William Friedewald on The Friedewald Equation

In the late 1960s when knowledge emerged of the different function and pathogenic importance of LP subfractions, measured as LDL, HDL, and VLDL cholesterol, a measure of LDL was needed for risk assessment and preventive practice that was less costly and more accessible than the Gofman ultracentrifuge. The risk index developed by Gofman and tested in Framingham data required measurement of total, LDL, and HDL cholesterol in serum or plasma and computing the ratio of total or LDL to HDL cholesterol, the chemical process for total and HDL cholesterol being straightforward.

A novel, rough-and-ready, indirect but adequately valid estimate of LDL cholesterol was found at the National Heart and Lung Institute, more or less serendipitously, as told here by William Friedewald:

“This was in 1969 going into ’70, and Bob Levy (Lipid investigator at NHLBI, subsequently its Director) had this idea that there was a stoichiometry, an actual necessary relationship, between triglycerides and cholesterol in the VLDL portion . . in a constant 5 to 1 ratio, he thought. A statistician there to whom he had given the problem said, ‘I can’t make it work,’ looking at the VLDL triglyceride divided by 5. But the correlation [of VLDL divided by 5 and total plasma cholesterol] wasn’t that good, so Bob gave it to me and said, ‘I think there’s really something here.’ I said, ‘We’re really trying to measure LDL; we don’t really care about VLDL cholesterol, so let’s look at that.’

Although there was a fair amount of error in the estimate of VLDL, because VLDL cholesterol is such a small percentage of the total [cholesterol] it didn’t make a big difference. When, in fact, we used [total plasma] triglycerides divided by 5 we got a really strong correlation between LDL [cholesterol] estimated by the equation and that measured [by ultracentrifuge].

Bob said, ‘Why don’t you write it up, then?’ So my name ended up first on the paper. I saw Don Frederickson (former Director of NIH) about five or six years ago and he said, ‘Out of all that stuff that we did [in lipoprotein classification], the only thing that seems to have survived really is the Friedewald Equation.’

It should have been the Levy Equation” (Friedewald, 2003).

The equation is still used for the routine laboratory estimate of LDL cholesterol, because of the constancy of cholesterol content in plasma triglycerides and the relative ease of measurement of VLDL, HDL, and total cholesterol, at least in chylomicron-free (fasting) plasma and among “normals” and run-of-the-mill dyslipidemias. (Henry Blackburn)

Resources

Friedewald, W. in an interview with Henry Blackburn, 21 March 2003. History of Cardiovascular Epidemiology Archive. University of Minnesota.

Friedewald, W.T., Levy, R.I., and Frederickson, D.S. 1972. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry 18: 499-502.