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146 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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for cTnI and 12 hours to 2 days for cTnT. Because of continuous
release from injured myocytes, cTnI levels may remain elevated
for 5 to 10 days after an MI versus 5 to 14 days for cTnT. Levels are
obtained at initial presentation of patients with chest discomfort
and repeated 3 to 6 hours later to conrm the diagnosis of MI.
3.
Describe the mechanism of action of the ARNI and its
effect on serum BNP and NT-proBNP.
ANSWER: The ARNI contains the angiotensin receptor blocker
drug called valsartan and the neprilysin inhibitor drug called
sacubitril. Sacubitril inhibits the enzyme neprilysin, which is
responsible for the breakdown of BNP. Because BNP is a sub
strate for neprilysin, the inhibition of neprilysin by the ARNI leads
to increased BNP levels. In contrast, NT-proBNP is not a substrate of neprilysin, so its serum levels remain relatively unaffected by the ARNI.
4. Dene the use of BNP levels in the clinical assessment of
patients presenting with heart failure.
ANSWER: The BNP levels are a good marker of left ventricular
dysfunction and a strong marker to predict morbidity and mortality in patients with heart failure. In conjunction with the standard clinical assessment, BNP is used to establish or exclude the
diagnosis of heart failure in patients presenting to the emergency
department for evaluation of acute dyspnea. Serum BNP levels
correlate with the clinical severity of heart failure as assessed by
New York Heart Association classication.
REFERENCES
1. Loscalzo J, Libby P, MacRae CA. Basic biology of the cardiovascular system.
In: Jameson J, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal
Medicine. 20th edition. New York, NY: McGraw-Hill; 2018: Chapter 232, 1-22.
2. ygesen K, Alpert JS, Jae AS etal. Fourth universal denition of
myocardial infarction. Circulation. 2018;138:e618-e651.
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16. James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic
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25. Al-Hadi HA, Fox KA. Cardiac markers in the early diagnosis and
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26. Puleo PR, Guadagno PA, Roberts R, et al. Early diagnosis of acute
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27. Puleo PR, Meyer D, Wathen C, et al. Use of a rapid assay of subforms of
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28. Ay H, Arsava EM, Sanbas O. Creatinine kinase-MB elevation aer stroke
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29. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for
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CHAPTER 7 • CARdiAC FunCTion And RElATEd TEsTs 147
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30. Pandit K, Mukhopadhyay P, Ghosh S, Chowdhury S. Natriuretic
peptides:diagnostic and therapeutic use. Indian J Endocrinol Metab.
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31. Tang WH, Francis GS, Morrow DA, et al. National Academy of
Clinical Biochemistry Laboratory Medicine practice guidelines: clinical
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2007;116(5):e99-e109.PubMed
32. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of
B-type natriuretic peptide in the emergency diagnosis of heart failure.
NEngl J Med. 2002;347(3):161-167.PubMed
33. Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. e N-terminal Pro-BNP
investigation of dyspnea in the emergency department (PRIDE) study.
Am J Cardiol. 2005;95(8):948-954.PubMed
34. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide
predicts sudden death in patients with chronic heart failure. Circulation.
2002;105(20):2392-2397.PubMed
35. Masson S, Latini R, Anand IS, et al. Direct comparison of B-type
natriuretic peptide (BNP) and amino-terminal proBNP in a large
population of patients with chronic and symptomatic heart failure:
theValsartan Heart Failure (Val-HeFT) data. Clin Chem. 2006;52(8):
1528-1538.PubMed
36. Richards M, Nicholls MG, Espiner EA, et al. Comparison of B-type
natriuretic peptides for assessment of cardiac function and prognosis
in stable ischemic heart disease. J Am Coll Cardiol. 2006;47(1):52-60.
PubMed
37. Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro brain
natriuretic peptide on admission for early risk stratication of patients
with chest pain and no ST-segment elevation. J Am Coll Cardiol.
2002;40(3):437-445.PubMed
38. James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic
peptide and other risk markers for the separate prediction of mortality
and subsequent myocardial infarction in patients with unstable coronary
artery disease: a Global Utilization of Strategies To Open occluded
arteries (GUSTO)-IV substudy. Circulation. 2003;108(3):275-281.
PubMed
39. Morrow DA, de Lemos JA, Sabatine MS, et al. Evaluation of B-type
natriuretic peptide for risk assessment in unstable angina/non-STelevation myocardial infarction: B-type natriuretic peptide and prognosis
in TACTICS-TIMI 18. J Am Coll Cardiol. 2003;41(8):1264-1272.PubMed
40. Galvani M, Ottani F, Oltrona L, et al. N-terminal pro-brain natriuretic
peptide on admission has prognostic value across the whole spectrum of
acute coronary syndromes. Circulation. 2004;110(2):128-134.PubMed
41. Balion CM, McKelvie RS, Reichert S, et al. Monitoring the response to
pharmacologic therapy in patients with stable chronic heart failure: is
BNP or NT-proBNP a useful assessment tool? Clin Biochem. 2008;
41(4-5):266-276.PubMed
42. Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart
failure guided by plasma aminoterminal brain natriuretic peptide
(N-BNP) concentrations. Lancet. 2000;355(9210):1126-1130.
43. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptideguided therapy to improve outcome in heart failure: the STARS-BNP
Multicenter Study. J Am Coll Cardiol. 2007;49(16):1733-1739.PubMed
44. Berger R, Moertl D, Peter S, et al. N-terminal pro-B-type natriuretic
peptide-guided, intensive patient management in addition to
multidisciplinary care in chronic heart failure a 3-arm, prospective,
randomized pilot study. J Am Coll Cardiol. 2010;55(7):645-653.PubMed
45. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal
pro-B-type natriuretic peptide-guided treatment for chronic heart
failure:results from the BATTLESCARRED (NT-proBNP-Assisted
Treatment ToLessen Serial Cardiac Readmissions and Death) trial.
J Am Coll Cardiol. 2009;55(1):53-60.PubMed
46. Psterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided
heart failure therapy: the Trial of Intensied vs Standard Medical
erapy in Elderly Patients With Congestive Heart Failure (TIME-CHF)
randomized trial. JAMA. 2009;301(4):383-392.PubMed
PubMed
47. Porapakkham P, Porapakkham P, Zimmet H, et al. B-type natriuretic
peptide-guided heart failure therapy: a meta-analysis. Arch Intern Med.
2010;170(6):507-514.PubMed
48. Thygesen K, Mair J, Mueller C, et al. Recommendations for the use of
natriuretic peptides in acute cardiac care: a position statement from
the Study Group on Biomarkers in Cardiology of the ESC Working
Group onAcute Cardiac Care. Eur Heart J. 2012;33(16):2001-2006.
PubMed
49. Mehra MR, Uber PA, Park MH, et al. Obesity and suppressed
B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol.
2004;43(9):1590-1595.PubMed
50. McCord J, Mundy BJ, Hudson MP, et al. Relationship between obesity
andB-type natriuretic peptide levels. Arch Intern Med. 2004;164(20):
2247-2252.PubMed
51. Krauser DG, Lloyd-Jones DM, Chae CU, et al. Eect of body mass
index on natriuretic peptide levels in patients with acute congestive
heart failure: a ProBNP Investigation of Dyspnea in the Emergency
Department (PRIDE) substudy. Am Heart J. 2005;149(4):744-750.
PubMed
52. Bayes-Genis A, Lloyd-Jones DM, van Kimmenade RR, et al. Eect of
body mass index on diagnostic and prognostic usefulness of aminoterminal pro-brain natriuretic peptide in patients with acute dyspnea.
Arch Intern Med. 2007;167(4):400-407.PubMed
53. Horwich TB, Hamilton MA, Fonarow GC. B-type natriuretic peptide
levels in obese patients with advanced heart failure. J Am Coll Cardiol.
2006;47(1):85-90.PubMed
54. Daniels LB, Clopton P, Bhalla V, et al. How obesity aects the cut-points
for B-type natriuretic peptide in the diagnosis of acute heart failure:
results from the Breathing Not Properly Multinational Study. Am Heart J.
2006;151(5):999-1005.PubMed
55. de Lemos JA, Morrow DA, Bentley JH, et al. e prognostic value of
B-type natriuretic peptide in patients with acute coronary syndromes.
NEngl J Med. 2001;345(14):1014-1021.PubMed
56. Morrow DA, de Lemos JA, Blazing MA, et al. Prognostic value of serial
B-type natriuretic peptide testing during follow-up of patients with
unstable coronary artery disease. JAMA. 2005;294(22):2866-2871.
PubMed
57. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal probrain natriuretic peptide and adrenomedullin: new neurohormonal
predictors of le ventricular function and prognosis aer myocardial
infarction. Circulation. 1998;97(19):1921-1929.PubMed
58. James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic
peptide and other risk markers for the separate prediction of mortality
and subsequent myocardial infarction in patients with unstable coronary
artery disease: a Global Utilization of Strategies To Open occluded
arteries (GUSTO)-IV substudy. Circulation. 2003;108(3):275-281.
PubMed
59. Poutanen T, Tikanoja T, Riikonen P, et al. Long-term prospective
follow-up study of cardiac function aer cardiotoxic therapy for
malignancy in children. J Clin Oncol. 2003;21(12):2349-2356.PubMed
60. Vogelsang TW, Jensen RJ, Hesse B, Kjaer A. BNP cannot replace
gated equilibrium radionuclide ventriculography in monitoring of
anthracycline-induced cardiotoxicity. Int J Cardiol. 2008;124(2):
193-197.PubMed
61. Feola M, Garrone O, Occelli M, et al. Cardiotoxicity aer anthracycline
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2011;148(2):194-198.PubMed
62. Goel S, Simes RJ, Beith JM. Exploratory analysis of cardiac biomarkers
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63. Stevens P, Freehardt D, Estis J, et al. e utility of cardiac biomarkers
during anthracycline chemotherapy for the detection of cardiac events:
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64. Pun SC, Nguyen A, Ades S, et al. Predictive value of high-sensitivity
cardiac troponin T, troponin I, NT-ProBNP, and high-sensitivity CRP
in the detection of myocardial injury following anthracycline-based
chemotherapy. J Am Coll Cardiol. 2015;65:10.
65. Morrison LK, Harrison A, Krishnaswamy P, et al. Utility of a rapid
B-natriuretic peptide assay in dierentiating congestive heart failure
fromlung disease in patients presenting with dyspnea. J Am Coll
Cardiol. 2002;39(2):202-209.PubMed
66. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic
peptide and norepinephrine over time and mortality and morbidity in
theValsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107(9):
1278-1283.PubMed
67. Entresto (sacubitril/valsartan) [prescribing information]. East Hanover,
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68. Perna ER, Macín SM, Cimbaro Canella JP, et al. Minor myocardial
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69. Demir M, Kanadasi M, Akpinar O, et al. Cardiac troponin T as a
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71. Miller WL, Hartman KA, Burritt MF, et al. Proles of serial changes in
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8
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Lipid Disorders
Jill S. Borchert and Kathy E. Komperda
OBJECTIVES
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 prole
and discuss how they should guide
treatment choices
Dyslipidemia, or an abnormal serum lipid prole, 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 aected by cardiovascular disease, with social determinants of
health aecting the burden of disease.2 Cardiovascular disease is a leading cause of
death and primary and secondary preventative eorts are essential to decrease associated morbidity and mortality.
Management of cholesterol is one of seven factors identied by the American
Heart Association (AHA) as critical to address to decrease ASCVD risk.2 Healthy People 2020 targets have been identied, with 2030 goals in development. Eorts 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 ≥240mg/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 eort to decrease overall cardiovascular risk.
is 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. e eects 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
DOI 10.37573/9781585286423.008
PHYSIOLOGY OF LIPID METABOLISM
Lipids are an essential component of several biological processes. e 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.
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. ese 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 dierent lipoproteins, an understanding of
the synthesis and metabolism of these lipoproteins is necessary for proper diagnosis
and treatment of dyslipidemia in eorts to reduce overall cardiovascular risk.
Cholesterol and TGs can be absorbed from the diet (exogenous) or synthesized
in the body (endogenous) (Figure8-1).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
5-7
TGs, the esteried form of glycerol and fatty acids, constitute
149
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FIGURE 8-1. Lipid metabolism. Apo = apolipoprotein;
FFA = free fatty acid; HL = hepatic lipase; IDL =
intermediate- density lipoprotein; LDL = low- density
lipoprotein; LDLR = lowLPL = lipoprotein lipase; VLDL = very low-
density lipoprotein receptor;
density
lipoprotein. Source: Reprinted with permission from
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.
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.
tion 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
e rate- limiting step in cholesterol synthesis is the conversion
of hepatic hydroxymethylglutaryl- coenzyme A (HMG-CoA)
to mevalonic acid.5 is conversion is catalyzed by the enzyme
HMG-CoA reductase.
5,6
An inhibitory feedback mechanism
modulates cholesterol synthesis.5 e 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.
Cholesterol, TGs, and phospholipid molecules com-
plex with specialized proteins (apolipoproteins) to form
5,7
Endogenous produc-
7
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. e 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 esteried and
unesteried cholesterol in varying amounts. ere are many
ways to classify these lipoproteins; however, lipoproteins are
classied most frequently by their density, size, and major apolipoprotein composition. Table8-1 summarizes the charac-
teristics of the ve major classes of lipoproteins.
6,7
e major
apolipoproteins listed in Table8-1 are a summary of the apolipoproteins involved in lipoprotein formation. Of note, ath
erogenic 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
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. Aer this process, the chylomicron is no longer TG rich and is now termed chylomicron remnant, which is
delivered to the liver. e 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
is 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. e 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. e last major lipoprotein is HDL and, unlike LDL, it is
considered protection against atherosclerosis via a mechanism
of reverse cholesterol transport (Figure8-2). 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 eective 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
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CHAPTER 8 • LiPid disoRdERs 151
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TABLE 8-1. Characteristics of Lipoproteins
MAJOR
LIPOPROTEIN SIZE DENSITY
APOLIPOPROTEIN ORIGIN COMMENTS
Chylomicrons and
Largest Least ApoB-48 Intestines Primarily TGs
chylomicron remnants
VLDL ApoB-100 Liver and intestines Primarily TGs
IDL or remnants ApoB-100 Chylomicrons and VLDL Transitional forms
LDL ApoB-100 End product of VLDL Major carrier of
cholesterol
HDL Smallest Most ApoA-I 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.
electrophoresis prole of lipoproteins. Currently, clinicians
classify by the primary lipid parameter aected. 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.
FIGURE 8-2. HDL metabolism and reverse cholesterol
transport. Apo = apolipoprotein; CETP = cholesteryl
ester transfer protein; HDL = high- density lipoprotein;
IDL = intermediatecholesterol acyltransferase; LDL = low-
density lipoprotein; LCAT = lecithin-
density
lipoprotein; LDLR = low- density lipoprotein receptor;
SR-BI = scavenger receptor class BI; VLDL = very
low- density lipoprotein. Source: Reprinted with
permission from 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.
Primary Lipid Disorders
Dyslipidemias, or abnormal concentrations of any lipoprotein
type, are classied by etiology into primary or secondary disorders. Primary disorders are caused by genetic defects in the
synthesis or metabolism of the lipoproteins. Table8-2 shows the
characteristics of the major primary dyslipidemias.
cally, familial dyslipidemias were categorized by the Fredrickson
3,6,9,10
Histori-
Secondary Lipid Disorders
Secondary dyslipidemias are disorders precipitated by other disease states, medications, or lifestyle (Table8-3).
secondary cause is likely responsible for the lipid abnormality,
treatment of the underlying cause should be strongly considered.
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.
ties 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 proles in patients with nephrotic syndrome are characterized by
markedly elevated LDL cholesterol and TGs.
disorders also have varying eects on lipid proles.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 signicant, and withdrawal of the precipitating medication usually leads to a reversal of secondary dyslipidemia.
6,11-13
When a
3,14
ese abnormali-
6,12,14
Dierent liver
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TABLE 8-2. Classication of Selected Primary Dyslipidemias
PRIMARY LIPID
ABNORMALITY
PRIMARY
DYSLIPIDEMIA SELECTED FEATURES
Increased LDL Familial
hypercholesterolemia
Familial defective
ApoB-100
Increased TGs Familial
hypertriglyceridemia
Familial apoC-II
deciency
Lipoprotein lipase
deciency
Increased TGs and
cholesterol
Familial combined
hyperlipidemia
a
LDL receptor defect, LDL 200–500 in
heterozygous, 500–800 in homozygous;
prevalence 1 in 500
ApoB-100 mutation impairs LDL binding,
LDL 200–400 in heterozygous, 500–800 in
homozygous; prevalence 1 in 1,500
Increases TG-
rich VLDL particles, TGs
>250; prevalence 5%
Autosomal recessive disorder; TGs >1,000;
prevalence <1 in 1,000,000
Autosomal recessive disorder, mutation
in lipoprotein lipase gene, TGs >1,000;
prevalence 1 in 1,000,000
Overproduction of ApoB, increased
production of VLDL, occurs in 1%–2% of
population, elevations in LDL, TGs, TC, but
degree varies widely
CLINICAL MANIFESTATIONS
Tendinous xanthomas,
premature ASCVD
Tendinous xanthomas,
premature ASCVD
Often asymptomatic unless
associated with metabolic
syndrome
Eruptive xanthomas,
hepatosplenomegaly,
pancreatitis
Eruptive xanthomas,
hepatosplenomegaly,
pancreatitis
Premature ASCVD
Familial
dysbetalipoproteinemia
ApoE mutation, elevations in TC and TGs
similarly elevated; occurs in 1 in 10,000
Palmar and plantar xanthomas,
premature ASCVD, peripheral
vascular disease
a
TGs, 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.
Source: Adapted from References 3,6,9,10.
Nonetheless, when interpreting a lipid prole, it is important
to evaluate how medication- related changes may have contributed to the prole. For example, antihypertensive agents are
frequently administered to patients with cardiovascular risk.
Nonselective beta- blocking agents, except carvedilol, which also
has α1- adrenergic receptor–blocking activity, may increase TG
concentrations and reduce HDL cholesterol concentrations.11
e eects on the lipid panel seem to be greater in individuals with high baseline TG concentrations. iazide diuretics
increase TC, LDL cholesterol, and TG concentrations. iazide
eects on the lipid panel are most pronounced with higher dosages; use of low doses is recommended. Although it is important
to realize the eect of antihypertensive agents on the lipid prole, agents that adversely aect the lipid prole are not contraindicated in patients with dyslipidemia. Careful consideration
of patient- specic factors is warranted.
Other drug classes have been implicated as sources of lipid
abnormalities; however, eects on the lipid panel should not be
considered a class eect 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 eects. Similar variability has been seen among oral contraceptives, immunosuppressive drugs, and protease inhibitors.
Various oral contraceptives aect lipoproteins dierently. Combination oral contraceptives increase TG concentrations. Eects
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 eects on HDL and LDL cholesterol levels but may
increase TGs. Immunosuppressive drugs such as cyclosporine,
sirolimus, and corticosteroids adversely aect the lipid prole,
but tacrolimus does not impact the lipid prole with the same
magnitude, and mycophenolate mofetil has no eect.
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 identied with other antiretroviral therapies, including the nucleoside reverse transcriptase inhibitor abacavir, the nonnucleoside
CHAPTER 8 • LiPid disoRdERs 153
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TABLE 8-3. Secondary Causes of Dyslipidemia and Major Associated Changes in Lipoprotein Component
MEDICAL OR DIET
a
Acute hepatitis (↑TGs)
Anorexia (↑LDL)
Autoimmune disease (↑LDL, ↑TGs)
Chronic kidney disease (↑LDL, ↑TGs)
Cigarette use (↓HDL)
Diabetes mellitus (↓HDL, ↑TGs)
Diet high in saturated or trans fats (↑LDL, ↑TGs)
Diet high in carbohydrates (↑TGs)
Glycogen storage disease (↑TGs)
Hypothyroidism (↑LDL, ↑TGs)
Liver failure (↓LDL, ↓TGs)
Metabolic syndrome (↑TGs)
Nephrotic syndrome (↑LDL, ↑TG)
Obesity (↓HDL, ↑TGs)
Obstructive liver disease (↑LDL)
Polycystic ovary syndrome (↑LDL, ↑TGs)
Pregnancy (↑ LDL, ↑TGs)
Sedentary lifestyle (↑TGs)
a
↑ = increase; ↓ = decrease.
b
Effect on HDL and LDL depends on specic components.
Source: Adapted from References 6,11–13.
a
DRUG
Alcohol (↑TGs)
Anabolic steroids (↑LDL, ↓HDL)
Atypical antipsychotics (↑TGs, ↓HDL)
Beta blockers (↑TGs, ↓HDL)
Combined contraceptivesb: oral, vaginal ring (↑TGs)
Corticosteroids (↑LDL, ↑TGs)
Cyclosporine (↑LDL, ↑TGs)
Estrogens, oral (↑TGs, ↑HDL, ↓LDL)
Estrogen- receptor modulators (↓LDL, ↑TGs)
Isotretinoin (↑LDL, ↓HDL, ↑TGs)
Progestins (↑LDL, ↓HDL, ↓TGs)
Protease inhibitors (↑TGs)
Propofol (↑TGs)
Sirolimus (↑LDL, ↑TGs)
Thiazide diuretics (↑LDL, ↑TGs)
reverse transcriptase inhibitor efavirenz, and the integrase inhibitor elvitegravir. Tenofovir disoproxil fumarate has been associated
with improvements in the lipid prole, but switching to tenofovir
alafenamide may increase lipids. Because drug- associated adverse
eects on the lipid prole have not been directly correlated with
increased risk for ASCVD, the importance of the ecacy, toxicity,
and pill burden of the antiretroviral regimen is emphasized when
considering a patient- centered treatment plan.
Lifestyle also may aect 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 modications, 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
e actual eect 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. Identication of patients at risk for ASCVD is a two- part
process. First, a laboratory assessment of the lipid prole 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.
guidelines exist, and a detailed summary of the recommenda
tions is beyond the scope of this chapter; however, key messages
regarding lipid monitoring are discussed.
e 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. is monitoring could be repeated more oen if a clinician determines a
patient’s ASCVD risk has increased14 or for adults between 40
and 75 years.4 e standard lipid panel includes TC, TGs, HDL,
and calculated LDL. is 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.
1,14
Some dierences between the
1,4
-
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Screening recommendations dier for pediatric patients.
e 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 uctuate. Reference ranges
and treatment strategies for pediatric patients dier 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
e lipid
panel was historically drawn as a fasting sample, requiring a
9- to 12- hour fast. However, eating causes clinically insignicant
dierences 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
ese changes typically do not aect 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- specic 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 benecial 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 48hours aer an event.22 A more recent study demonstrated that cholesterol levels remained relatively stable in the
4days aer an ACS event; however, no comparisons to pre-ACS
levels were performed.23 Despite the possible eect of cardiovascular events on lipid levels, the recommendations are to obtain a
lipid panel, preferably within the rst 24 hours aer 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 identied 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 prole measurement used by
the laboratory that the clinician uses regularly.
Total Cholesterol
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
Triglycerides
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 aer eating and are typically eliminated within 6 to 9 hours aer a meal. If chylomicrons persist
12hours 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 (>50g of fat) may provide a
clinically signicant 50% increase in TGs whereas a low- fat meal
(<15g 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 4weeks can be considered
if a high- fat meal was ingested before the measurement.
Triglyceride classication varies slightly between sources,
but recommendations aimed at reducing complications of hypertriglyceridemia are consistent with a focus on lifestyle modications and drug therapy, when necessary. e 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 oen 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 pre-
cipitate pancreatitis.
1,28
Before initiating drug therapy, underlying
1,3,12
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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 modication
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
brates 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. e 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 oen 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
modications 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 signicant increases in glycerol concentrations can
occur in uncontrolled diabetes or aer 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 aect laboratory TG measurement,
MINICASE 1
Hypertriglyceridemia
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 >50g 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.
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