Sunday, November 11, 2012

Troubleshooting High Cholesterol

This blog post is for informational purposes only and is not meant to diagnose or treat any medical condition. 

Cholesterol      1 mmol/l = 38 mg/dl
Triglycerides   1 mmol/l = 88 mg/dl 

Before reading this post you should probably read the links on Cardiovascular Disease if you haven't already

Firstly, Is Your Cholesterol Actually High? 

Make sure you took the test in a fasted state as this can affect blood lipids, particularly triglycerides 

Total Cholesterol 

The threshold for ‘high cholesterol’ is being pushed lower and lower, likely to boost drug sales more than anything else. 

If you take a look at the graphs on The Lipid Hypothesis: Total Cholesterol you’ll see a meta-analysis that found all-cause mortality (what we’re interested in) is lowest between 160-239 mg/dl (4.2-6.3 mmol/l), and yet ‘high cholesterol’ is often defined as >200 mg/dl or >5 mmol/l, which is within the bracket for lowest all-cause mortality [1]. 

You would think that based on total cholesterol vs. all-cause mortality data that ‘high cholesterol’ should probably be defined as 240 mg/dl at the minimum, and probably more like 260 or 280 mg/dl 

The Total:HDL-C Ratio 

Unfortunately many people only look at total cholesterol.  But the ratio of total cholesterol to HDL cholesterol is a better risk factor than total cholesterol, HDL-C, LDL-C or triglycerides [2] [3].  The reason why, is that it accounts for LDL-C, IDL-C, VLDL-C (non-HDL-C) and the lower risk of having higher HDL-C.  It also indicates how long the LDL particles stay in the bloodstream 

“So what would the total-to-HDL cholesterol mean? The longer LDL stays in the blood, the more two things happen: it is exposed to oxidants, and as its limited supply of antioxidants run out, the polyunsaturated fatty acids in its membrane oxidize, leading to the further oxidation of its proteins and cholesterol; it is exposed to cholesterol ester transfer protein (CETP), which transfers cholesterol from HDL to LDL, thus boosting the total-to-HDL cholesterol ratio.” - Chris Masterjohn [4] 

Ratios less than 4 are associated with a lower risk of CVD while ratios greater than 4 are associated with a higher risk of CVD 

Calculating LDL-C 

LDL-C is calculated based by using the Friedewald equation: 

LDL-C = TC – HDL-C – k x Triglycerides
(where k is 0.45 if measured in mmol/l and 0.20 if measured in mg/dl) 

However, the Friedewald equation overestimates LDL-C in people who have triglycerides below 1.1 mmol/l (100 mg/dl), whereas the Iranian equation is more accurate at those triglyceride levels [5].  The Iranian equation is: 

LDL-C = TC/1.19 – HDL-C/1.10 + Triglycerides/0.81 – 0.98 (mmol/l)
LDL-C = TC/1.19 – HDL-C/1.10 + Triglycerides/1.90 – 38 (mg/dl) 

VLDL-C isn’t measured either, but rather is calculated by: VLDL-C = TC – HDL-C – LDL-C.  On a standard blood test it will be equal to triglycerides/5 if mg/dl or triglycerides/2.2 if mmol/l (so there’s no point mentioning both triglycerides and calculated VLDL-C) 

Not that this really matters because non-HDL-C and the total:HDL-C are better risk factors than LDL-C, and in both risk factors it doesn’t matter whether the cholesterol is in LDL, IDL or VLDL, as it’s still in an ApoB lipoprotein, which is the measurement that LDL-C and non-HDL-C tries to approximate [6] 

Intra-individual Variation in Cholesterol Levels 

Even if diet and lifestyle are kept constant, there can be a huge variation in an individual’s blood lipids.  Chris Masterjohn discusses the mean intra-individual variation is as follows 

Blood Lipid
2 Standard Deviations (mg/dl)
2 Standard Deviations (mmol/l)
Total Cholesterol

“If you’ve only measured it two times, you should expect to see an increase or a decrease greater than 35 mg/dl before you can be 95% confident that your cholesterol has increased or decreased” – Chris Masterjohn 

So your average cholesterol level could be within ‘normal range’ but due to intra-individual variation you could take a blood test and it comes back high, then you’re prescribed a statin or get a higher premium for life insurance.  This also makes it difficult to judge whether a diet or lifestyle change has actually changed your cholesterol levels. 

What’s mentioned is the mean intra-individual variation.  Not everyone has the same degree of variation and you can get a rough idea how variable your cholesterol levels are with repeated tests (while controlling diet and lifestyle) 

If I have High Cholesterol, Am I at Risk of a having a Heart Attack? 

LDL-P > non-HDL-C > LDL-C 

The value of both LDL-C and LDL particle size as risk factors are abolished when you look the number of LDL particles (LDL-P) [7].  The reasons are that: 

  • LDL-C and LDL particle size are only approximate measures of LDL-P 
  • Elevated LDL-P has a legitimate mechanism for atherosclerosis (the response to retention hypothesis), whereas elevated LDL-C or small, dense LDL particles do not. 

The response to retention hypothesis is where some LDL particles penetrate the endothelium, generate an inflammatory response, become oxidised, then macrophages come along and engulf the LDL particle, turn into foam cells, which develop into atherosclerotic plaque.  The penetration of LDL particles into the endothelium is driven by a concentration gradient, in other words: more LDL-P more penetration [8] 

So the next thing to do if you’re concerned is to check to see whether you have a high number of LDL particles or not.  If you have high LDL-C you probably do, just as if you have low LDL-C you probably don’t, but you can also have discordant LDL-C and LDL-P.  Two main reasons for discordance are insulin resistance and triglyceride levels: 

Insulin inhibits LDL particle production and increases the activity of the LDL receptor.  So in insulin resistance there is an increased secretion and decreased clearance of LDL particles, which elevates LDL-P [9] 

LDL particles also contain triglycerides so if you have higher triglyceride levels you need more LDL particles to transport them.  So one could have: normal LDL-P despite slightly elevated LDL-C because they have low triglycerides; high LDL-P despite low or normal LDL-C because they have high triglycerides [10].  While carbohydrates (relative to fats) can increase triglycerides, the real culprit of high triglycerides is insulin resistance 

…And If I Have High LDL-P? 

There’s more to atherosclerosis and getting heart attacks than LDL-P and since I don’t know you, I can’t say what you’re risk is.  Look at this list and consider how many of these apply to you: 

  • Are you overweight/obese
  • Do you have insulin resistance or type 2 diabetes
  • Do you have hypertension or evidence of endothelial dysfunction
  • Do you have an autoimmune disease, allergies or asthma
  • Do you have GI symptoms (GERD, IBS, etc) 
  • Do you have poor dental health (bleeding gums, gum recession, gingivitis, periodontitis) 
  • Do you smoke
  • Do you eat a poor diet (high in processed foods, refined vegetable oils, refined grains, refined sugar or alcohol)
  • Are you physically inactive
  • Do you have poor sleep or not much of it (< 7 hours)
  • Do you have low HDL-C or HDL-P (ApoA) or high triglycerides
  • Are your liver enzymes elevated on a standard blood test (bilirubin, GGT, AST or ALT)
  • Do you show evidence of poor kidney function (low GFR, high urea/creatinine, etc)
  • Are your markers of inflammation high (such as CRP/hsCRP, Lp-PLA2, etc)
  • Are your iron levels high (such as ferritin > 150)
  • Do you have low vitamin D (< 30 ng/dl or < 75 nmol/l)
  • Do you have hypothyroidism or low thyroid function
  • Do you have high homocysteine 

The more of the above you have (and the worse each one is) I would suspect the greater your risk, whether you have high LDL-P or not.  If you have high LDL-P and none of the other issues then you’re probably not at risk, but if you do have some of them you should try harder to correct both the LDL-P and the other issues.  The good thing is those are all modifiable (unlike age, sex, ethnicity and family history) 

Also, using non-invasive tests to see your level of atherosclerosis and tracking that over time is better than any blood test.  Discuss with your doctor to find out what options are available to you

See Part 2 for some possible causes of high cholesterol or LDL-P


  1. Do you recommend statins in the case of someone suspected of familial hypercholesterolemia at 25 years old with 357ng/dl LDL cholesterol levels? My doctor does. I have been on the Paleo diet for 7 years.

    1. I'm not a doctor and I don't any experience with familial hypercholesterolemia. If you're taking statins then supplementing CoQ10 should help protect against the side effects.

      One thing you could try is to have a heart scan like this (or something similar). If your score is low and remains low with later scans that would suggest you're not developing atherosclerosis.

      Wow 7 years, you're a veteran