A Tale of Two Lipid Panels

Awhile ago, TheFatNurse noticed something strange while reviewing some Lipid panels. Normally, when you receive a lab result, a reference range is given and any numbers above or below the reference range is flagged. What was strange about some of these lipid panels was the lack of flags for patient numbers that were clearly in the high risk range. For example, Let’s take a hypothetical patient:

Total Cholesterol: 165
HDL: 35
LDL: 105
Triglycerides: 244

If you’ve read through the critique of LDL Cholesterol as an indicator of risk you’ll know that LDL cholesterol can sometimes be inaccurate in gauging heart disease risk. However, that is a different problem all together (addressed later in the post) and for the purposes of this post let’s just use the standard numbers provided by the ATP-III clinical guidelines:

So according to the clinical guidelines, this patient’s total cholesterol would be classified as “desirable,” his HDL cholesterol would be “low,” his LDL cholesterol  is pretty much at “optimal,” and his triglycerides are “High.” Therefore, on a lipid panel  you may assume that his Triglycerides and HDL will be flagged. However, depending on what reference ranges a lab uses, this can differ. Here are two example:

ReferenceRange1

This patient is within “range” according to this reference

ReferenceRange2

This patient is not within “range” according to this reference

Before going on, it should be made clear that one should never make the mistake of thinking a reference range is the same thing as target goals (which change according to an individual’s risk category) for a patient. A reference range is simply the distribution of values that are seen in the folks of a given population. However, patients can make the mistake of comparing their numbers to the reference range (and sadly sometimes even clinicians make this mistake) and therefore think they are at low risk when the opposite is really true.

In the first panel, the numbers from our hypothetical patient would not be flagged and a person may think they are at low risk. In the second panel, the numbers from HDL and Triglyceride would be flagged as abnormal. Therefore, it’s more important to go by target goals rather than what a lab supplies as a reference range. As a side note, the advance lipid panels such as the NMR, VAP, and Ion Mobility advance lipoprotein tests, suggest a reference range for triglycerides at <150 mg/dL. The reference range supplied by the first lab at <250 is obviously way too high to be viewed as a target goal and should never be viewed as such.

However, as mentioned in a previous post, even reaching the target goals of LDL cholesterol can be inaccurate to risk. This is even mentioned in the ATP-III where it is suggested to use Non-HDL cholesterol as a target goal if triglycerides are above 200 like our hypothetical patient. However,  Non-HDL isn’t always supplied in a lipid panel and many clinicians do not understand its purpose nor do they know how to calculate it even if they wanted to use it. The same dilemma holds true for looking at the TG/HDL ratio as well. In this scenario, our hypothetical patient’s TG/HDL ratio of 6.97 indicates a high likely hood of increased small and total LDL particles which means he’s at risk for atherosclerosis despite being at target for his LDL cholesterol. If we could advance test everyone with LDL particle testing that could solve a lot of confusion but that would be very expensive  and it’s not always an appropriate test if the regular lipid panel is concordant. With this in mind and everything else we’ve discussed so far on reference ranges and target goals, it’s not hard to imagine a situation where the interpretation of risk between the patient and the clinician and another clinician is vastly different between each party.

TL:DR; Different labs provide different reference ranges which are not the same as target goals. Some of the supplied reference ranges can be vastly outside what would typically be considered a target goal. This can lead to different interpretations of a lipid panel where risk may be judged inaccurately.

Red Meat and Saturated Fat: a Tasty but Cautious Combo?

So if carbohydrates are the suspects, what should we replace them with? Most people naturally gravitate towards a Low Carb High Fat diet (LCHF) but even that can be ambiguous due to what kinds of fats should be selected. While browsing through the American Journal of Clinical Nutrition TheFatNurse found an interesting study about low carbohydrates, saturated fats and beef.

This study, which involved Dr. Krauss (famous for differentiating LDL particles and risk), decided to look at how much of a role red meat and its association with saturated fat plays in CVD risk. Red meat is often thought of as a CVD risk from the questionable lipid hypothesis due to the amount of saturated fat it has.

Free Beef to be a research subject? LETS DO IT

Participants were given a baseline diet that consisted of 50% carbohydrates before being divided up into a Low Carb High Saturated Fat group (LCHSF) or Low Carb Low Saturated Fat (LCLSF) group for another 3 weeks. Both groups dropped to 31% of their energy from carbs but increased their protein consumption to 31% of energy and fat to 38% of energy. The differences between the groups occurred in the percentage of saturated fat (made up from dairy). The Low Carb High saturated fat group took in 15% of their energy from saturated fat whereas the low carb low saturated fat group only took in 8% (with an increase in monounsaturated fat to keep the total fat even). So what were the results?

***Atherogenic dyslipidemia is often associated with elevated triglycerides, low HDL cholesterol and more small LDL particles***

Triglycerides: Baseline diet (1.22+/-0.61), LCHSF (1.10+/-0.61), LCLSF (1.05 +/- 0.49)

HDL-C: Baseline diet (1.08+/-0.27), LCHSF (1.07+/-0.30), LCLSF (1.04 +/- 0.27)

So based off those results it seems that both Low Carb options here perform much better than the Baseline diet that was higher in carbohydrate right? Not so fast. While it’s true that the LCHSF yielded much lower triglycerides, it also yielded increases in LDL than the baseline group. This shouldn’t be surprising tho due to the saturated fats. However, what concerns TheFatNurse is the types of LDLs raised. The LCHSF group had increases in the large LDLs and medium LDLs (as expected) but also in the small LDLs!

This is a bit concerning since Krauss had shown through previous studies that it’s the small LDL particles that are associated to CVD risk and not so much the larger ones (Recent findings are also suggesting its the total particle count that matters most). Perhaps the saving grace for LCHSF is that it did yield a smaller result for “very small LDLs” but this was not statistically significant (p=0.23).

In his study, Krauss reports previous studies showing saturated fats raising LDLs and total cholesterol but not contributing towards levels of small LDL particles. Could the results of this study have been due to the type of protein eaten with the saturated fat? Additionally, could these results have been due to the substitution of monounsaturated fats for the LCLSF group? Krauss addresses these points and remarks that the difference in this study was the strict use of beef as the protein source. Does this mean it’s the beef protein itself with saturated fat that is causing these changes to LDLs? Krauss remarks that it can be due to other factors such as iron which has been shown to contribute with lipid metabolism as well.

The Bottom Line: So while some previous studies did not show any cardiovascular risk with saturated fat intake…does this study mean that people should be careful if they are eating lots of saturated fat with red meat (specifically beef)? Maybe, maybe not. As Krauss notes, more studies are definitely needed, and this experiment had people eating more beef than what is typically normal. TheFatNurse think the biggest thing to take away for now is more evidence that carbohydrates are a risk factor since both low carb diets in the study yielded lower triglycerides. As for the increase in small LDLs from the higher saturated fat diet? Just cut out a little saturated fat from red meat in your diet and replace with non red meat saturated fats if this one study makes you cautious. In the meantime, TheFatNurse is gonna go fry up a steak.

***Of note, some people would consider the 31% of calories from carbohydrates in the Low carb groups not low enough to be considered a “true low-carb” diet***

Steak

Changes in Atherogenic Dyslipidemia Induced by Carbohydrate Restriction in Men Are Dependent on Dietary Protein Source

Lara M MangraviteSally ChiuKathleen WojnoonskiRobin S Rawlings, et al. The Journal of Nutrition. Bethesda: Dec 2011. Vol. 141, Iss. 12; pg. 2180, 6 pgs

Fat Research During the MadMen Era

My friends keep obsessing over the new season of MadMen, so lets take a look at some of the landmarks of obesity related topics in this era. This era is well known for establishing Ancel Key’s Lipid hypothesis which states saturated fat increases cholesterol and increased cholesterol is a risk for heart disease therefore reduction of cholesterol and saturated fat reduced heart disease. This hypothesis is still widely accepted today. However, contradictory evidence was emerging around the same time. Two notable scientists providing an alternate hypothesis to heart disease at this time were Peter Ahrens and John Gofman.

John Gofman is famous for pioneering cholesterol research. While everyone was focusing on cholesterol as the circulating fat during the 50s, Gofman pointed out that the body circulated more lipid like substances than just cholesterol such as triglycerides. Additionally, there was also the lipoproteins that were involved in these lipids. This discovery naturally lead to the question: is there more to this story than just cholesterol? However, due to the technology at the time, it was only feasible to measure cholesterol (total).

With time, scientists eventually discovered three important Lipoproteins involved with cholesterol: HDL (the so called good one), LDL (what we commonly think of as the bad one) and VLDL (which carries most of the triglycerides). While everyone else was concerned about total cholesterol, Gofman realized that LDL seemed to be in larger amounts in patients with atherosclerosis independent of their total cholesterol. Therefore, Gofman pointed out that measuring total cholesterol was useless. However, even more compelling, was Gofman’s research on VLDL.

Gofman discovered that eating saturated fats could raise LDL which would fall in line with our current way of thinking. However, he also discovered that eating more carbohydrates would raise VLDL levels! The implications of this finding showed the potential dangers of using a low fat – high carbohydrate diet. For example, Gofman pointed out that the substitution of saturated fats for carbohydrates (the “carbohydrate factor” as he put it) could potentially cause more harm for individuals if it elevated their VLDL levels too high. This was of particular concern since cholesterol levels during this era was measured as total cholesterol and not into more specific subsets.

John W. Gofman

“If LDL was abnormally elevated, then this low-fat diet might help, but what Gofman called the ‘carbohydrate factor’ in these low-fat diets might raise VLDL so much that the diet would do more harm than good.”

– Gary Taubes, Good Calories Bad Calories

Another prominent scientist at this time was Peter Ahrens who is associated with terming the phenomenon of carbohydrate-induced lipemia. Simply put, this is circulation of fatty triglycerides in the blood (carried by VLDLs as shown from Gofman’s research) which is a risk for heart disease. The question is: was a person more likely to have this circulating systemically on a high carb or a high fat diet?

Since VLDLs were more likely to increase under carbohydrates consumption, you would be right if you said a diet focused more on carbohydrates. Ahrens demonstrated this by showing blood serum from the same patient following a high fat or high carbohydrate meal. The test tube was cloudy with triglycerides if they had eaten the carbohydrate diet but clear if they had eaten the high fat diet. However, during this period, having a high triglyceride level was still being questioned whether or not to play a role in heart disease. Ahrens warned the lipid hypothesis needed more questioning before low-fat diets (which would mean an increase of calories from carbohydrates) should be recommended since they did not know whether carbohydrates, fats or some other factor played a role in heart disease.
***Of note, Ahrens showed that a high carbohydrate diet would have less triglyceride levels if the total caloric intake was very low. A point he used to argue certain Asian countries having lower heart disease despite having a high carbohydrate diet at the time.

Margaret Albrink, at the metabolic division of Yale Medical School would provide some observations on the importance of triglycerides. Her findings showed high triglycerides were more common than elevation of cholesterol in patients with cerebral, coronary and aortic atherosclerosis. And that potential accumulation of triglycerides may be the most common lipid derangement in coronary artery disease.

Albrink presented her results to the association of the American Physicians but was met with anger and disbelief. This occurred only recently after the American Heart Association decided to accept and endorse Ancel Key’s idea of saturated fat and cholesterol (Lipid hypothesis) being the culprit. Albrink would continually be attacked by proponent’s of the lipid hypothesis. However, she would receive more support from other scientists later such as Nobel laureate Joseph Goldstein who found elevated triglyerides just as common if not more so than cholesterol in over 500 patients with heart disease. Even more interesting was a study done by Peter Kuo which showed:

More than 90% of the 286 patients were found to have hyperglyceridemia derived from increased endogenous lipogenesis from carbohydrate. This abnormal carbohydrate sensitivity was revealed with an ad libitum carbohydrate (35% to 40%) diet. Since lipoproteins synthesized from carbohydrates were shown to be rich in both triglyceride and cholesterol, carbohydrate-sensitive hyperglyceridemia was frequently found in association with hypercholesteremia. The abnormal metabolism was controlled by a sugar-free diet, with a carbohydrate allowance of 125 to 150 gm supplied as starches.

So 90% of the subjects had elevated triglycerides related to carbohydrate consumption. Additionally, since VLDLs carry triglycerides and cholesterol (majority triglycerides), that could potentially mean increases in cholesterol levels could be related to carbohydrate consumption as well. Interestingly enough, the elevated triglycerides and cholesterol were controlled when patients were put on limited carbohydrates…

Even more interesting was an editorial put out by the Journal of the American Medical Association about these new discoveries:

“Research,like therapeutics, experiences cyclic fads. These are characterized by a rush of investigators towards an avenue of research initiated by publication of a few promising studies. For nearly fifteen years, an almost embarrassingly high number of researchers boarded the “cholesterol bandwagon” in pursuit of understanding of atherosclerosis. This fervent embrace of cholesterol to the exclusion of other biochemical alterations resulted in a narrow scope of study of a disease which is probably multifaceted in causation. Fortunately, other fruitful approaches have been made possible in the past few years by identification of the fundamental role of such factors as triglycerides and carbohydrate metabolism in atherogenesis.”

Somehow tho, saturated fats and cholesterol being the culprit behind heart disease has still become unquestionable medical facts to many practitioners and thus society. Just how sure are we of this?

Peter Ahrens

“Some thought him to be obtuse or stubborn, as he refused to endorse claims that changing our diets by lowering cholesterol intake would be the sole and most effective weapon to win the battle against heart disease. He was indefatigable in pointing out the necessity of additional clinical research in human subjects to delineate individual differences in response to diet. Unpopular as these views may have been, time has revealed the correctness of his views.
http://www.jlr.org/content/42/6/891.full

Serum Lipids and Cerebral Vascular Disease
ROBERT G. FELDMAN, MD; NEW HAVEN; MARGARET J. ALBRINK, MD
Arch Neurol. 1964;10(1):91-100.

Hyperlipidemia in Coronary Heart Disease I. Lipid levels in 500 survivors of  Myocardial InfarctionJOSEPHL.GOLDSTEIN,WILLIAMR.HAzzmm, HELMUTG.ScinoTT, EDWINL.BIERMAN,andARNoG.MOTULSKYwiththeassistanceof MARYJoLEVINSKIandELLEND.CAMPBELL

Hyperglyceridemia in Coronary Artery Disease and Its Management
Peter T. Kuo, MD JAMA.1967;201(2):87-94. doi: 10.1001/jama.1967.03130020033007

CORONARY HEART DISEASE AND CARBOHYDRATE METABOLISM JAMA.1967;201(13):1040-1041. doi:10.1001/jama.1967.03130130066017CORONARY HEART DISEASE AND CARBOHYDRATE METABOLISM JAMA.1967;201(13):1040-1041. doi:10.1001/jama.1967.03130130066017