Impact of Change in HDL Measurement Technology on the Prediction of the Population at
Risk of Atherothrombotic Disease
Science achieves knowledge occasionally by a giant leap into the unknown, but usually it does so by
the continuous accumulation of knowledge in a layer upon layer effect, such as the layering of
sediments in a lake bed. As Isaac Newton once remarked,”If I have seen a little farther, it is because I
have stood on the shoulders of giants.” So it is with the fields of interventional lipidology and
preventive cardiology. The Framingham Heart Study (FHS) led the way in identifying risk factors for
atherothrombotic disease (ATD), showing that lipids were a prime cause of ATD and that the spectrum
of lipids typical of the ATD population was different than the lipid spectrum of the population without
clinical ATD. Eventually, the FHS developed the concept of the CT:HDL ratio (or Framingham Fraction
[FF]) as the best lipid predictor. The FF predicts the population at risk of ATD better than LDL by itself.
(1-5)
On or about the year 2000, the methodology for measuring HDL changed. Perhaps not fully
appreciating what they were doing, the manufacturers of the auto-analyzers switched from the
precipitation (indirect) method of measuring HDL to the enzymatic (direct) method. This method
change was not much publicized, even though the two measurement techniques do not give equivalent
results. Indeed, the direct measurement of HDL gives a value about 10 mg/dl higher than the result that
would have been obtained had the indirect measurement of HDL been performed. Since LDL is not
usually measured but rather calculated by the Friedewald equation, this means that of necessity the LDL
calculated when the direct measurement of HDL is utilized will be about 10 mg/dl lower than the result
that would have been obtained had the indirect method been utilized.
This is important because most of the trials that have given lipidologists their goals for predicting the
population at risk of ATD and the goals of therapy to stabilize/regress plaque or prevent ATD events
were done using the indirect measurement of HDL, and hence the goals promulgated in the 21st century
will be off target and not relevant to the goals set by the trials of the 20th century. In other words, the
lipids on paper will not reflect the atherogenic potential of the lipids at the level of the arterial wall. In
addition, ratios such as FF will be useless..
These points are not trivial. I reported a case of a 55 year-old patient of mine who sustained an
acute myocardial infarction (AMI). (6) I had been treating him for years and he had no obvious reason to
measure his lipids: no obesity, cigarette smoking, hypertension, diabetes, or even a family history of
ATD. I had seen him for recurrent bouts of job-related depression. When he had his AMI, the hospital
performed a lipid panel on admission. Details of this panel are given in the letter to the editor (6) but in
brief reveal an LDL of 143 mg/dl, and HDL of 43 mg/dl, and TG of 66 mg/dl. Many lipidologists may have
elected not to treat such a lipid panel in a primary prevention scenario. However, when converted to
the lipids that would have been obtained using the indirect method of HDL measurement, the LDL level
would have been 153 mg/dl and the HDL would have been 35 mg/dl. I would have treated a lipid panel
such as this last because such lipids are consistent with ATD occurring in the sixth decade of life (7),
which is of course precisely when he had his event.
When the manufacturers initially brought out their new technology, I requested our hospital
laboratory to find out the formula to convert the direct measure-HDL to its equivalent indirect-HDL
value. The formula is as follows: indirect-HDL=(direct-HDL minus 12)/0.93. This correction could easily
be programmed into the computers printing out the laboratory reports. Other authors (8,9) have
commented on the effects of this change in technology and the interpretation of current lipid values,
but have not suggested a remedy. I believe that my suggestion constitutes such a remedy, and I urge
lipidologists to request their laboratories to make such conversions on their reports. This will permit
the trials in interventional lipidology and preventive cardiology to build one upon the other over the
years.
Sincerely,
W.E. Feeman, Jr., MD
NB: Readers of the LipidSpin will know that my preferred lipid predictor is the Cholesterol Retention
Fraction ([LDL-HDL]/LDL) since it predicts the population at risk of ATD better than the LDL:HDL ratio
and since it avoids the pitfalls of FF. (10) In my practice I always use the above formula to convert
direct-measure HDL to its indirect-measure HDL equivalent. This permits my recommendations to be
based on decades of research, not just the last 10 years.
References:
1. Nam BH, Kannel WB, D’Agostino RB. Search for an Optimal Atherogenic Lipid Risk Profile: From the
Framinghan Study. Am J Cardiol 2006; 97: 372-375.
2. Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, Pencina MJ, Schoonmaker C,
Wilson PWF, D’Agostino RB, Vasan RS. Clinical Utility of Different Lipid Measures for Prediction of
Coronary Heart Disease in Men and Women. JAMA, 2007; 298 (7):776-785.
3. Nawaz H, Comerford BP, Nijike VY, Dhond AJ, Plavec M, Katz DL. Repeated Serum Lipid
Measurements During the Peri-Hospitalization Period. Am J Cardiol, 2006; 98: 1379-1382.
4. Wang TD, Chen WJ, Chien KL, Su SSY, Hsu HC, Chen MF, Liau CS, Lee YT. Efficacy of Cholesterol Levels
and Ratios in Predicting Future Coronary Heart Disease in a Chinese Population. Am J Cardiol. 2001; 88:
737-743.
5. Kinosian B, Glick H, Garland G. Cholesterol and Coronary Heart Disease: Predicting Risks by Levels
and Ratios. Ann Internal Med. 1994; 121:641-647.
6. Feeman Jr. WE. Letter to the Editor. Journal of Clinical Lipidology. 2008; 2, 401-402.
7. Feeman JR. W.E. Prediction of the Population at Risk of Atherothrombotic Disease. Experimental
and Clinical Cardiology. Winter 2004. 9: (4); 235-241.
8. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ, Durrington P,
Hitman GA, Welch KMA, DeMicco DA, Zwinderman AH, Clearfield MB, Downs JR, Tonkin AM, Colhoun
HM, Gotto Jr. AM, Ridker PM, Kastelein JJP. Association of LDL Cholesterol, Non-HDL Cholesterol , and
Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins. JAMA.
2012; 307 (12): 1302-1309.
9. Carroll MD, Kit BK, Lacher DA, Shero ST, Mussolino ME. Trends in Lipids and Lipoproteins in US
Adults, 1988-2010. JAMA. 2012; 308 (15): 1545-1554.
10. Feeman Jr., W.E. The Best Lipid Predictor. Presented at The 14th International Symposium on
Atherosclerosis, June 2006, Rome Italy.