Elevated LDL-cholesterol (LDL-C) is common among people who adopt a low-carb, high-fat (LCHF) lifestyle. That’s why many physicians and nutritionists remain doubtful when it comes to LCHF, despite overwhelming evidence that such a dietary approach improves several other lipid parameters, usually leads to weight loss and positively affects glucose metabolism.

Several studies have shown that LDL-C constitutes a major risk factor for the development of atherosclerotic cardiovascular disease (1). Lowering LDL-C is considered a major target for reducing risk. The American College of Cardiology and the American Heart Associated advocate statin treatment for individuals with LDL-C above 190 mg/dL (4.9 mmol/L).

However, LDL-C is not a reliable risk marker for everyone. The main reason is that it is usually not measured in the laboratory. Although direct measurements are available, they are seldom performed due to costs. A standard lipid profile measures total cholesterol, triglycerides (TG)(2), and HDL-cholesterol (HDL-C)(3). LDL-C is indirectly estimated from these variables.

The bulk of cholesterol in the blood is carried by three lipoproteins, LDL, HDL and very low-density lipoprotein (VLDL). Other lipoproteins carry a negligible amount. Hence, if we subtract the cholesterol carried by HDL and VLDL from the total cholesterol, we will have an estimation of LDL-C. HDL-C is available from the standard lipid panel, so that’s not a problem. But, how can we estimate VLDL-C?

VLDL is an important carrier for TG’s in the blood. Although it also carries cholesterol, it is usually classified as a TG-rich lipoprotein. The ratio of the mass of TG to that of cholesterol in VLDL appears to be relatively constant and about 5:1 in healthy subjects.

So, if we subtract the HDL-C mass and 1/5 of the TG mass from the total cholesterol we will have an estimation of LDL-C. This is the Friedwald equation (4), named after William Friedewald, an American scientist and former professor of public health. This equation has been used for decades around the world to calculate LDL-C.

The Friedewald equation is used to estimate LDL-cholesterol (LDL-C)

If mg/dL is the unit (like in the United States) the formula looks like this:

LDL cholesterol = [Total cholesterol] – [HDL cholesterol] – [TG]/5If mmol/L is the unit (like in Australia, Canada, and Europe) the formula looks like this:

LDL cholesterol = [Total cholesterol] – [HDL cholesterol] – [TG]/2.2

## The Drawbacks of Calculating LDL-cholesterol

The major drawback of using the Friedewald formula to calculate LDL-C has to do with the assumption that the ratio of TG to cholesterol in VLDL is always the same which is not the case. LDL-C will be underestimated if the ratio of TG’s to cholesterol is higher than 5, and overestimated if it is lower than 5.

Following a fatty meal, blood levels of TG’s will rise. However, raised blood TG following a meal is caused by chylomicrons produced in the intestine, whereas elevated fasting levels are due to VLDL produced from TG’s in the liver. Chylomicrons disappear from the circulation soon after the TG’s have been delivered to the tissues. Therefore, using the Friedewald formula to calculate LDL-C is only applicable when chylomicrons are not detectable, and all the TG’s are being carried by VLDL. Hence, a fasting blood sample is necessary

The Friedewald equation is not applicable when TG’s are high. A recent study even suggested that the Friedewald equation tends to underestimate LDL-C among people with low LDL-C if triglyceride levels are moderately elevated (≥ 150 mg/dl) (6).

At present, only TG concentration higher than 400 mg/dL (4.5 mmol/L) is considered a limiting factor for the application of routine Friedewald equation. However, the fact that low TG levels may overestimate LDL-C also needs to be highlighted, not least because this may have practical implications for the growing number of people who adopt an LCHF lifestyle.

## Introducing the Iranian Equation to Calculate LDL-Cholesterol

In a paper published 2001, Wang and colleagues described a patient with a low TG value of approximately 50 mg/dL, a high cholesterol level, and a discrepant LDL-C level (7). The LDL-C level using the Friedewald calculation turned out to be much higher than the LDL-C level using direct measurement. The authors suggested for the first time that in the presence of low TG and high cholesterol levels, the LDL-C level should be measured directly instead of using the Friedewald calculation.

These results were later confirmed in a paper published 2008 by Iranian investigators showing that with low concentrations of TG, the Friedwald equation may overestimate LDL-C to such a degree that may affect the clinical decision-making (8)

The Iranian investigators suggested a different equation for calculating LDL-C

If mg/dL is the unit (like in the United States) the formula looks like this:

LDL cholesterol =

[Total cholesterol]/1.19 +TG/1.9 – [HDL cholesterol]/1.1 – 38If mmol/L is the unit (like in Australia, Canada, and Europe) the formula looks like this:

LDL cholesterol =

[Total cholesterol]/1.19 +TG/0.81 – [HDL cholesterol]/1.1 – 0.98

The investigators concluded that when using the unmodified Friedewald equation, low serum TG may positively affect the LDL-C calculation and to correct this error, the LDL-C level should either be directly measured or be adjusted by a modified formula.

This could have practical implications for people who follow an LCHF lifestyle which is fairly common nowadays. One of the first thing that happens during carbohydrate restriction is that blood levels of TG drop, often dramatically. Let’s take a real-life example.

A 47 year old man who adopted an LCHF lifestyle 6 months ago has

- Total cholesterol: 293 mg/dL (7.6 mmol/L)
- HDL-C: 60 mg/dL (1.5 mmol/L)
- TG: 70 mg/dL (0.8 mmol/L)
- Calculated LDL-C is 219 mg/dL (5,7 mmol/L) according to the Friedwald formula
- Calculated LDL-C is 190 mg/dL (4.9 mmol/L) according to the Iranian formula

That’s a fairly big difference isn’t it?

So, one of the reasons LDL-C is elevated on an LCHF diet may be that the Friedewald equation overestimates LDL-C when TG’s are low.