Overview and Risk Factors

Hyperlipidemia is characterized by elevated concentrations of circulating lipids, increasing the risk of atherosclerosis and other serious conditions. Specific classes of hyperlipidemia include hyperlipoproteinemia, elevated very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, hypercholesterolemia (elevated cholesterol levels), and hypertriglyceridemia (elevated triglyceride levels).

Hyperlipidemia is typically asymptomatic and is frequently detected during routine screening. Occasionally, xanthelasmas and xanthomas are present. These are fatty deposits under the skin surface commonly found in patients with genetic disorders such as familial hypercholesterolemia.

Hyperlipidemia often results from delayed or defective clearance, or overproduction of VLDL by the liver, which is subsequently transformed into LDL. Familial hypercholesterolemia involves defective hepatic and nonhepatic LDL receptors. Excess intake of saturated fats increases the liver's production of VLDL and triglycerides via a molecular mechanism involving protein activators.¹ Saturated fats are found in animal products, such as meat, whole milk dairy products (milk, cream, cheese), and butter, and tropical oils (palm, palm kernel, and coconut).

High concentrations of total and LDL cholesterol and low levels of high-density lipoprotein (HDL) cholesterol predict cardiovascular risk in both men and women. High triglyceride levels have been associated with greater risk in women only.² The risk of cardiovascular disease increases by an average of 2% for each corresponding 1% rise in total cholesterol.

Risk Factors

Although hyperlipidemia is a frequent finding in all demographic groups that follow Western diets, it occurs somewhat more commonly in men. Additional risk factors include:

• Family history
• Diets high in total fat, saturated fat, and cholesterol (see Nutritional Considerations)
• Diabetes mellitus and metabolic syndrome: Hyperinsulinemia is associated with low HDL levels and hypertriglyceridemia.
• Chronic renal failure is associated with hypertriglyceridemia.
• Nephrotic syndrome: Decreased vascular oncotic pressure due to proteinuria leads to increased lipoprotein production by the liver.
• Hypothyroidism
• Hypopituitarism.
• Obesity: Obesity is associated with increased total cholesterol, LDL, VLDL, and triglycerides, as well as with decreased levels of HDL.
• Physical inactivity
• Alcoholism
• Steroid use
• Oral contraceptives
• Smoking: Cigarette smoking lowers HDL levels and is an independent risk factor for cardiovascular disease.

Diagnosis and Treatment

Diagnosis

The patient's medical and lifestyle history must be taken into account when assessing the lipid profile. Ideally, the patient should be in a steady state (no significant weight change or acute illness). Medications should be noted, since some drugs may interfere with lipid metabolism. Improvement of the conditions listed above that lead to hyperlipidemia may also improve the lipid profile.

Laboratory Testing

Patients must fast for at least 12 hours before blood sampling, because chylomicron clearance can take up to 10 hours. However, a fasted sample is not required for simple cholesterol screening.

Laboratory testing of the lipid profile measures total plasma cholesterol, HDL, and triglycerides directly. VLDL cholesterol levels are calculated by dividing the triglyceride value by 5. LDL cholesterol is calculated by subtracting HDL cholesterol and VLDL cholesterol from total cholesterol. When triglycerides are above 400 mg/dL, LDL calculation is inaccurate, and specialized laboratory tests measuring direct LDL are indicated.

Classification of Lipid Concentrations

Total cholesterol. According to NCEP guidelines, total cholesterol concentrations below 200 mg/dL are "desirable." A borderline high concentration is 200 to 239 mg/dL, and hypercholesterolemia is defined as greater than 240 mg/dL. However, epidemiological evidence suggests that stricter standards may be appropriate. Risk of cardiac events decreases as total cholesterol levels fall until plateauing at a total cholesterol of approximately 150 mg/dL. For children, total cholesterol should be less than 180 mg/dL.

Triglyceride. Normal triglyceride concentration is less than 150 mg/dL. Borderline is 150 to 199 mg/dL, and high is 200 to 499 mg/dL. Concentrations of 500 mg/dL or higher are considered very high.

HDL cholesterol. Concentrations of 60 mg/dL or higher are optimal. In general, an HDL concentration below 40 mg/dL is considered a major risk factor for coronary heart disease (CHD), although women's risk of CHD increases marginally with HDL cholesterol < 50.³ However, HDL is often interpreted in the context of total cholesterol and LDL concentrations, and may be less significant when LDL is low.

LDL cholesterol. According to the NCEP, LDL cholesterol concentrations below 100mg/dL are considered optimal. A range of 100 to129 mg/dL is near optimal. Borderline is 130 to 159 mg/dL. High is 160 to189 mg/dL. However, increasing evidence supports stricter standards, including reductions below 70 mg/dL for very high-risk patients. Studies of hunter-gatherer populations and normal neonates have modified the concept of "normal" cholesterol levels.⁴ Normal human LDL cholesterol concentration may be as low as 50 to 70 mg/dL, approximately half the US adult population mean. Coronary heart disease risk decreases as LDL cholesterol concentration decreases, reaching a nadir at approximately 40 mg/dL.⁵ NCEP classification and treatment guidelines have changed to reflect revised normal values and risk estimates.

Treatment

The mainstay of treatment for hyperlipidemia is dietary and lifestyle modification, followed by drug therapy, as necessary. Hyperlipidemia should not be considered refractory to dietary treatment if the therapeutic regimen included animal products or more than minimal amounts of vegetable oils. Such diets do not lower LDL cholesterol concentrations as effectively as high-fiber, low-fat diets that exclude animal products (see Nutritional Considerations).

Regular exercise can improve lipid concentrations. Low to moderate amounts of physical activity such as walking lower triglyceride concentrations by an average of 10 mg/dL, while raising HDL by 5 mg/dL/ (these numbers are means drawn from large groups). More strenuous activity may have greater effects.⁶

Patients with familial hypercholesterolemia typically require medication starting in early childhood.

HMG CoA reductase inhibitors (statins) decrease cholesterol production in the liver, and are first-line agents in the treatment of elevated LDL cholesterol. Statins also have important effects on cardiovascular risk aside from their ability to reduce lipid concentrations, and may be indicated for high-risk patients even when lipid targets can be achieved without drug therapy. Potential side effects include myopathy and increased liver enzymes. Some statins may also lower HDL to a below-goal level.

 

Bile acid sequestrants (eg, cholestyramine, colestipol) are second-line agents for the treatment of elevated LDL cholesterol. These medications can produce gastrointestinal distress, constipation, and impaired absorption of other drugs. 

Fibrates (eg, gemfibrozil, fenofibrate) are used as first-line treatment for elevated triglyceride concentrations and may be prescribed in combination with the above drug classes. Gallstones, dyspepsia, and myopathy may occur. Myopathy risk may be particularly high when fibrates are combined with statins.

Nicotinic acid (niacin) is a second-line therapy for all lipid disorders. Niacin is often combined with statins, but is also effective as a single agent. Its use is often limited by skin itching or burning. Other side effects include GI distress, hepatotoxicity, hyperglycemia, and gout.

Ezetimibe and colesevelam decrease GI cholesterol absorption, and have emerged as a favored second-line therapy due to their effectiveness, safety, and lack of side effects. They lower LDL and often raise HDL, and are particularly effective when combined with statins (often achieving lipid targets at lower statin doses). Ezetimibe has emerged as the more effective drug.

Nutritional Considerations

Elevated concentrations of blood lipids, particularly LDL cholesterol, are a significant risk factor for atherosclerosis and coronary heart disease (see Coronary Heart Disease). Reducing saturated fat and cholesterol intake decreases these concentrations. Cholesterol is present only in foods of animal origin, and these products are often the primary source of saturated fat in a person's diet. Thus, a diet that reduces or eliminates these products lowers total and LDL cholesterol and triglycerides.

Adding foods that prevent cholesterol manufacture in the body or that cause cholesterol to be bound and excreted in the gut also reduces serum lipids. Diet and lifestyle changes that lower triglycerides are important, because triglycerides may independently increase risk for coronary heart disease.⁷

The key nutritional interventions are as follows:

Reduced Dietary Fat and Cholesterol: Following a diet low in saturated fat and total fat and replacing saturated with unsaturated fat lower cholesterol production and blood lipids. The NCEP recommends Therapeutic Lifestyle Changes, which include a diet deriving ≤ 7% of calories from saturated fat and ≤ 200 mg/day of cholesterol. In outpatients, such a diet typically lowers LDL by about 5%,⁸ which may not be enough to achieve blood lipid goals.

More substantial diet changes appear to produce better results. Vegetarian (especially vegan) diets that are free of cholesterol and very low in saturated fat reduce LDL cholesterol by 17% to 40%, with the strongest effects seen when the diet is combined with exercise.^9,10 Reducing total fat, saturated fat, and cholesterol intake also lowers triglyceride levels by approximately 20%.¹¹

Although some authorities recommend replacing saturated fat and/or trans fatty acids with monounsaturated and polyunsaturated fats, it is important to remember that all oils are mixtures containing varying amounts of saturated fat. For example, olive oil is approximately 13% saturated fat, and fish oils range from 15% to 30% saturated fat.

For maximal lipid lowering, all fats and oils should be used sparingly, if at all. Greater fat intake leads to weight gain,¹² and many patients with hyperlipidemia need to lose excess weight to prevent cardiovascular disease. Diets very low in fat are an essential component of interventions that may reverse atherosclerotic lesions.¹³ Consuming small amounts of fats in their naturally occurring form (eg, nuts) may be preferable to using oils because of their potentially cardioprotective nutrients: magnesium, fiber, vitamin E, and flavonoids.

Soluble fiber: Soluble fiber reduces cholesterol concentrations chiefly through binding of bile acids, leading to increased cholesterol excretion, although several other mechanisms have also been suggested.¹⁴ Soluble fiber appears to be most effective in the context of a diet low in saturated fat.¹⁴ At an intake of 8 grams per day, soluble fiber lowers total cholesterol and lowers the LDL:HDL cholesterol ratio.¹⁵ Common sources include oats, barley, legumes, and many fruits and vegetables.

While diets high in refined carbohydrates (eg, white flour) can increase plasma triglyceride concentrations, the opposite is typically seen with diets high in unrefined, low-glycemic-index carbohydrate sources, such as legumes and most whole grains.¹⁶

Soy protein reduces hepatic cholesterol synthesis and may increase the hepatic LDL receptor uptake of cholesterol. In clinical tests, soy protein decreased total cholesterol by 9%, LDL by 13%, and triglycerides by 10%.¹⁷

Nuts (almonds, peanuts, pecans, and walnuts) appear to have hypolipidemic effects, apparently due to their fiber, plant sterol, and unsaturated fat content.¹⁸ Walnuts, for example, lowered total cholesterol by 12% and LDL cholesterol by 16%, and lowered the LDL:HDL ratio by 12%.¹⁹

Plant sterols (often in the form of margarine) reduce LDL cholesterol concentrations by roughly 10% by inhibiting cholesterol absorption.²⁰

A regimen combining the effects of a vegetarian diet, soluble fiber, soy protein, nuts, and plant sterols has been shown to lower LDL by nearly 30% in short-term clinical trials,²¹ an effect similar to that of statins. Although each of these foods alone contributes to lowering lipids, their effects are complementary when the foods are combined.

Avoiding alcohol may help reduce triglycerides. Alcohol appears to raise triglycerides by 5 to 10 mg/dL.^6,22 Restricting its consumption joins diet, exercise, and weight loss as cornerstones of treatment for patients with elevated triglyceride levels.²³

Orders

1. Diet: Vegetarian, low-fat, nondairy, high in soluble fiber. Avoid trans fats.
2. Nutrition consultation to advise patient in above diet and arrange follow-up.
3. Smoking cessation.
4. Exercise prescription (patient-specific).
5. Alcohol restriction for hypertriglyceridemia.
6. Change oral contraceptives to another form of contraception, as needed.

What to Tell the Family

Hyperlipidemia is a common preventable contributor to atherosclerosis. Both cholesterol and triglyceride concentrations can be reduced through restriction of saturated fat, cholesterol, transfatty acids, and total fat. Increasing dietary fiber, soy foods, and exercise can make these measures more effective. The patient's family may also be at risk for hyperlipidemia and other cardiovascular diseases. Their adoption of the same diet and lifestyle changes being made by the patient, including smoking cessation, will encourage patient adherence and improve family members' health.

References

1. Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell. 2005;120:261-273

2. Sharett AR, Ballantyne M, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001;104:1108-1113.

3. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.

4. O'Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dL: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142-2146.

5. 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 2004;110:227-239.

6. Hata Y, Nakajima K. Life-style and serum lipids and lipoproteins. J Atheroscler Thromb. 2000;7:177-197.

7. Cullen P. Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol. 2000;86:943-949.

8. Hunninghake DB, Stein EA, Dujovne CA, et al. The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia. N Engl J Med. 1993;328:1213-1219.

9. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998;280:2001-2007.

10. Barnard ND, Scialli AR, Bertron P, Hurlock D, Edmonds K, Talev L. Effectiveness of a low-fat vegetarian diet in altering serum lipids in healthy premenopausal women. Am J Cardiol. 2000;85:969-972.

11. Pelkman CL, Fishell VK, Maddox DH, Pearson TA, Mauger DT, Kris-Etherton PM. Effects of moderate-fat (from monounsaturated fat) and low-fat weight-loss diets on the serum lipid profile in overweight and obese men and women. Am J Clin Nutr. 2004;79:204-212.

12. Peters JC. Dietary fat and body weight control. Lipids. 2003;38:123-127.

13. Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet.1990 ;336:129-133.

14. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr. 1999; 69:30-42.

15. Jenkins DJ, Kendall CW, Vuksan V, et al. Soluble fiber intake at a dose approved by the US Food and Drug Administration for a claim of health benefits: serum lipid risk factors for cardiovascular disease assessed in a randomized controlled crossover trial. Am J Clin Nutr. 2002;75: 834-839.

16. Jenkins DJ, Wolever TM, Kalmusky J, et al. Low-glycemic index diet in hyperlipidemia: use of traditional starchy foods. Am J Clin Nutr. 1987;46:66-71.

17. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Eng J Med. 1995;333:276-282. 

18. Kris-Etherton PM, Yu-Poth S, Sabate J, Ratcliffe HE, Zhao G, Etherton TD. Nuts and their bioactive constituents: effects on serum lipids and other factors that affect disease risk. Am J Clin Nutr. 1999;70:504S-511S.

19. Hu FB, Manson JE, Willett WC. Types of dietary fat and risk of coronary heart disease: a critical review. J Am Coll Nutr. 2001;20:5-19.

20. Katan MB, Grundy SM, Jones P, et al. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc. 2003;78:965-978.

21. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA. 2003;290:502-510.

22. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ. 1999;319:1523-1528.

23. Malloy MJ, Kane JP. A risk factor for atherosclerosis: triglyceride-rich lipoproteins. Adv Intern Med. 2001;47:111-136.