## Monday, October 26, 2015

### The Friedewald and Iranian equations: Fasting triglycerides can seriously distort calculated LDL

Standard lipid profiles provide LDL cholesterol measures based on equations that usually have the following as their inputs (or independent variables): total cholesterol, HDL cholesterol, and triglycerides.

Yes, LDL cholesterol is not measured directly in standard lipid profile tests! This is indeed surprising, since cholesterol-lowering drugs with negative side effects are usually prescribed based on estimated (or "fictitious") LDL cholesterol levels.

The most common of these equations is the Friedewald equation. Through the Friedewald equation, LDL cholesterol is calculated as follows (where TC = total cholesterol, and TG = triglycerides). The inputs and result are in mg/dl.

LDL = TC – HDL – TG / 5

Here is one of the problems with the Friedewald equation. Let us assume that an individual has the following lipid profile numbers: TC = 200, HDL = 50, and trigs. = 150. The calculated LDL will be 120. Let us assume that this same individual reduces triglycerides to 50, from the previous 150, keeping all of the other measures constant with except of HDL, which goes up a bit to compensate for the small loss in total cholesterol associated with the decrease in triglycerides (there is always some loss, because the main carrier of triglycerides, VLDL, also carries some cholesterol). This would normally be seen as an improvement. However, the calculated LDL will now be 140, and a doctor will tell this person to consider taking statins!

There is evidence that, for individuals with low fasting triglycerides, a more precise equation is one that has come to be known as the “Iranian equation”. The equation has been proposed by Iranian researchers in an article published in the Archives of Iranian Medicine (Ahmadi et al., 2008), hence its nickname. Through the Iranian equation, LDL is calculated as follows. Again, the inputs and result are in mg/dl.

LDL = TC / 1.19 + TG / 1.9 – HDL / 1.1 – 38

The Iranian equation is based on linear regression modeling, which is a good sign, although I would have liked it even better if it was based on nonlinear regression modeling. The reason is that relationships between variables describing health-related phenomena are often nonlinear, leading to biased linear estimations. With a good nonlinear analysis algorithm, a linear relationship will also be captured; that is, the “curve” that describes the relationship will default to a line if the relationship is truly linear (see: warppls.com).

Anyway, an online calculator that implements both equations (Friedewald and Iranian) is linked here; it was the top Google hit on a search for “Iranian equation LDL” at the time of this post’s writing.

As you will see if you try it, the online calculator linked above is useful in showing the difference in calculated LDL cholesterol, using both equations, when fasting triglycerides are very low (e.g., below 50).

The Iranian equation yields high values of LDL cholesterol when triglycerides are high; much higher than those generated by the Friedewald equation. If those are not overestimations (and there is some evidence that, if they are, it is not by much), they describe an alarming metabolic pattern, because high triglycerides are associated with small-dense LDL particles. These particles are the most potentially atherogenic of the LDL particles, in the presence of other factors such as chronic inflammation.

In other words, the Iranian equation gives a clearer idea than the Friedewald equation about the negative health effects of high triglycerides. You need a large number of small-dense LDL particles to carry a high amount of LDL cholesterol.

An even more precise measure of LDL particle configuration is the VAP test; this post has a discussion of a sample VAP test report.

Reference:

Ahmadi SA, Boroumand MA, Gohari-Moghaddam K, Tajik P, Dibaj SM. (2008). The impact of low serum triglyceride on LDL-cholesterol estimation. Archives of Iranian Medicine, 11(3), 318-21.

#### 11 comments:

Anonymous said...

LDL should be measured and more focus should be put on TG rather than LDL.

I think critisism of the Friedman equation is valid, though I think your example (lowering TG would lead to increased LDL) is not very convincing. If you lower TG and total cholesterol and HDL remain the same then something has to give right (if TG drops then TC also drops unless something else rises i.e. in this case, LDL)!

Charles Grashow said...

http://content.onlinejacc.org/article.aspx?articleid=1671271

Objectives The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.

Background LDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients.

Methods We examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl.

Results Patients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl).

Conclusions The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥70 mg/dl, and therefore additional evaluation is warranted in high-risk patients.

http://www.cobblescorner.com/2013/04/friedewald-falters-as-major-study-identifies-ldl-inaccuracy/

http://www.cobblescorner.com/2013/02/challenges-in-todays-clinical-practice-misclassification-of-ldlc/

Ned Kock said...

Thanks Anon. I revised the text a bit to make it more realistic.

Anonymous said...

Cheers Ned, always good to see when people are open to suggestions.
I always read your posts with great interest, you seem to have a unique point of view among the paleo community.

Any thoughts on the resistant starch hype?

Ned Kock said...

The “carbs-transformed-into-fiber” phenomenon associated with resistant starches is real, but it certainly is not a panacea. Almost anything that one can think of in terms of diet and lifestyle has been tried before, and there is no known case of anyone living to the age of 150.

Anonymous said...

I have three cholesterol measurements, from mid-2011, end 2011, mid-2013. I went paleo after the first measurements, and have been ever since. I've also lost almost 20kg of bodyfat since then.

Friedewald LDL figures given by the lab are 3.63, 4.25 and 4 (mmol/l), as confirmed by the formulas in the link you gave. Iranian yields 2.96, 3.6 and 3.14, so significantly lower. My Triglycerides were at the "low" end you gave, around 50 mg/dl (0.62, 0.68 and 0.55 mmol/l).

I take this means I shouldn't be as worried about my LDL, which are above the lab's recommended levels of 3.5 mmol/l according to Friedewald, but below it according to Iranian in the latest measurement.

Ned Kock said...

Hi Anon. Generally speaking, I'd suggest focusing on HDL and trigs. But a more important suggestion is this: bring this issue to your dr's attention, and have a dialogue with him/her.

obat herbal wasir kronis tanpa operasi said...
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Ned Kock said...

Spam comment above deleted.

PhilT said...

Thanks for the post. If we are to calculate LDL from other measurements then should we not focus on using the primary meaurements alone in CVD risk analysis ?

It seems artificial to me to introduce a calculated parameter like say "Total cholesterol - HDL - Triglycerides/2.2" which is highly correlated with those measurements and hence redundant.

Ratios like Total/HDL and Triglycerides/HDL should perhaps be the primary concern in CVD ?

Anonymous said...

Hi, Ned,

thanks for your article.

don't know if you have read this: 2012 study that uses non-linear regression --- log(TG), also by Iranians

J Lab Physicians. 2015 Jan-Jun; 7(1): 11–16.

this looks like the full text.

http://bmsu.ac.ir/UserFiles/File/maghale%20latin/17849.pdf

(i have also found some other formulae but all linear fits)

i agree with you that they should really use non-linear methods. (Friedewald was devised in the days computing nonlinear equations maybe difficult for those mathematically challenged)

regards,

pam