Low Triglyceride Levels Affect Calculation of Low-Density Lipoprotein Cholesterol Values

Hyperlipidemia leads to arthrosclerosis and an increased risk of coronary heart disease (CHD).1,2 Blood lipids, such as total cholesterol (CH), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and especially low-density lipoprotein cholesterol (LDL-C), become increasingly important in the diagnosis and management of CHD and related diseases. Epidemiological, autopsy, and animal studies have firmly established that a high LDL-C level is arthrogenic.3,4 The National Cholesterol Education Program, Adult Treatment Panel II (NCEP ATP II) in 1993 classified an LDL-C level of 160 mg/dL or more as a high-risk level, a value between 130 and 159 mg/dL as a borderline value, and a level of less than 130 mg/dL as optimal.1 

Currently, most clinical laboratories are using the Friedewald estimation to calculate LDL-C values, ie, LDL-C (calc.) = CH − HDL-C − (TG/5).5 The estimation is fairly accurate provided the TG level is less than 400 mg/dL. We have also observed in our own setting that the LDL-C (calc.) values matched closely with direct measurements (unpublished data). In the presence of rare type 3 hyperlipoproteinemia, or if the TG level exceeds 400 mg/dL, the LDL-C (calc.) is no longer reliable and should be measured directly or the result would be erroneously lower.6 We report herein a different type of potential error in the calculation of LDL-C levels. In this case, because of an unusually low TG level, the LDL-C (calc.) level was much higher than the value from direct measurement.

Our patient was a 63-year-old man in good health who recently completed a routine checkup that revealed the following laboratory data from SmithKline Beecham Clinical Laboratories in Seattle, Wash: CH, 263 mg/dL; HDL-C, 85 mg/dL; LDL-C (calc.), 170 mg/dL; and TG, 42 mg/dL. Other chemistry tests, hematology analyses, and urinalysis revealed nothing unusual. Because of the elevated CH and LDL-C levels, his family physician prescribed pravastatin, 10 mg/d.7 Before he started taking his medication, the patient took a business trip to Taiwan and, while in Taiwan, had similar laboratory work done at Sinlau Christian Hospital.

Both CH and TG levels were measured with a Vitros 750 (Johnson & Johnson, Ortho Clinical Diagnostics, Raritan, NJ) following the manufacturer's instructions—HDL-C using dextran sulfate/magnesium precipitation followed by Vitro 750 CH method; LDL-C (calc.) using the Friedewald formula; LDL-C direct measurement using bio-Mérieux Vitek Inc (Hazelwood, Mo) reagents and an agarose electrophoresis using Rep Direct-Sep (Helena Laboratories, Beaumont, Tex); and apolipoprotein B by the nephelometric method.

The test results at our laboratory were as follows: CH, 262 mg/dL; HDL-C, 79 mg/dl, LDL-C (calc.), 172 mg/dL, and TG, 55 mg/dL (Table). The other laboratory results were similar to the SmithKline Beecham results. According to the NCEP ATP II guideline, the patient had 2 CHD risk factors, ie, male older than 45 years and an LDL-C (calc.) level of greater than 160 mg/dL. After subtracting out the negative risk factor, an HDL-C level of more than 60 mg/dL, the patient still had one risk factor.8 Does this patient need treatment for elevated CH and LDL-C levels? Although most clinical laboratories perform LDL-C by calculation and only switch to direct measurement when TG levels have exceeded 400 mg/dL, we looked at his unusually low TG levels and wondered if this would inaccurately drive the LDL-C (calc.) value higher than the actual value. We, therefore, measured the LDL-C values on the same specimen using the direct method and obtained a normal value of 126 mg/dL! This value was further confirmed by the agarose electrophoretic method (130 mg/dL) and was also substantiated by a normal apolipoprotein B level of 116 mg/dL (60–130 mg/dL).9 

To further demonstrate our observation that, under normal TG levels, LDL-C (calc.) values matched closely with direct measurement, we also directly measured LDL-C values using the Rep Direct-Sep method on 20 routine chemistry specimens on which a lipid panel was ordered and the LDL-C values were derived by using the Friedewald formula. We found no significant difference (P < .001) but a good correlation (r = 0.981) between the 2 methods, Friedewald calculation and Rep Direct-Sep (mean, 173.7 and 175.9 mg/dL; SD, 26.4 and 38.2; N = 20). The TG values in this group ranged from 120 to 270 mg/dL.

The LDL-C (calc.) level of the patient was much higher than the direct measurement level. We attribute this to the low TG value, resulting in an overestimation of the LDL-C value. Our finding suggests that, similar to high TG levels, low TG levels can also affect the calculation of LDL-C values. As to how low the TG levels need to be before affecting the LDL-C (calc.) is currently under our investigation. As far as we know, this phenomenon has not been previously reported. Although low TG can be due to conditions such as hyperthyroidism by increased utilization or liver disease by decreased mobilization and production,10 the patient did not have any indications of these abnormalities. The only explanation that we could attribute to his low TG values was his carefully watched low-fat and low-protein diet. Persons following low-protein and low-fat diets similar to the probable diet of our distant ancestors have low TG levels.4,11 

Most clinicians follow the NCEP ATP II guidelines in managing their patients. If a patient has a LDL-C value greater than 160 mg/dL and has 2 CHD risk factors, he or she is likely to be given drug therapy in addition to a dietary regimen. Since drug therapy is likely to continue for many years, the decision to add drug therapy should be made only after careful evaluation of LDL-C levels. Also a low TG and high LDL-C value may be a sign of liver disease (like biliary cirrhosis). The accuracy of LDL-C levels whether by direct measurement or by calculation is thus of the utmost importance. Although calculation of LDL-C in routine work is fairly accurate, this study suggests that, in the presence of low TG and high CH levels, use of the calculation method of LDL-C should be cautioned and a direct measurement of LDL-C may be warranted. In addition, one should also be aware of the very large known intraindividual variability of TG levels and the many conditions that can result in hypotriglyceridemia.11–14 

We thank Louisa Wu, MT, BS, and other laboratory staff at Sinlau Christian Hospital for their contribution.