After completing this chapter, the reader should be able to
List primary and secondary causes of dyslipidemia
Outline the physiology of lipid metabolism
Identify clinical manifestations of dyslipidemias
Calculate low-density lipoprotein when provided with total cholesterol, high-density lipoprotein, and triglyceride values
Given a case study, interpret laboratory results from a lipid profile and discuss how they should guide treatment choices
Dyslipidemia, or an abnormal serum lipid profile, is a major risk factor in the development of atherosclerotic cardiovascular disease (ASCVD).1 Clinical manifestations of ASCVD include acute coronary syndrome (eg, myocardial infarction), angina, coronary revascularization (eg, percutaneous coronary intervention), peripheral arterial disease, stroke, and transient ischemic attack.1 More than 121 million adults in the United States are affected by cardiovascular disease, with social determinants of health affecting the burden of disease.2 Cardiovascular disease is a leading cause of death and primary and secondary preventative efforts are essential to decrease associated morbidity and mortality.
Management of cholesterol is one of seven factors identified by the American Heart Association (AHA) as critical to address to decrease ASCVD risk.2 Healthy People 2020 targets have been identified, with 2030 goals in development. Efforts in the management of dyslipidemia have contributed to a decline in the prevalence of high total cholesterol (TC) and a decline in mean serum TC for adults meeting the Healthy People 2020 target for the proportion of adults with high TC (TC ≥240 mg/dL). Nonetheless, the Healthy People 2020 target for mean TC (177.9 mg/dL) has not been met overall or in any race/ethnicity subgroup. Further, approximately 30% of American adults have not been screened for dyslipidemia with a lipid panel. Practitioners are being asked to assess the lipid panel in an effort to decrease overall cardiovascular risk.
This chapter primarily covers the physiology of cholesterol and metabolism of triglycerides (TGs), their actions as part of lipoproteins, disorders of lipids and lipoproteins, and consequences of elevated lipid levels. The effects of diet, exercise, and drugs on these lipid values are also discussed. A detailed interpretation of test results and drug therapy with regard to cardiovascular risk is beyond the scope of this chapter, but references provide additional information.1,3,4
PHYSIOLOGY OF LIPID METABOLISM
Lipids are an essential component of several biological processes. The major plasma lipids are cholesterol, TGs, and phospholipids. Cholesterol serves as a structural component of cell wall membranes and is a precursor for the synthesis of steroid hormones and bile acids.5–7 TGs, the esterified form of glycerol and fatty acids, constitute the main form of lipid storage in humans and serve as a reservoir of fatty acids to be used as an energy source for the body.7 Phospholipids are lipid molecules that contain a phosphate group. Like cholesterol, phospholipids become constituents of cell wall membranes. Both cholesterol and TGs are hydrophobic, while phospholipids are hydrophilic. Cholesterol and TGs are surrounded by proteins and phospholipids to form lipoproteins. These lipoproteins are more water soluble and can then be transported in the body. Because the laboratory measurement of plasma lipids is the sum of cholesterol and TGs circulating in the different lipoproteins, an understanding of the synthesis and metabolism of these lipoproteins is necessary for proper diagnosis and treatment of dyslipidemia in efforts to reduce overall cardiovascular risk.
Cholesterol and TGs can be absorbed from the diet (exogenous) or synthesized in the body (endogenous) (Figure 8-1).6 Cholesterol is continuously undergoing synthesis, degradation, and recycling. Approximately one- to two-thirds of cholesterol consumed in the diet is absorbed; however, dietary cholesterol directly contributes relatively little to serum cholesterol levels. Instead, exogenous dietary intake of lipids and carbohydrates regulates endogenous synthesis of lipoproteins. Exogenous TGs are transported from the intestine to the systemic circulation via chylomicrons, which are predominantly TG-rich lipoproteins.5,7 Endogenous production of cholesterol, TGs, and phospholipids primarily occurs in the liver and intestinal tract. Most serum cholesterol is created from cholesterol synthesis in the liver. Intestinal cholesterol absorption, hepatic cholesterol synthesis, and excretion of cholesterol and bile acids regulate serum cholesterol concentrations.5–7 Most cholesterol synthesis occurs during the night.8 The rate-limiting step in cholesterol synthesis is the conversion of hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) to mevalonic acid.5 This conversion is catalyzed by the enzyme HMG-CoA reductase.5,6 An inhibitory feedback mechanism modulates cholesterol synthesis.5 The presence of cholesterol in hepatic cells leads to decreased biosynthesis of cholesterol. Conversely, when hepatic cholesterol concentrations decrease, there is a resulting increase in hepatic cholesterol biosynthesis. However, the feedback inhibition mechanism is inadequate in preventing a rise in serum cholesterol levels in the presence of disorders of carbohydrate and lipid metabolism.7
Cholesterol, TGs, and phospholipid molecules complex with specialized proteins (apolipoproteins) to form lipoproteins, the transport form in which lipids are measured in the blood.6,7 Because lipids are insoluble in aqueous plasma, they are formed into complexes with an outer hydrophilic coat of phospholipids and proteins and an inner core of fatty cholesterol and TGs. The apolipoproteins not only serve to support the formation of lipoproteins but also mediate binding to receptors and activate enzymes in lipoprotein metabolism. All lipoproteins contain phospholipids, TGs, and esterified and unesterified cholesterol in varying amounts. There are many ways to classify these lipoproteins; however, lipoproteins are classified most frequently by their density, size, and major apolipoprotein composition. Table 8-1 summarizes the characteristics of the five major classes of lipoproteins.6,7 The major apolipoproteins listed in Table 8-1 are a summary of the apolipoproteins involved in lipoprotein formation. Of note, atherogenic lipoproteins contain apolipoprotein B (apoB), while high-density lipoprotein (HDL) contains apoA. Another atherogenic lipoprotein is lipoprotein(a) [Lp(a)], which is associated with apo(a).6
Characteristics of Lipoproteins
Chylomicrons and chylomicron remnants
Liver and intestines
IDL or remnants
Chylomicrons and VLDL
End product of VLDL
Major carrier of cholesterol
Intestines and liver
Removes cholesterol from atherosclerotic plaques in arteries
Source: Adapted from Rader DJ, Kathiresan S. Disorders of lipoprotein metabolism. In: Jameson JL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: The McGraw-Hill Companies, Inc.; 2018:2889–2902; Freeman MW, Walford GA. Lipoprotein metabolism and the treatment of lipid disorders. In: Jameson JL, De Groot LJ, de Kretser DM, et al, eds. Endocrinology: Adult and Pediatric. 7th ed. Philadelphia, PA: W.B. Saunders Elsevier; 2016:715–736.
All major lipoproteins play a role in cholesterol metabolism and transport in the body.5,6 Chylomicrons, which are primarily TG rich, deliver TG from the gastrointestinal tract to the muscle and adipose tissue, where lipoprotein lipase (LPL) releases fatty acids and glycerol. After this process, the chylomicron is no longer TG rich and is now termed chylomicron remnant, which is delivered to the liver. The liver can export cholesterol and other TGs in the form of very low-density lipoproteins (VLDLs) into the circulation. Similar to chylomicrons, VLDLs are predominantly TG rich but have a higher cholesterol composition than chylomicrons (5 mg of TGs per 1 mg of cholesterol).6 Once in circulation, VLDL undergoes the same hydrolyzation as chylomicrons via LPL.5,6 This LPL activity then converts VLDL particles to intermediate-density lipoproteins (IDLs) and eventually low-density lipoproteins (LDLs). LDL typically carries the largest portion of cholesterol in the body. The liver degrades most circulating LDL; however, other tissues can take up a small portion of LDL that provides necessary cholesterol for cell membrane and steroid synthesis. LDL in general is considered atherogenic and has been a focus of dyslipidemia management. The last major lipoprotein is HDL and, unlike LDL, it is considered protection against atherosclerosis via a mechanism of reverse cholesterol transport (Figure 8-2). One role of HDL is to acquire excess cholesterol from degraded VLDL and the periphery. HDL undergoes an enzymatic reaction via lecithin cholesterol acyltransferase to become HDL cholesteryl ester and then is selectively taken up by the liver and targeted for excretion via bile. In addition, the cholesteryl ester transfer protein can transfer cholesteryl ester from HDL to the apoB-containing lipoproteins VLDL, IDL, and LDL, which then can be taken up by the liver more easily.
Elevated cholesterol is a known contributor to the development of atherosclerosis. Proper diagnosis and treatment of dyslipidemia can be an important preventative strategy. Numerous trials of effective treatment have demonstrated reductions in cardiovascular events, stroke, and total mortality in patients with ASCVD (secondary prevention) and in patients with asymptomatic dyslipidemia (primary prevention).1
Primary Lipid Disorders
Dyslipidemias, or abnormal concentrations of any lipoprotein type, are classified by etiology into primary or secondary disorders. Primary disorders are caused by genetic defects in the synthesis or metabolism of the lipoproteins. Table 8-2 shows the characteristics of the major primary dyslipidemias.3,6,9,10 Historically, familial dyslipidemias were categorized by the Fredrickson electrophoresis profile of lipoproteins. Currently, clinicians classify by the primary lipid parameter affected. Primary lipid disorders rarely occur alone, and it is unlikely for a genetic predisposition to be the sole cause of a lipid disorder. Clinically, other causes, such as diet or medications, should be considered and minimized in all patients.
Overproduction of ApoB, increased production of VLDL, occurs in 1%–2% of population, elevations in LDL, TGs, TC, but degree varies widely
ApoE mutation, elevations in TC and TGs similarly elevated; occurs in 1 in 10,000
Palmar and plantar xanthomas, premature ASCVD, peripheral vascular disease
aTGs, LDL, HDL, and TC in milligrams/deciliter. Conversion factor for LDL, HDL, and TC in International System (SI) units (millimoles/liter) is 0.02586. Conversion factor for TGs in SI units (millimoles/liter) is 0.01129.
Secondary dyslipidemias are disorders precipitated by other disease states, medications, or lifestyle (Table 8-3).6,11–13 When a secondary cause is likely responsible for the lipid abnormality, treatment of the underlying cause should be strongly considered.
Secondary Causes of Dyslipidemia and Major Associated Changes in Lipoprotein Component
Common disease-related causes of dyslipidemia are diabetes and thyroid disorders. Patients with type 2 diabetes may present with elevated TG levels, decreased HDL cholesterol levels, and increased levels of small, dense LDL.3,14 These abnormalities may persist despite adequate glycemic control, but optimization of glycemic control is still considered an important step. LDL cholesterol concentrations and, in some cases, TG levels increase in hypothyroidism.6 In addition to these endocrine disorders, chronic kidney disease and liver disorders should be excluded. Alterations in lipid concentrations depend on the type of renal disorder present. For example, patients with chronic kidney disease present with elevations in TGs, whereas lipid profiles in patients with nephrotic syndrome are characterized by markedly elevated LDL cholesterol and TGs.6,12,14 Different liver disorders also have varying effects on lipid profiles.6 It is recommended that secondary causes be excluded by patient history, physical examination, and laboratory data. Laboratory tests such as fasting blood glucose, thyroid-stimulating hormone, serum creatinine, and urinalysis for proteinuria are useful to exclude common secondary causes of dyslipidemia.
In drug-induced dyslipidemia, changes are not always clinically significant, and withdrawal of the precipitating medication usually leads to a reversal of secondary dyslipidemia. Nonetheless, when interpreting a lipid profile, it is important to evaluate how medication-related changes may have contributed to the profile. For example, antihypertensive agents are frequently administered to patients with cardiovascular risk. Nonselective beta-blocking agents, except carvedilol, which also has α 1-adrenergic receptor–blocking activity, may increase TG concentrations and reduce HDL cholesterol concentrations.11 The effects on the lipid panel seem to be greater in individuals with high baseline TG concentrations. Thiazide diuretics increase TC, LDL cholesterol, and TG concentrations. Thiazide effects on the lipid panel are most pronounced with higher dosages; use of low doses is recommended. Although it is important to realize the effect of antihypertensive agents on the lipid profile, agents that adversely affect the lipid profile are not contraindicated in patients with dyslipidemia. Careful consideration of patient-specific factors is warranted.
Other drug classes have been implicated as sources of lipid abnormalities; however, effects on the lipid panel should not be considered a class effect for these medications. Atypical antipsychotics are known to cause lipid abnormalities, with olanzapine and clozapine possessing the greatest potential to increase LDL cholesterol, TC, and TG levels.11 Other atypical antipsychotics, such as aripiprazole and ziprasidone, have a low risk of metabolic effects. Similar variability has been seen among oral contraceptives, immunosuppressive drugs, and protease inhibitors. Various oral contraceptives affect lipoproteins differently. Combination oral contraceptives increase TG concentrations. Effects on LDL and HDL are variable, depending on oral contraceptive components. Oral contraceptives with second-generation progestins (eg, levonorgestrel) that have strong androgenic properties may increase TG and LDL cholesterol levels and decrease HDL cholesterol levels. However, combined oral contraceptives with third-generation progestins (eg, desogestrel) do not cause unfavorable effects on HDL and LDL cholesterol levels but may increase TGs. Immunosuppressive drugs such as cyclosporine, sirolimus, and corticosteroids adversely affect the lipid profile, but tacrolimus does not impact the lipid profile with the same magnitude, and mycophenolate mofetil has no effect.
Protease inhibitors are known to primarily cause an increase in TG levels but may also increase LDL.13 Ritonavir-boosted lopinavir seems to have the greatest impact over ritonavir-boosted darunavir or atazanavir. Lipid abnormalities have also been identified with other antiretroviral therapies, including the nucleoside reverse transcriptase inhibitor abacavir, the nonnucleoside reverse transcriptase inhibitor efavirenz, and the integrase inhibitor elvitegravir. Tenofovir disoproxil fumarate has been associated with improvements in the lipid profile, but switching to tenofovir alafenamide may increase lipids. Because drug-associated adverse effects on the lipid profile have not been directly correlated with increased risk for ASCVD, the importance of the efficacy, toxicity, and pill burden of the antiretroviral regimen is emphasized when considering a patient-centered treatment plan.
Lifestyle also may affect lipoprotein concentrations. Besides contributing to ASCVD risk, obesity and cigarette smoking cause a decrease in HDL cholesterol, and obesity further causes an increase in serum TGs.6 Lifestyle modifications, including smoking cessation, physical activity, heart-healthy dietary patterns, and maintenance of a healthy weight, aid in reducing ASCVD risk and atherogenic lipid levels.1,2,4 A diet that is high in saturated fats and trans fatty acids increases LDL cholesterol levels. A diet low in saturated fats with avoidance of trans fatty acids is recommended to reduce risk of ASCVD.4 Low-carbohydrate diets favorably change TGs and HDL cholesterol, but they may increase LDL cholesterol levels and contribute to increased mortality if carbohydrates are replaced with animal-derived protein and fat. Light-to-moderate alcohol intake (one to two glasses of beer or wine or 1 to 2 oz of liquor per day) increases HDL.6,15 The actual effect of alcohol consumption on TGs is variable.3 It appears that light alcohol consumption may be associated with little to no change in TG levels. However, TG levels increase as alcohol consumption increases, particularly when excess alcohol is consumed with a diet high in saturated fat.
LABORATORY TESTS FOR LIPIDS AND LIPOPROTEINS
Laboratory tests can be used to assess the concentrations of various lipids in the blood, making ASCVD risk assessment possible. Identification of patients at risk for ASCVD is a two-part process. First, a laboratory assessment of the lipid profile must occur. Second, an assessment of the overall ASCVD risk, including an assessment of additional cardiovascular risk factors, must occur. Multiple guidelines regarding dyslipidemia screening and management are available.1,14 Some differences between the guidelines exist, and a detailed summary of the recommendations is beyond the scope of this chapter; however, key messages regarding lipid monitoring are discussed.
The American College of Cardiology (ACC) and the AHA published dyslipidemia guidelines (AHA/ACC guidelines) in 2018 with input and approval from several other professional organizations.1 ASCVD risk assessment for primary prevention, including a lipid panel, is recommended every 4 to 6 years for any adult patient between 20 and 39 years old. This monitoring could be repeated more often if a clinician determines a patient’s ASCVD risk has increased14 or for adults between 40 and 75 years.4 The standard lipid panel includes TC, TGs, HDL, and calculated LDL. This is only one component of the overall ASCVD risk assessment and should be done in conjunction with a review of information associated with established risk factors, such as age, diet, physical activity, weight, gender, blood pressure, diabetes, and smoking status.1,4
Screening recommendations differ for pediatric patients. The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents recommends a fasting lipid panel for children between the ages of 2 and 8 years if a child has a positive family history for premature cardiovascular disease or has a parent with known dyslipidemia or if the child has cardiovascular risk factors, such as hypertension, diabetes, or elevated body mass index.16 In addition, universal screening is recommended in all pediatric patients between 9 and 11 years. No routine screening is recommended during puberty because levels may fluctuate. Reference ranges and treatment strategies for pediatric patients differ from the adult population. A review of such pediatric recommendations is beyond the scope of this chapter.
Recent guidelines recommend that a fasting or nonfasting lipid panel can be used in ASCVD risk assessment.1,16 The lipid panel was historically drawn as a fasting sample, requiring a 9- to 12-hour fast. However, eating causes clinically insignificant differences in TC and HDL levels.17 Previous recommendations for fasting were based on the increase of TGs demonstrated with a fat tolerance test, which typically includes a much higher fat intake than average meals.18,19 It has been estimated that compared with the fasting state, a nonfasting LDL cholesterol level is up to 10% lower and a nonfasting TG level is up to 20% higher.20 These changes typically do not affect clinical decision-making. Allowing nonfasting lipid panels may increase screening rates, especially if the burden of obtaining the lipid panel under fasting conditions may delay and/or prevent lipid testing.21 Exceptions to nonfasting measurement in which a fasting lipid panel is recommended are if TG measurement is the focus of the lab test or if TGs are >400 mg/dL in a nonfasting sample.1
Several laboratory factors may cause deviations in the lipid values obtained. Ideally, the patient should remain seated 5 minutes before phlebotomy, and tourniquet application should be limited to <1 minute to avoid hemoconcentration, which may cause falsely elevated lipid levels.3,17 Plasma concentration lipid values are approximately 3% lower than those values associated with serum measurements.3,17
Patient-specific factors may also interfere with the lipid panel results. Recent weight changes, pregnancy, acute infection, trauma, and cardiovascular events may result in levels that are not representative of the patient’s usual value.17 For some of these circumstances (eg, pregnancy and acute infection), it may be beneficial to wait several weeks to months to obtain a lipid panel. For other circumstances, such as in the setting of acute coronary syndrome, a lipid panel should not be delayed. Measurement of plasma lipids in the setting of acute coronary syndrome usually provides LDL values that are lower than baseline 25 to 48 hours after an event.22 A more recent study demonstrated that cholesterol levels remained relatively stable in the 4 days after an ACS event; however, no comparisons to pre-ACS levels were performed.23 Despite the possible effect of cardiovascular events on lipid levels, the recommendations are to obtain a lipid panel, preferably within the first 24 hours after the event.24,25
Unlike most other laboratory values, “normal” ranges for lipid lab values are not determined by reference studies of normal subjects. Instead, values below a certain value (TC, LDL, and TGs) or values above a certain value (HDL) have been identified based on epidemiologic studies to determine ideal levels for decreasing cardiovascular disease risk.26 Methods used to assay lipid panels vary among institutions. It is important to become familiar with the method of lipid profile measurement used by the laboratory that the clinician uses regularly.
For adults ≥20 years, total cholesterol levels are categorized in the following ways27:
desirable: <200 mg/dL (5.2 mmol/L)
borderline high: 200 to 239 mg/dL (5.2 to 6.2 mmol/L)
high: ≥240 mg/dL (6.2 mmol/L)
Current recommendations are to use the other components of the lipid panel (eg, LDL) instead of TC to guide patient-care decisions.1 However, TC is still reported as part of a lipid panel, and the desirable levels included on laboratory reports are typically those from previous versions of cholesterol guidelines.27
For adults ≥20 years, TG levels are categorized in the following ways12:
normal: <150 mg/dL (1.7 mmol/L)
borderline high: 150 to 199 mg/dL (1.7 to 2.2 mmol/L)
high: 200 to 499 mg/dL (2.3 to 5.6 mmol/L)
very high: ≥500 mg/dL (5.6 mmol/L)
Disorders leading to hypertriglyceridemia involve dysregulation of chylomicrons and/or VLDL. Chylomicrons are typically only present postprandially, whereas VLDL, LDL, and HDL are present in the fasting state.17 TGs in the form of chylomicrons appear in the plasma soon after eating and are typically eliminated within 6 to 9 hours after a meal. If chylomicrons persist 12 hours postprandially, this indicates an abnormal state. As previously discussed, an overnight fast is recommended if TGs are the focus of measurement or if TGs are >400 mg/dL on a nonfasting sample1 because a high-fat meal (>50 g of fat) may provide a clinically significant 50% increase in TGs whereas a low-fat meal (<15 g of fat) does not.3 If a nonfasting TG level is elevated, it is important to inquire about a patient’s eating pattern to determine if retesting is valuable. Retesting in 2 to 4 weeks can be considered if a high-fat meal was ingested before the measurement.
Triglyceride classification varies slightly between sources,1,3,12 but recommendations aimed at reducing complications of hypertriglyceridemia are consistent with a focus on lifestyle modifications and drug therapy, when necessary. The AHA/ACC guidelines classify fasting or nonfasting TGs of 175 to 499 mg/dL (2.0 to 5.6 mmol/L) as moderate hypertriglyceridemia and fasting TGs of 500 mg/dL (5.6 mmol/L) or higher as severe hypertriglyceridemia.1 In moderate hypertriglyceridemia, VLDL is the primary carrier of excess TGs, whereas patients with severe hypertriglyceridemia often have both elevated VLDL and chylomicrons. Excess VLDL increases ASCVD risk, and chylomicrons contribute to the elevated risk of acute pancreatitis. Severe hypertriglyceridemia, especially concentrations ≥1,000 mg/dL or 11.3 mmol/L, may precipitate pancreatitis.1,28 Before initiating drug therapy, underlying factors should be addressed, such as physical inactivity, poor diet, uncontrolled diabetes, and use of medications that increase TGs. In patients with severe hypertriglyceridemia, the goal of therapy is to reduce TGs <500 mg/dL (5.6 mmol/L).28 Dietary modification includes an avoidance of trans fats and reduction in saturated fats without a concomitant increase in carbohydrates.1,3 For patients with diabetes, glycemic control may help to lower TG concentrations. For very high TGs, the drugs of choice for lowering TGs are fibrates or omega-3 fatty acids.1 An alternative approach to drug therapy for patients at lower risk for pancreatitis is to intensify statin therapy, which provides some reduction in TGs. Bile acid sequestrants should be avoided because these agents are known to increase TG concentrations (Minicase 1).
In addition to the risk of pancreatitis, extremely high concentrations of TGs—concentrations in excess of 2,000 mg/dL (22.6 mmol/L)—may also lead to eruptive cutaneous xanthomas on the elbows, knees, and buttocks.26 Once TG concentrations are reduced, the xanthomas gradually disappear over the course of 1 to 3 months. Such extremely high TGs may also manifest as lipemia retinalis (a salmon-pink cast in the vascular bed of the retina) because TG particles scatter light in the blood, which is seen in the retinal vessels during an eye exam. The presence of such signs and symptoms warrants a detailed patient history and laboratory testing to ensure appropriate treatment.
Many patients with high TGs lead a sedentary lifestyle and are obese. Patients encountered in clinical practice with elevated TGs often have similar lipid and nonlipid risk factors of metabolic origin termed metabolic syndrome, which is associated with an increased ASCVD risk.1,3 Metabolic syndrome is characterized by abdominal obesity, insulin resistance, hypertension, low HDL, and elevations in TGs. Metabolic syndrome is managed by correcting underlying causes, such as obesity, with lifestyle modifications and treating associated lipid risk factors.
Enzymatic methods for TG measurements are susceptible to interference by glycerol, which is normally present in serum.17,26 Clinically significant increases in glycerol concentrations can occur in uncontrolled diabetes or after extremely vigorous physical exercise.17 However, clinical laboratories incorporate means for correcting excess glycerol as part of the measurement process to provide accurate TG measurements.17,26
An excess of TGs in the blood can lead to errors in other laboratory measurements. Patients with severe hypertriglyceridemia may have lipemic samples, characterized by a milky appearance.29 Although it does not affect laboratory TG measurement, it may cause interference in measurement of other laboratory tests such as alanine aminotransferase and aspartate aminotransferase, which depend on spectrophotometric methods for analysis. Most technologists and automated systems can identify lipemic samples, and processes can be used to remove lipemia. This produces a clear specimen and eliminates interferences in these assay methods.
Felicia C., a 52-year-old woman, presents to the clinic to review lab results provided recently for routine screening. Her past medical history is significant for hypertension, bipolar disorder, and obesity. She has no premature family history of ASCVD. Daily medications include lisinopril 40 mg and olanzapine 15 mg. Her diet primarily consists of processed foods and significant amounts of carbohydrates. She denies any history of tobacco use but does report one to two glasses of wine most nights of the week. Physical activity is minimal beyond general daily activities. Felicia C. has no physical complaints. She is 5′6″ and 220 lb. Lab results are as follows: TC, 242 mg/dL; TG, 594 mg/dL; HDL, 40 mg/dL; and direct LDL, 80 mg/dL. The labs were drawn at 9 a.m.
QUESTION: How should the lipid results be interpreted? What should be done next?
DISCUSSION: The first step should be to confirm with the patient if the lab specimens were obtained when the patient was fasting. TGs are affected by recent food intake, and the impact varies depending on the fat content of the meal. If a typical low-fat meal is ingested before lab measurements, then the effect is clinically insignificant. However, if the meal contains >50 g of fat, then the TG levels could be increased by as high as 50%.3 If a patient fails to fast and the TG levels are >400 mg/dL upon screening, a repeat fasting lipid panel to confirm elevated TG levels should be ordered.1 Felicia C. confirms the lipids were drawn in the fasting state. The LDL value in her lipid panel is a direct measurement. Lipid panels are often ordered to provide a calculated LDL with a reflex measurement of direct LDL if the TGs are >400 mg/dL because LDL can only be calculated with the Friedewald formula when TGs are <400 mg/dL.
Felicia C. has very high TGs, with a TG level >500 mg/dL; therefore, TG lowering is the initial therapeutic goal.28 Very high TG levels, especially those >1,000 mg/dL, are associated with an increased risk of pancreatitis. Despite no symptoms or physical signs of pancreatitis, Felicia C. should take immediate steps to reduce her risk. To prevent acute pancreatitis, TGs should be lowered through lifestyle modifications, including dietary changes, alcohol avoidance, weight loss, and exercise. Dietary modifications include a reduction in saturated fat and avoidance of trans fat intake without an increase in carbohydrates.3 Felicia C.’s current diet is high in saturated fat and carbohydrates, which is an established secondary cause of hypertriglyceridemia. Abstention from all alcohol intake is important to minimize the risk of pancreatitis. Of the atypical antipsychotics, olanzapine has a greater potential to contribute to increases in TGs than other agents, such as aripiprazole or ziprasidone. However, the risks and benefits of modifications in therapy must be carefully weighed, and any changes to her bipolar treatment should only occur in consultation with her mental health care provider for close monitoring. Hypertriglyceridemia is often present in patients who are obese and physically inactive. Because diabetes or metabolic syndrome is a common secondary cause of hypertriglyceridemia, a fasting glucose level should be obtained to determine if this is a factor in Felicia C.’s case. Further, a TG-lowering drug, such as a fibrate or omega-3 fatty acid, should be considered.1 Bile acid sequestrants should be avoided because they may increase TGs. If Felicia C. experiences epigastric pain or vomiting, it may be prudent to check amylase and lipase levels and proceed with further evaluation for pancreatitis. Once TG levels have been lowered to <500 mg/dL, then attention can be turned to assessment of the lipid panel for ASCVD risk reduction.
Low-Density Lipoprotein Cholesterol
For adults ≥20 years, LDL levels are categorized in the following ways12:
desirable: <100 mg/dL (2.6 mmol/L)
above desirable: 100 to 129 mg/dL (2.6 to 3.3 mmol/L)
borderline high: 130 to 159 mg/dL (3.4 to 4.1 mmol/L)
high: 160 to 189 mg/dL (4.1 to 4.9 mmol/L)
very high: ≥190 mg/dL (4.9 mmol/L)
Low-density lipoprotein cholesterol can be measured directly or estimated indirectly by a method determined by Friedewald.30 The Friedewald formula subtracts the HDL and VLDL cholesterol from TC. The VLDL is estimated to be the TG level divided by five. Using the following formula (all in milligrams/deciliter), LDL may be estimated in patients with a TG concentration <400 mg/dL (4.5 mmol/L):
If a patient’s serum TG concentration exceeds 400 mg/dL (4.5 mmol/L), LDL cholesterol should not be calculated with this formula. A direct LDL measurement by laboratory would provide an LDL value. In patients with severe hypertriglyceridemia, TG-lowering therapy is often implemented to reduce pancreatitis risk. Once TG values have decreased to <400 mg/dL (4.5 mmol/L), a standard lipid panel provides LDL cholesterol data. Clinicians should be aware that other factors, such as low LDL levels (<70 mg/dL), especially when TGs are above normal, may also affect the reliability of the Friedewald equation and that calculation adjustments have been published.1,31,32 AHA/ACC guidelines recommend initiating statin therapy in patients based on ASCVD risk.1 Patients at high risk, including presence of clinical ASCVD or very high LDL levels (≥190 mg/dL or ≥4.9 mmol/L), would benefit from high-intensity statin therapy, with a goal LDL reduction of ≥50%. In patients between 40 and 75 years of age with diabetes, a moderate intensity statin with a goal LDL reduction of 30% to 49% is recommended. A high-intensity statin can be considered for select patients with diabetes with additional risk factors. For all other patients (ie, patients considered for primary prevention therapy without diabetes), an estimation of ASCVD risk is recommended via use of a risk calculator. Ten-year ASCVD risk calculations of 7.5% to 19.9% are classified as intermediate risk, whereas ≥20% are high risk. A patient’s ASCVD risk calculation and the presence of risk-enhancing factors (eg, family history of premature ASCVD, chronic kidney disease, metabolic syndrome) can help guide the clinician–patient risk discussion on statin therapy. When risk discussion favors the initiation of statin therapy, a moderate intensity statin can be used in patients with an intermediate ASCVD risk calculation, whereas a high-intensity statin can be recommended in a patient with a high 10-year ASCVD risk (Minicases 2 and 3).
Lifestyle modifications aimed at lowering ASCVD risk are appropriate for all patients.1 Detailed education should be provided to patients regarding the adoption of a low saturated fat diet that reduces the percent of calories from saturated fats and avoids trans fats.4,33 Physical activity should also be encouraged, with a goal of at least 150 min/wk of moderate-intensity exercise. Improvements in diet and physical activity are imperative to aid in weight loss in overweight or obese patients. A weight loss of ≥5% has been associated with a significant improvement in LDL and TGs.4 For patients at elevated ASCVD risk, lifestyle modifications with concurrent statin therapy should be recommended.1
High-Density Lipoprotein Cholesterol
For adults ≥20 years, HDL levels are categorized in the following ways12:
low (men): <40 mg/dL (1.0 mmol/L)
low (women): <50 mg/dL (1.3 mmol/L)
Based on epidemiologic evidence, HDL acts as an antiatherogenic factor.12 Whereas a high HDL concentration is associated with cardioprotection, low levels are associated with increased risk of ASCVD. The Framingham Study demonstrated that higher HDL levels are protective against cardiovascular risk, even in the setting of elevations in LDL.34 HDL has several antiatherogenic properties, such as reverse cholesterol transport and antiplatelet activity; however, clinical studies aimed at raising HDL with medications have failed to demonstrate a decrease in cardiovascular risk.12,34 Therefore, the mechanism of the association between low HDL and cardiovascular risk is not fully understood. It is possible that low HDL may be a marker of other atherogenic changes in the full lipid profile.
HDL cholesterol <40 mg/dL (1.0 mmol/L) in men or <50 mg/dL (1.3 mmol/L) in women is considered a risk factor of metabolic syndrome.1 Most patients with low HDL levels have concomitant elevated TG levels.6 In these patients, lifestyle therapy or drug therapy to decrease other atherosclerotic particles usually results in a desirable increase in HDL.34 HDL is negatively correlated with TGs, smoking, and obesity and positively correlated with physical activity and smoking cessation. Women typically have higher HDL levels than men, likely due to the beneficial effects of estrogen.6,34 Because of a lack of evidence, drug therapy decisions are not centered on raising HDL alone.1
Non–High-Density Lipoprotein Cholesterol
For adults ≥20 years, non-HDL levels are categorized in the following ways12:
desirable: <130 mg/dL (3.4 mmol/L)
above desirable: 130 to 159 mg/dL (3.4 to 4.1 mmol/L)
borderline high: 160 to 189 mg/dL (4.1 to 4.9 mmol/L)
high: 190 to 219 mg/dL (4.9 to 5.7 mmol/L)
very high: ≥220 mg/dL (5.7 mmol/L)
Non-HDL cholesterol (TC−HDL) provides an estimate of the sum of cholesterol carried by atherogenic particles that contain apolipoprotein B (apoB) such as LDL, VLDL chylomicrons, and Lp(a).1,12 For patients at very-high ASCVD risk (eg, multiple ASCVD events), non-HDL levels as well as LDL levels may guide when nonstatin therapies (eg, ezetimibe) are recommended.1
Julia K., a 46-year-old woman, presents to the clinic for a new patient consultation. She has been receiving care from a specialist (rheumatologist) but has not seen a primary care provider in many years. Her past medical history includes rheumatoid arthritis but no other chronic conditions; she is premenopausal and has an intrauterine device for pregnancy prevention. Her only medication is biweekly adalimumab, and she states the medication controls her symptoms well. She does not follow a specific diet but notes that she tries to limit her fast-food intake and eat a variety of fruits and vegetables. She walks at a moderate pace for 30 minutes three times a week. She denies any current tobacco use; she quit 10 years ago after smoking one pack per day for 10 years. She reports drinking one to two glasses of wine once a month. Her family history is notable, with a father who had a myocardial infarction at age 54. At her office visit, she has an unremarkable physical exam with a blood pressure reading of 112/74 mm Hg. She had a set of labs drawn the previous day that were nonfasting. The following laboratory results were obtained: TC, 270 mg/dL; HDL, 48 mg/dL; TG, 135 mg/dL; LDL, 195 mg/dL; and glucose, 102 mg/dL. Electrolyte, hematology, liver, renal, and thyroid tests are all normal. She is 5′6″ and weighs 159 lb.
QUESTION: How should the lipid results be interpreted? Based on this interpretation, is medication therapy recommended?
DISCUSSION: Julia K. is asymptomatic and follows a reasonable lifestyle that includes a diet rich in fruits and vegetables, routine aerobic exercise, no tobacco use, and low alcohol intake. Autoimmune disorders such as rheumatoid arthritis may be a secondary cause of dyslipidemia, and chronic inflammatory conditions may be a risk-enhancing factor for ASCVD.1 She does not have type 2 diabetes or thyroid, renal, or liver disease. She has a family history of premature ASCVD, with her father having a clinical ASCVD event at an age <55 years.
Guidelines recommend checking a lipid panel in a fasting or nonfasting state because evidence suggests the variation between fasting and nonfasting results is clinically insignificant if labs are drawn after a standard meal.1 Julia K.’s LDL is very high, her TC is high, her HDL is low, and her TGs are in normal range. The primary concern is the very high LDL because LDL ≥190 mg/dL highly suggests the presence of a primary lipid disorder. Patients with very high LDL cholesterol are known to be at an increased lifetime risk for ASCVD events because of their lifetime exposure to elevated atherogenic cholesterol. Julia K. would be considered high risk for ASCVD because of her very high LDL.
Julia K. should be encouraged to adhere to a low saturated fat diet that emphasizes reduced saturated fat and avoidance of trans fat and to maintain her physical activity. Because she is considered at high risk, high-intensity statin therapy is recommended. AHA/ACC guidelines recommend high-intensity statins for all adult patients with an LDL ≥190 mg/dL.1 Once treatment is started, a repeat lipid panel could be ordered in 4 to 12 weeks to assess for adherence and percentage reduction in LDL.
A number of risk-enhancing factors may be incorporated into patient-specific ASCVD risk assessment, including apoB, Lp(a), and high-sensitivity C reactive protein (hs-CRP).1 ApoB and Lp(a) are lipid specific markers whereas hs-CRP is an inflammatory marker. Current AHA/ACC guidelines do not offer specific testing recommendations for these laboratory tests. However, guidelines do recommend considering these results, when available, as part of the clinician–patient risk discussion, especially for primary prevention in patients at either borderline or intermediate risk. Elevated levels of these markers imply higher ASCVD risk and support statin initiation for primary prevention or the intensification of statin therapy in patients with high-risk or very high-risk ASCVD. ApoB is a major component of all atherogenic lipoproteins; however, apoB levels have not demonstrated superiority over non-HDL levels in ASCVD risk prediction.12 Thus, apoB is typically not measured because non-HDL is readily available with a standard lipid profile. Lp(a) is an atherogenic lipoprotein that can predict elevated ASCVD risk independent of other atherogenic lipid values.35 Lp(a) levels are stable throughout a patient’s life and are not affected by diet, exercise, fasting status, or statins. There is concern about the lack of standardization of Lp(a) measurement in clinical laboratories, and results may be reported in either milligrams/deciliter or nanomoles/liter. There is no acceptable conversion factor between the two units, and the preference is for assays that are calibrated and report results in nanomoles/liter. Currently, no evidence exists that treatment directed at lowering Lp(a) provides any additional ASCVD risk reduction beyond guideline recommendations. Of the LDL-lowering drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to lower Lp(a). Finally, hs-CRP is an inflammatory marker that has been linked to excess ASCVD risk.1,36 In a meta-analysis, elevated hs-CRP levels were linked to the risk of cardiovascular events, cerebrovascular events, and cardiovascular mortality.37 Therefore, current AHA/ACC guidelines consider elevated hs-CRP levels as a risk enhancing factor to be incorporated into a patient’s ASCVD risk assessment.1 Currently, there are no clear recommendations on when these laboratory markers should be ordered, but elevated results can assist in identifying patients who benefit from statin initiation or intensification of LDL-lowering therapy.
When the ASCVD risk assessment, including a lipid panel, results in an uncertain statin therapy decision, the coronary artery calcium (CAC) score is recommended by AHA/ACC guidelines.1,38 This is not a laboratory test but a scan that can assist in guiding decisions of statin initiation in primary prevention. If the CAC score is zero, then patients can be considered lower risk and statin therapy can be delayed. However, in certain patients (ie, current smokers and patients with diabetes, premature ASCVD family history, or certain inflammatory conditions) ASCVD risk may still be elevated despite the zero CAC score. Because CAC scans do expose patients to radiation, it is recommended that these tests be ordered by clinicians who are knowledgeable in diagnostic radiology.
James P., a 62-year-old man who is 5′ 9″ and weighs 260 lb, presents to the clinic after a positive stress test and is diagnosed with stable angina. He reported chest pain and shortness of breath with physical exertion that prompted the stress test. His past medical history is significant for obesity, hypertension treated with hydrochlorothiazide, and tobacco dependence. He does not have a history of diabetes or thyroid disorder. In addition to his hydrochlorothiazide, he is being prescribed metoprolol succinate, atorvastatin, and low-dose aspirin daily. He is hesitant to start these new medications and wonders if they are all necessary. He has never previously taken cholesterol-lowering medication. He does plan to quit smoking, has already purchased a nicotine replacement patch, and has set a quit date in the next week. His wife does most of the cooking and tries to prepare low-fat and low-salt meals, but he eats fast food for lunch most days of the week. He does not exercise routinely because exercise was limited by his chest pain but he would like to start walking regularly. His mother died of a stroke at age 62.
His blood pressure today at the clinic is 138/86 mm Hg, and his heart rate is 80 beats/min. Fasting lipid profile is as follows: TC, 212 mg/dL; TG, 160 mg/dL; LDL, 140 mg/dL; and HDL 40 mg/dL. Fasting glucose is 88 mg/dL; electrolyte, hematology, liver, renal, and thyroid test results are all normal.
QUESTION: How should the lipid profile be interpreted? Why should James P. receive a prescription for a lipid-lowering medication?
DISCUSSION: Even before this diagnosis, James P. was at risk for clinical ASCVD. At that time, he was an obese, male smoker—older than 45 years—with hypertension who lived a sedentary lifestyle and had some poor dietary habits. His mother died prematurely of ASCVD (female age <65 years).1 James P. is obese, which may contribute to an increase in TGs and decrease in HDL cholesterol; he has no other evidence of disease-related secondary causes of dyslipidemia (eg, diabetes, hypothyroidism, obstructive liver disease, renal dysfunction). However, there are potential substance- or medication-related secondary causes of dyslipidemia in James P.’s case. Although hydrochlorothiazide may increase LDL cholesterol and TGs, the effect is most pronounced at higher doses.11 Consideration of the lowest effective dose for blood pressure control would be valuable. He is a smoker but does have plans to quit in the immediate future. Smoking is associated with decreases in HDL cholesterol. James P.’s newly prescribed beta blocker may impact the lipid profile by causing decreases in HDL and increases in TGs. However, James P. should still start therapy with a beta blocker because the benefits of beta blockers in stable angina outweigh the impact on the lipid profile.
James P. should initiate therapy with a high-intensity statin (eg, atorvastatin 40 to 80 mg, rosuvastatin 20 mg). AHA/ACC recommendations are to initiate a high-intensity statin in all patients with clinical ASCVD, such as stable angina.1 Lifestyle modifications are appropriate for James P., including weight loss, increasing physical activity, and a greater emphasis on reducing saturated fat and avoiding trans fat in the diet. His smoking cessation efforts should be supported and assessed periodically. A lipid panel and hepatic transaminases were performed recently, and no additional baseline laboratory tests are needed. After starting atorvastatin, the lipid profile should be repeated in 4 to 12 weeks to check for adherence and LDL response.
Point-of-Care Testing Options
In addition to laboratory monitoring, point-of-care testing (POCT) options that range from at-home testing kits to healthcare practitioner–administered fingerstick tests are available.39,40 Many at-home testing kits only provide TC results, providing limited results for an ASCVD risk assessment. Other over-the-counter testing kits provide results of the full lipid panel. At-home tests typically require a patient to apply blood to a card and mail the sample into a laboratory for processing. In addition to at-home testing methods, there are relatively inexpensive compact devices for POCT outside the laboratory that are waived from the Clinical Laboratory Improvement Amendments. These devices enable testing for TC, HDL, TGs, and calculated LDL.
One important consideration when evaluating POCT devices is awareness that some variability may be explained by the fact that different sample types are often compared. For example, a fingerstick provides a sample with capillary blood and a venous draw provides venous whole blood. No strong evidence supports that these two sample types give equivalent results.17 The general conclusion is capillary blood samples provide lower lipid values than venous collection. Nevertheless, the POCT devices are accepted methods for screening for dyslipidemia and are frequently used at health fairs and other screening opportunities. In any POCT setting, quality control should be ensured to maintain accuracy of testing.
One of the benefits of POCT is that it involves the patient in the laboratory process. These visits become opportunities for the clinician to provide the patient with feedback on progress and reinforce the steps needed to reduce ASCVD risk. Because guidelines recommend a complete ASCVD risk assessment on all adult patients, it is important that patients still follow-up with a provider for a complete cardiovascular risk assessment because lipids are only one component of cardiovascular health.4
EFFECTS OF HYPOLIPEMIC MEDICATIONS
Clinicians must be aware of how hypolipemic drugs can influence laboratory test results. The ultimate goal of drug therapy is to reduce ASCVD risk or, in the case of very high TGs alone, reduce the risk of pancreatitis. In general, HMG-CoA reductase inhibitors (statins), ezetimibe, bile acid sequestrants, PCSK9 inhibitors, and bempedoic acid are considered LDL-lowering drug therapy. Fibrates and omega-3 fatty acids are considered drugs for lowering TGs. Niacin is an agent that has a favorable effect on multiple lipid parameters; however, it is no longer routinely recommended. Specific actions of the drugs and laboratory parameters used for monitoring safety are summarized in Table 8-4.1,12,28,41–43
BUN = blood urea nitrogen; WBC = white blood cell.
a↑ = increase; ↓ = decrease.
bRoutine monitoring of this lab test is not recommended with use of this drug therapy.
cRoutine monitoring of this lab test is recommended with use of this drug therapy.
dDifferent omega-3 fatty acid products exhibit varying effects on LDL and HDL depending on whether product contains both dehydroepiandrosterone and eicosapentaenoic acid or eicosapentaenoic acid only.
eThis information was not statistically analyzed in clinical trials but rather reported as exploratory endpoints.
fDue to lack of data, there are no current recommendations for or against routine monitoring of this lab test with use of this drug therapy.
The lipid panel consisting of TC, LDL cholesterol, HDL cholesterol, and TGs is an essential component of ASCVD risk assessment. Assessment of the lipid panel guides the identification of patients that may benefit from lifestyle modifications and/or drug therapy to reduce ASCVD risk. In the setting of hypertriglyceridemia, assessment of the lipid profile aids the clinician in identifying patients at risk for pancreatitis and assists with diagnostic, prognostic, and therapeutic decisions. For all patients with dyslipidemia, periodic measurement of the lipid profile is recommended to monitor progress and/or adherence.
1. Who should receive lipid testing?
ANSWER: The lipid panel, including TC, TGs, HDL, and LDL, is part of the ASCVD risk assessment that is recommended every 4 to 6 years for any adult patient between 20 and 39 years.1 This monitoring could be repeated more often for adults between 40 and 75 years4 or if a clinician determines that a patient’s ASCVD risk has increased.14 Screening is also recommended in all pediatric patients between 9 and 11 years.16
2. Why is the measured LDL marked as calculated or direct?
ANSWER: LDL cholesterol concentrations can be estimated indirectly by a calculation method determined by Friedewald1: LDL = TC – HDL – (TGs/5). If a patient’s serum TG concentration exceeds 400 mg/dL (4.5 mmol/L), LDL cholesterol cannot be calculated with this formula. Direct measurement of LDL is performed when the calculation would be inaccurate. Laboratory results typically indicate whether the LDL value is calculated or directly measured.
3. If a lipid panel is drawn in the nonfasting state, are the results clinically usable?
ANSWER: Recent guidelines recommend that a fasting or nonfasting lipid panel can be used in ASCVD risk assessment.1,19 The lipid panel was historically performed under fasting conditions after a 9- to 12-hour fast.17 Recent literature suggests the change in lipid levels after a meal are less significant; however, meals with >50 g of fat may increase TGs substantially.3,18–20 If TG measurement is the focus of the lab or if TGs are >400 mg/dL in a nonfasting sample, then a fasting lipid panel should be performed.1
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