Mary Young Lipid disorders are a significant risk factor in the development of atherosclerotic cardiovascular disease (ASCVD), which remains the leading cause of death in the United States. Adults older than 20 years in the United States have a 12.9% incidence of high total cholesterol, defined as total blood cholesterol above 240 mg/dL.1 The 2013 American College of Cardiology (ACC) and American Heart Association (AHA) guidelines on the assessment of cardiovascular (CV) risk2 identify four groups of patients who will benefit from treatment with cholesterol-lowering 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). This new guideline does not focus on goal treatment of low-density lipoprotein (LDL) levels. Rather, it focuses on the groups of patients for whom LDL lowering is proven most beneficial, including persons at risk of stroke. These new guideline recommendations replace the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines of 2003.2–5 Therapeutic lifestyle changes (TLCs), which include a heart-healthy diet, exercise, weight loss, and avoidance of tobacco, remain the first and most important intervention, followed by moderate- to high-intensity statin drugs to lower total cholesterol and low-density lipoprotein cholesterol (LDL-C), and to prevent coronary heart disease (CHD). Titrating statin drugs is no longer recommended to achieve goal levels of LDL.2 Lipid disorders are primarily caused by a combination of genetic, lifestyle, and nutritional factors. The primary goal of treatment is to decrease the lifetime and 10-year risk of ASCVD, based on risk calculations. The new guidelines support the initiation of statin drugs to lower overall risk, in conjunction with lifestyle changes. Four target groups for treatment with moderate- or high-intensity statin therapy have been identified2: • Patients who have CV disease • Patients with an LDL-C, or “bad” cholesterol, level of 190 mg/dL or higher • Patients with type 2 diabetes who are age 40 to 75 years These benefits affect both men and women, in all age ranges, including older adults. Fats and cholesterol are essential components of human cells and are synthesized by the liver. Additional cholesterol and a variety of other lipids are absorbed from the gastrointestinal tract during digestion and are transported through the bloodstream to the liver for processing. Deposition of cholesterol into arterial and venous walls promotes atherosclerosis. This pathologic process is influenced by a number of factors, including toxins and inflammatory mediators within the bloodstream and in the vessel wall, and by the types and concentrations of the various lipoproteins. Lipoproteins are characterized by their density and include chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and high-density lipoprotein (HDL). The progressive buildup of atheromatous plaque in the intimal arterial layer causes inflammation and narrowing of the vessel lumen. Gradually the atheromatous plaque enlarges and may rupture, causing coronary ischemia and infarction. LDL carries most of the cholesterol in the plasma and is the cause of atherogenic changes associated with the development of ASCVD. The principal function of LDL is to transport cholesterol to hepatic and extrahepatic cells. Although LDL particles are small, they carry approximately 70% of the circulating cholesterol in plasma. LDL is removed from the plasma by a single type of receptor located on the surface of many cells throughout the body: the LDL receptor. LDL’s apolipoprotein B (apo B) binds to the LDL receptor when LDL is carried into the cells. One molecule of apo B is present for each LDL particle, but the quantity of cholesterol per particle can vary considerably. The ratio of LDL to apo B correlates with the size of the LDL particles. Low LDL-C/apo B ratios reflect small LDL particles. These smaller, denser LDL particles are more atherogenic than normal-sized LDL particles and are associated with insulin resistance, diabetes, hypertriglyceridemia, and low HDL levels, all of which are significant risk factors for ASCVD. Elevation of lipoprotein(a) (Lp[a]) is significant in patients with known coronary artery disease (CAD) and elevated LDL, increasing the risk of CV events. Studies have indicated that the independent elevation of Lp(a) in persons without CAD may not be prognostic of CAD.6 HDL is an independent predictor of ASCVD risk. The role of HDL is significant; it lowers LDL by preventing oxidation of LDL within the arterial wall. In addition, when free cholesterol is released from cells into the plasma, it binds to HDL particles, resulting in a reverse cholesterol transport system. Cholesterol is returned to the liver, where it is excreted into bile, converted to bile acids, or reprocessed. There is an inverse relationship among VLDL remnants and small, dense LDL particles—known as atherogenic factors—and HDL. Because of the inverse relationship between levels of HDL and ASCVD risk, low levels of HDL (<40 mg/dL) have been identified as an independent risk factor for ASCVD regardless of the total cholesterol level. Higher high-density lipoprotein cholesterol (HDL-C) has a protective effect, and levels above 60 mg/dL are considered to be a negative risk factor, lowering the overall risk. The ratio of total cholesterol to HDL-C is correlated to cardiac risk. A total cholesterol/HDL-C ratio of more than 4.5 is associated with increased cardiac risk. Apolipoprotein A-I (apo A-I) is the predominant lipoprotein in HDL, and measurement of apo A-I in addition to the apo B found in LDL may allow more accurate assessment of cardiac risk. Physical activity increases HDL-C levels, emphasizing the importance of exercise in managing dyslipidemia. In addition, modest alcohol consumption (one or two drinks/day) increases HDL-C and appears to reduce cardiac risk. Excessive alcohol intake, however, increases triglycerides and detrimentally affects liver function. Hypertriglyceridemia is also associated with CAD, in conjunction with increased LDL and decreased HDL. Premature CAD associated with hypertriglyceridemia has a high correlation with familial hyperlipidemia, type 2 diabetes mellitus, and familial hypoalphalipoproteinemia. All of these are common in metabolic syndrome as well (see Chapter 212). Obesity is a primary risk factor for hypertriglyceridemia, and central obesity correlated with insulin resistance contributes to dyslipidemia. Poorly managed diabetes, some medications, and alcohol consumption are risk factors for secondary hypertriglyceridemia. Triglyceride levels above 2000 mg/dL are most associated with secondary and familial causes. The sedentary lifestyle of many Americans has increased the incidence of obesity and hyperlipidemia, with a subsequent rise in ASCVD and diabetes. A consistently maintained program of improved nutrition, weight reduction, and exercise improves the lipid profile, decreasing LDL and raising HDL.2–4 Despite increased awareness of healthy lifestyle choices in the United States, obesity is an American epidemic affecting overall morbidity and mortality. Obesity increases triglyceride levels, total cholesterol, and LDL-C and decreases HDL-C. Dietary cholesterol is derived from eating fatty meats and full fat dairy products. These food items are also high in saturated fats and calories and should be eaten in the lowest quantity possible. There are three major types of dietary fats: saturated, monounsaturated, and polyunsaturated. Each subtype exerts different influences on lipid metabolism, with saturated fats being the most harmful. Saturated fats increase blood cholesterol levels significantly more than dietary cholesterol does. Reducing saturated fats in the diet from 14% to 7% of total calories can decrease total blood cholesterol levels by nearly 20 mg/dL. Unfortunately, the major sources of saturated fats in the American diet are meats, eggs, and dairy products, which are highly consumed by Americans. Certain vegetable oils, namely, tropical oils such as palm and coconut oil, are highly saturated and are most often found in commercially prepared cakes, muffins, cookies, and other baked goods. Monounsaturated fats are derived from animal and plant oils. The main sources of monounsaturated fats in the American diet are peanuts, olives, avocados, and almonds. Monounsaturated fats do not by themselves raise or lower cholesterol levels but have been shown to help preserve baseline HDL levels when they are substituted for other fats. Their inclusion is a major feature of the popular Mediterranean diet. Polyunsaturated fats are considered essential fatty acids because they cannot be synthesized by the body, unlike the saturated and monounsaturated fatty acids. Polyunsaturated fats are derived from vegetable oils consisting of omega-3 fatty acids or omega-6 fatty acids found in fish products. Dietary fish oils have been shown to lower total cholesterol and LDL levels while also increasing HDL levels. Trans–fatty acids, from vegetable oils that have undergone extensive chemical processing or exposure to excess heat, have a detrimental effect on lipid levels. The most common sources in the American diet are margarine spreads, commercially produced baked goods, and deep-fried foods. Adult-onset diabetes is caused by a combination of factors, including progressive insulin resistance and inadequate insulin supply. Insulin resistance may or may not be associated with frank diabetes or even detectable high blood glucose levels. It is strongly influenced by genetic factors and is associated with abdominal obesity. Physical inactivity and a diet high in carbohydrates are major contributing factors. Insulin resistance, together with physical inactivity and obesity, often appears with other comorbidities, which include hypertension, high triglyceride levels, low HDL-C levels, and small, dense LDL particles, which are particularly atherogenic. Patients with these comorbid factors have metabolic syndrome (see Chapter 212), with a significantly increased risk for ASCVD.7 Persons with lipid disorders may be unaware of this, because signs and symptoms do not appear unless other comorbidities are associated with elevated lipids, such as heart disease. Physical signs and symptoms, such as xanthomas, are present only when the disease is severe and prolonged. Initial clinical evaluation should include a complete medical and family history, with documentation of any known ASCVD, symptoms of exertional angina or claudication, hypertension, diet and exercise patterns, smoking, drug and alcohol history and use, obesity, and diabetes. Hypothyroidism and liver and renal diseases affect lipid metabolism and should also be evaluated. All cardiac risk factors, including a family history of premature ASCVD, should be reviewed with the patient. Assessment of lifetime risk of ASCVD is recommended, using published risk assessment tables available at http://my.americanheart.org/cvriskcalculator and www.cardiosource.org/en/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx.2,6 Accurate successive measurement of cardiac rate and rhythm, blood pressure, and height and weight, with determination of waist-to-hip ratio and body mass index, is important for all persons being evaluated for hyperlipidemia and ASCVD. Fatty deposits or xanthomas may be observed or palpated in persons with very high cholesterol levels from a familial hyperlipidemia. Xanthomas may be present on areas such as the Achilles tendon and on elbows, knees, and metacarpal joints. Deposits of cholesterol on the eyelids, called xanthelasma, may also be present. The presence of corneal arcus, an opaque white ring about the corneal periphery, should alert the provider to seek further evaluation, especially when it is observed in the young adult. Obtaining a fasting lipid panel, which includes total blood cholesterol, LDL-C, HDL, and triglycerides, is recommended for all adults older than 20 years, every 5 years. After the initiation of lipid-lowering drugs, a second panel should be obtained in 4 to 12 weeks to ensure adherence and efficacy. Thereafter, blood testing every 3 to 12 months is adequate, based on patient response and clinician assessment. An initial test of liver function is important before statins are initiated; this does not need to be repeated unless the patient is symptomatic of liver disease or has adverse effects of statin therapy. Monitoring of creatine kinase (CK) is not necessary unless the patient has muscle symptoms.2 Before initiating medical therapy for dyslipidemia, the health care provider must consider other factors that may influence lipid metabolism. Diet, particularly excesses in overall calorie intake, and saturated fat may have an overall elevation effect on the lipid profile. Starvation states such as anorexia nervosa may cause an elevation in total serum cholesterol, whereas excessive intake of alcohol, poorly managed diabetes, or a familial tendency may elevate the triglyceride level.8 Other major causes of secondary dyslipidemia include adverse effects of some drugs, disorders of metabolism, and certain disease states. Drugs can affect lipid metabolism in a variety of ways. Glucocorticoids and estrogens may elevate triglyceride and HDL levels, whereas anabolic steroids can markedly reduce HDL levels. Thiazide diuretics elevate total cholesterol, triglyceride, and LDL levels. Alpha blockers may cause increases in HDL, whereas beta blockers can decrease HDL levels and increase triglyceride levels. Elevation of total cholesterol and triglyceride levels has been reported in individuals taking protease inhibitors to treat human immunodeficiency virus (HIV) infection. The most common endocrine disorders associated with lipid abnormalities are hypothyroidism and diabetes. Screening for thyroid disease (thyroid-stimulating hormone concentration, T3 and T4) and diabetes (fasting blood glucose concentration and hemoglobin A1c [HbA1c]) must be completed when abnormalities in the lipid profile are evaluated. Stabilization to a euthyroid state should be achieved before initiation of lipid treatment. In diabetics, achievement of adequate glycemic control will improve the lipid profile and is an integral component of therapy. Other disease states, such as nephrotic syndrome and obstructive liver disease, also contribute to lipid abnormalities and must be evaluated with a thorough medical history, physical examination, and laboratory tests, including urinalysis, blood urea nitrogen, creatinine, and liver function tests (LFTs). Differential Diagnosis Lipid Disorders
Lipid Disorders
Definition and Epidemiology
Pathophysiology
Low-Density Lipoprotein
High-Density Lipoprotein
Triglycerides
Role of Lifestyle, Including Diet and Exercise
Insulin Resistance, Diabetes, and Metabolic Syndrome
Clinical Presentation
Physical Examination
Diagnostics
Differential Diagnosis
Lipid Disorders
Chapter 211
