density lipoprotein; HDL-C = HDL cholesterol; LDL = low-density lipoprotein; LDL-C = LDL cholesterol; Lp(a) = lipoprotein (a) ; TG = triglyceride.
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For children, the AAP recommends dietary treatment for children with LDL cholesterol > 110 mg/dL. Drug therapy is recommended for children > 8 yr and with either of the following:
Childhood risk factors besides family history and diabetes include cigarette smoking, hypertension, low HDL cholesterol (< 35 mg/dL), obesity, and physical inactivity.
Treatment options to lower LDL cholesterol in all age groups include lifestyle changes (diet and exercise), drugs, dietary supplements, procedural interventions, and experimental therapies. Many of these options are also effective for treating other lipid abnormalities. Exercise lowers LDL cholesterol in some people; it is also essential to maintain ideal body weight. Dietary changes and exercise should be the initial approach whenever feasible.
Lifestyle changes can involve diet and exercise. Dietary changes include decreasing intake of saturated fats and cholesterol; increasing the proportion of dietary fiber, and complex carbohydrates; and maintaining ideal body weight. Referral to a dietitian is often useful, especially for older people. The length of time for which lifestyle changes should be attempted before beginning lipid-lowering drugs is controversial. In patients at average or low cardiovascular risk, 3 to 6 mo is reasonable. Generally, 2 to 3 visits with a patient over 2 to 3 mo are sufficient to assess motivation and adherence.
Drugs are the next step when lifestyle changes are not effective. However, for patients with extremely elevated LDL 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 gemfibrozil. 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 [< 1.04 mmol/L]; the guidelines do not specify an HDL cholesterol target level and recommend interventions to raise HDL cholesterol only after LDL cholesterol targets have been reached. Treatments for LDL cholesterol and TG reduction often increase HDL cholesterol, and the 3 objectives can sometimes be achieved simultaneously. No guidelines specifically address treatment of low HDL cholesterol in children.
Treatment includes lifestyle changes such as an increase in exercise and weight loss. Alcohol raises HDL cholesterol but is not routinely recommended as a therapy because of its many other adverse effects. Drugs are useful when lifestyle changes alone are insufficient.
Nicotinic acid (niacin) is the most effective drug for increasing HDL. Its mechanism of action is unknown, but it appears to both increase HDL production and inhibit HDL clearance; it may also mobilize cholesterol from macrophages. Niacin also decreases TGs and, in doses of 1500 to 2000 mg/day, reduces LDL cholesterol. Niacin causes flushing, pruritus, and nausea; premedication with low-dose aspirin may prevent these adverse effects. Extended-release preparations cause flushing less often. However, most OTC slow-release preparations are not recommended; an exception is polygel controlled-release niacin. Niacin can cause liver enzyme elevations and occasionally liver failure, insulin resistance, and hyperuricemia and gout. It may also increase homocysteine levels. In patients with average LDL cholesterol and below-average HDL cholesterol levels, niacin combined with statin treatment may be effective in preventing cardiovascular disorders.
Fibrates increase HDL. Infusion of recombinant HDL (eg, apoprotein A-1 Milano, an HDL variant in which a cysteine is substituted for an arginine at position 173 allowing for dimer formation) appears promising as a treatment for atherosclerosis but requires further study.
Elevated Lp(a):
The upper limit of normal for Lp(a) is about 30 mg/dL (0.8 mmol/L), but values in African Americans run higher. Few data exist to guide the treatment of elevated Lp(a) or to establish treatment efficacy. Niacin is the only drug that directly decreases Lp(a); it can lower Lp(a) by ≤ 20% at higher doses. The usual approach in patients with elevated Lp(a) is to lower LDL cholesterol aggressively.
Secondary causes:
Treatment of diabetic dyslipidemia should always involve lifestyle changes, with statins to reduce LDL cholesterol, fibrates to decrease TGs, or both drugs. Metformin lowers TGs, which may be a reason to choose it over other oral antihyperglycemic drugs when treating diabetes. Some thiazolidinediones (TZDs) increase both HDL cholesterol and LDL cholesterol (probably the less atherogenic large, buoyant type of LDL). Some TZDs also decrease TGs. These antihyperglycemic drugs should not be chosen over lipid-lowering drugs to treat lipid abnormalities in diabetic patients but may be useful adjuncts. Patients with very high TG levels and less than optimally controlled diabetes may have better response to insulin than to oral antihyperglycemic drugs.
Treatment of dyslipidemia in patients with hypothyroidism, renal disease, liver disease, or a combination of these disorders involves treating the underlying disorders primarily and lipid abnormalities secondarily. Abnormal lipid levels in patients with low-normal thyroid function (high-normal TSH levels) improve with hormone replacement. Reducing the dosage of or stopping drugs that cause lipid abnormalities should be considered.
Monitoring treatment:
Lipid levels should be monitored periodically after starting treatment. No data support specific monitoring intervals, but measuring lipid levels 2 to 3 mo after starting or changing therapies and once or twice yearly after lipid levels are stabilized is common practice.
Despite the low incidence of liver and muscle toxicity with statin use (0.5 to 2% of all users), current recommendations are for baseline measurements of liver and muscle enzyme levels at the beginning of treatment. Many practitioners obtain at least one additional set of liver enzyme measurements 4 to 12 wk after beginning treatment and annually thereafter. Statin therapy can be continued unless liver enzymes increase to > 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:
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.
Last full review/revision September 2008 by Anne Carol Goldberg, MD
Content last modified July 2012
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