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July 2002
Q. What are the internal and external variables that can retain
abnormal values for triglycerides in light of Zocor or Lipitor (20mg
or 10mg) prescribed treatment? The low-density lipoprotein, high-density
lipoprotein, and cholesterol values were within normal limits; prior
lipid electrophoresis was reported as normal.
A. Zocor, Lipitor, and other statin treatments induce
maximum reduction in serum LDL cholesterol between 24 and 60 percent,
reduce triglycerides an average of about 15 percent, and increase
the serum HDL cholesterol an average of about eight percent.1
In hypertriglyceridemia, the statins usually are unable to lower
the triglycerides to the new desirable cutpoint of 150 mg/dL (1.70
mmol/L). The triglycerides medical decision cutpoints (multiply
by 0.0113 for conversion from mg/dL to mmol/L) recommended by the
third report of the Adult Treatment Panel of the National Cholesterol
Education Program (ATP III) in mg/dL (mmol/L) are normal, <150 (<1.70);
borderline high, 150-199 (1.70-2.25); high, 200-499 (2.26-5.64);
very high, ≥500 (≥5.65).2
Patients with severe hypertriglyceridemia are usually treated with
diet and fibrate alone or in combination with nicotinic acid, n-3
fatty acids, a statin, or, as a last resort, an anabolic steroid,
to prevent pancreatitis.1
Hypertriglyceridemia occurs with genetic defects, such as deficiency
of apolipoprotein C-II3 and apolipoprotein
E polymorphism associated with decrease in sequestration and removal
of remnants of triglyceride-rich lipoproteins.4
Decreased tissue or endothelial lipoprotein lipase is associated
with accumulation of triglycerides when hydrolysis of triglycerides
from chylomicrons and hydrolysis of very-low-density lipoprotein
is decreased.5
References
1. Knopp RH. Drug treatment of lipid disorders.
N Engl J Med. 1999;341:498-511
2. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III). JAMA. 2001;285: 2486-2497.
3. Breckenridge WC, Little JA, Steiner G, et al.
Hypertriglyceridemia associated with deficiency of apolipoprotein
C-II. N Engl J Med. 1978;298:1265-1273.
4. Davignon J, Gregg RE, Sing CF. Apolipoprotein
E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8:1-21.
5. Nordestgaard BG, Abildgaard S, Wittrup HH,
et al. Heterozygous lipoprotein lipase deficiency. Frequency in
the general population, effect on plasma lipid levels, and risk
of ischemic heart disease. Circulation. 1997;96:1737-1744.
Gary L. Myers, PhD
Chief, Clinical Chemistry Branch
Division of Laboratory Sciences
National Center for
Environmental Health
Centers for Disease
Control and Prevention
Atlanta
Consultant, CAP
Chemistry Resource Committee Q. What guidance
is available for interpreting direct LDL measurements? My clinicians
fall back to manual Friedewald calculations because the imprecision
of two independent tests does not always equal the total cholesterol
(direct HDL plus direct LDL) value. It is understood that other
lipid fractions are not being measured, but what clinical range
of differences between tests should we see?
A. The National Cholesterol Education Program Third
Report of the Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (ATP III) recommends classifying
patients on the basis of serum LDL cholesterol for risk for cardiovascular
disease. The ATP III suggests that medical decisions using LDL-C
values in mg/dL (mmol/L) be based on the following cutpoints (multiply
by 0.02583 for conversion from mg/dL to mmol/L): optimal, <100 (<2.58);
near optimal, 100-129 (2.58-3.33); borderline high, 130-159 (3.36-4.11);
high, 160-189 (4.13-4.88); very high ≥190 (≥4.91).1
The impact of the ATP III on the clinical laboratory is to add LDL-C
and triglycerides to the fasting lipoprotein profile for screening,
adjust reporting formats, and expect more requests for tests to
characterize secondary causes of dyslipidemia.2
An assessment of the effect of systematic bias and random error,
quality control, and intraperson biological variation on the NCEP
medical decision classification LDL-C cutpoints demonstrates that
if laboratories are meeting the NCEP analytical performance guidelines
for LDL-C (measurement of less than four percent for bias and less
than four percent as coefficient of variation for precision), these
current NCEP guidelines are adequate to ensure (probability >0.90)
correct classification for risk of cardiovascular disease.3
It is recommended, therefore, that any method, either homogeneous
or chemical, being used to analyze patient specimens meet the NCEP
analytical performance recommendations for LDL-C measurements.
Currently, most clinical laboratories continue to use the screening
lipid and lipoprotein profile of total cholesterol, high-density
lipoprotein cholesterol, TG, and calculated LDL-C for patient samples
with a serum triglyceride level less than 400 mg/dL (4.52 mmol/L)
and substituting homogeneous LDL-C measurements for samples with
a triglyceride level above 400 mg/dL (4.52 mmol/L). This continued
use of the TC, HDL-C, and TG screening profile to calculate LDL-C
values when the TG is less than 400 mg/dL (4.52 mmol/L) has resulted
from findings of several studies comparing LDL-C quantitative methods.
Evaluation of the LDL-C results determined by four homogeneous
direct methods concluded that the homogeneous LDL-C results do not
improve on the LDL-C results calculated by the Friedewald equation
at triglyceride concentrations less than 400mg/dL (4.52 mmol/L).4
Fasting samples are recommended also for the homogeneous methods
since 16 percent of the patients with nonfasting values were greater
than five percent different from their fasting value. Some individuals
had large enough changes that nonfasting specimens could have produced
erroneous conclusions regarding LDL-C status. Three patients with
type III dyslipoproteinemia showed a decreased percentage difference
range from the reference method from -13.6 percent to +276 percent.4
In a multicenter evaluation of a homogeneous LDL-C assay that
was found to meet the currently established NCEP analytical performance
goals, findings confirm that the LDL-C results of the homogeneous
method are not improved over those of the calculated LDL-C when
the serum samples contain less than 400 mg/dL (4.52 mmol/L) of triglycerides.5
A study comparing the homogeneous LDL-C assay with the ultracentrifuge
reference method confirmed that the homogeneous method meets NCEP
analytical performance recommendations and showed acceptable predictive
values at the NCEP medical decision cutoff points.6
In a Veterans Medical Center study, researchers found that the studied
homogeneous LDL-C assay did not reduce the variability in LDL-C
measurements compared with the conventional LDL-C calculation but
has a specific role in lipid disorder evaluation, monitoring when
triglycerides are increased, or when the LDL-C value alone is needed.7
Other studies on the application of the homogeneous methods have
concluded that interpretation is limited in results of patients
with hyperlipoproteinemias,8 renal
disease,9 and liver disease,10
as well as in children.11
In summary, the interpretation of the result of the direct LDL-C
measurement, like for the result of any type of LDL-C measurement,
must consider any sources of variation known to exist in the samples
from clinical practice or in the instrument-reagent analytical system
from matrix effects.
If the question posed by the reader is interpreted to mean that
the TC does not always equal the sum of direct LDL-C and direct
HDL-C, this cannot happen. The TC includes very low-density lipoprotein
cholesterol as well as LDL-C and HDL-C. The NCEP desirable (normal)
value of TG for a population group is less than 150 mg/dL (1.70
mmol/L), which corresponds to approximately 30 mg/dL (0.78mmol/L)
of VLDL-C. The difference between TC and the sum of LDL-C and HDL-C
will range, therefore, between 15 and 30 mg/dL (0.39-0.78 mmol/L)
for most population samples.
A new classification of non-HDL-C lipoproteins was discussed in
the ATP III report1 and in the
report of the impact of ATP III on the clinical laboratory.2
This non-HDL-C classification is being investigated to determine
if it is a more accurate cholesterol measure of risk of CVD than
LDL-C. The non-HDL-C cutoffs are the ATP III LDL-C cutoffs plus
30 mg/dL (0.78 mmol/L).
References
1. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III). JAMA. 2001;285: 2486-2497.
2. Warnick GR, Myers GL, Cooper GR, et al. Impact
of the Third Cholesterol Report from the Adult Treatment Panel of
the National Cholesterol Education Program on the clinical laboratory.
Clin Chem. 2002;48:11-17.
3. Caudill SP, Cooper GR, Smith SJ, et al. Assessment
of current National Cholesterol Education Program guidelines for
total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol
measurements. Clin Chem. 1998;44:1650-1658.
4. Miller WG, Waymack PP, Anderson FP, et al.
Performance of four homogeneous direct methods for LDL-cholesterol.
Clin Chem. 2002;48:489-498.
5. Nauck M, Graziani MS, Bruton D, et al. Analytical
and clinical performance of a detergent-based homogeneous LDL-cholesterol
assay: a multi-center evaluation. Clin Chem. 2000;46:506-514.
6. Rifai N, Iannotti E, DeAngelis K, et al. Analytical
and clinical performance of a homogeneous enzymatic LDL-cholesterol
assay compared with the ultra-centrifugation dextran sulfate-Mg
method. Clin Chem. 1998;44:1242-1250.
7. Schectman G, Patsches M, Sasse EA. Variability
in cholesterol measurements: comparison of calculated and direct
LDL cholesterol determinations. Clin Chem. 1996;42:732-737.
8. Esteban-Salan M, Guimon-Bardesi A, De La Viuda-Unzueta
JM, et al. Analytical and clinical evaluation of two homogeneous
assays for LDL-cholesterol in hyperlipidemic patients. Clin Chem.
2000;46:1121-1131.
9. Akanji AO. Direct method for the measurement
of low-density lipoprotein cholesterol levels in patients with chronic
renal disease: a comparative assessment. Nephron. 1998;79:154-161.
10. Camps FGJ, Simo JM, Ferre N, et al. Agreement
study of methods based on the elimination principle for the measurement
of LDL- and HDL-cholesterol compared with ultracentrifugation in
patients with liver cirrhosis. Clin Chem. 2000;46:1188-1191.
11. Yu HH, Markowitz R, De Ferranti SD, et al. Direct measurement
of LDL-C in children: Performance of two surfactant-based methods in a general
pediatric population. Clin Biochem. 2000;33: 89-95.
Gary L. Myers, PhD
Chief, Clinical Chemistry Branch
Division of Laboratory Sciences
Gerald R. Cooper, MD, PhD
Medical Research
Officer,
Clinical Chemistry Branch
Division of Laboratory Sciences
National Center for
Environmental Health
Centers for Disease
Control and Prevention
Atlanta
Dr. Myers is a consultant for the CAP Chemistry Resource Committee.
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