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cap today

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.