Category Archives: Dyslipidemia

Answer Day: What Causes High LDL on Low-Carb Paleo?

Posted by on March 3, 2011 383 comments

First, thank you to everyone who commented on the quiz. I enjoyed reading your thoughts.

Is High LDL Something to Worry About?

Perhaps this ought to be the first question. Jack Kronk says “I don’t believe that high LDL is necessarily a problem” and Poisonguy writes “Treat the symptoms, Larry, not the numbers.” Poisonguy’s comment assumes that the LDL number is not a symptom of trouble. Is it?

I think so. It helps to know a little about the biology of cholesterol and of blood vessels.

When cells in culture plates are separated from their neighbors and need to move, they make a lot of cholesterol and transport it to their membranes. When cells find good neighbors and settle down, they stop producing cholesterol.

The same thing happens in the body. Any time there is a wound or injury that needs to be healed, cholesterol production gets jacked up.

When people have widespread vascular injuries, cholesterol is produced in large quantities by cells lining blood vessels. Now, to repair injuries cells have to coordinate their functions. Endothelial cells are the coordinators of vascular repair: they direct other cell types, like smooth muscle cells and fibroblasts, in the healing of vascular injuries.

To heal vascular injuries, these cells not only need more cholesterol for movement; they also need to multiply. It turns out that LDL, which carries cholesterol, also causes vascular cells to reproduce (“mitogenesis”):

The best-characterized function of LDLs is to deliver cholesterol to cells. They may, however, have functions in addition to transporting cholesterol. For example, they seem to produce a mitogenic effect on endothelial cells, smooth muscle cells, and fibroblasts, and induce growth-factor production, chemotaxis, cell proliferation, and cytotoxicity (3). Moreover, an increase of LDL plasma concentration, which is observed during the development of atherosclerosis, can activate various mitogen-activated protein kinase (MAPK) pathways …

We also show … LDL-induced fibroblast spreading … [1]

If endothelial cells are the coordinators of vascular repair, and LDL particles their messengers to fibroblasts and smooth muscle cells, then ECs should be able to generate LDL particles locally. Guess what:  ECs make a lipase whose main effect is to decrease HDL levels but can also convert VLDL and IDL particles into LDL particles and remove fat from LDL particles to make them into small, dense LDL:

Endothelial lipase (EL) has recently been identified as a new member of the triglyceride lipase gene family. EL shares a relatively high degree of homology with lipoprotein lipase and hepatic lipase …

In vitro, EL has hydrolyzed phospholipids in chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein and LDL. [2]

Immune cells, of course, are essential for wound healing and they should be attracted to any site of vascular injury. It turns out that immune cells have LDL receptors and these receptors may help them congregate at sites of vascular injury. [3]

I don’t want to exaggerate the state of the literature here:  this is a surprisingly poorly investigated area. But I believe these things:

1.      Cholesterol and LDL particles are part of the vascular wound repair process.

2.      Very high LDL levels are a marker of widespread vascular injury.

Now this is not the “lipid hypothesis.” Compare the two views:

  • The lipid hypothesis:  LDL cholesterol causes vascular injury.
  • My view:  LDL cholesterol is the ambulance crew that arrives at the scene of the crime to help the victims. The lipid hypothesis is the view that ambulance drivers should be arrested for homicide because they are commonly found at murder scenes.

So, to Poisonguy, on my view high LDL numbers are a symptom of vascular injury and are a cause for concern.

Big-Picture View of the Cause of High LDL

So, on a micro-level, I think vascular damage causes high LDL. But what causes vascular damage?

Here I notice a striking difference in commenters’ perspectives and mine. I tend to take a big-picture, top-down view of biology. There are three basic causes of nearly all pathologies:

1.      Toxins, usually food toxins.

2.      Malnutrition.

3.      Pathogens.

The whole organization of our book is dictated by this view. It is organized in four Steps. Step One is about re-orienting people’s views of macronutrients away from high-grain, fat-phobic, vegetable-oil-rich diets toward diets rich in animal fats. The other steps are about removing the causes of disease:

1.      Step Two is “Eat Paleo, Not Toxic” – remove food toxins.

2.      Step Three is “Be Well Nourished” – eliminate malnutrition.

3.      Step Four is “Heal and Prevent Disease” – address pathogens by enhancing immunity and, where appropriate, taking advantage of antibiotic therapies.

So when someone offers a pathology, any pathology, my first question is: Which cause is behind this, and which step do they need to focus on?

In Larry’s case, he had been eating low-carb Paleo for years. So toxins were not a problem.

Pathogens might be a problem – after all, he’s 64, and everybody collects chronic infections which tend to grow increasingly severe with age – but Larry hadn’t reported any other symptoms. More to the point, low-carb Paleo diets typically enhance immunity, yet Larry had fine LDL numbers before adopting low-carb Paleo and then his LDL got worse. So it wouldn’t be infectious in origin unless his diet had suppressed immunity through malnutrition – in which case the first step would be to address the malnutrition.

Step Three, malnutrition, was the only logical answer. The conversion to Paleo removes a lot of foods from the diet and could easily have removed the primary sources of some micronutrients.

So I was immediately convinced, just from the time-course of the pathology, that the cause was malnutrition.

Micronutrient Deficiencies are Very Common

In the book (Step Three) we explain why nearly everyone is deficient in micronutrients. The problems are most severe for minerals:  water treatment removes minerals from water, and mineral depletion of soil by industrial agriculture leads to mineral deficiencies in farmed plants and grain-fed animals.

This is why our “essential supplements” include a multimineral supplement plus additional quantities of five minerals – magnesium, copper, chromium, iodine, and selenium. Vitamins get a lot of attention, but minerals are where the big health gains are.

Copper Deficiency and LDL

Some micronutrient deficiencies are known to cause elevated LDL.

Readers of our book know that copper causes vascular disease; blog readers may be more familiar with an excellent post by Stephan, “Copper and Cardiovascular Disease”, discussing evidence that copper deficiency causes cardiovascular disease. As I’ve just argued that cardiovascular disease causes high LDL, it shouldn’t be a surprise that copper deficiency also causes hypercholesterolemia:

Copper and iron are essential nutrients in human physiology as their importance is linked to their role as cofactors of many redox enzymes involved in a wide range of biological processes, as well as in oxygen and electron transport. Mild dietary deficiencies of both metals … may cause long-term deleterious effects in cardiovascular system and alterations in lipid metabolism (3)….

Several studies showed a clear correlation among copper deficiency and dyslipidemia. The main alterations concern higher plasma CL and triglyceride (TG) concentrations, increased VLDL-LDL to HDL lipoproteins ratio, and the shape alteration of HDL lipoproteins.  [4]

The essentiality of copper (Cu) in humans is demonstrated by various clinical features associated with deficiency, such as anaemia, hypercholesterolaemia and bone malformations. [5]

Over the last couple of decades, dietary copper deficiency has been shown to cause a variety of metabolic changes, including hypercholesterolemia, hypertriglyceridemia, hypertension, and glucose intolerance. [6]

Copper deficiency is, I believe, the single most likely cause of elevated LDL on low-carb Paleo diets. The solution is to eat beef liver or supplement.

So, was my advice to Larry to supplement copper?  Yes, but that was not my only advice.

Other Micronutrient Deficiencies and Elevated LDL

Another common micronutrient deficiency that causes elevated LDL cholesterol is choline deficiency that is NOT accompanied by methionine deficiency. That is discussed in my post “Choline Deficiency and Plant Oil Induced Diabetes”:

Choline deficiency (CD) by itself induces metabolic syndrome (indicated by insulin resistance and elevated serum triglycerides and cholesterol) and obesity.

A combined methionine and choline deficiency (MCD) actually causes weight loss and reduces serum triglycerides and cholesterol …

I quote both these effects because it illustrates the complexity of nutrition. A deficiency of a micronutrient can present with totally different symptoms depending on the status of other micronutrients.

Julianne had a really nice comment, unfortunately caught in the spam filter for a while, with a number of links. She mentions vitamin C deficiency and, with other commenters, noted the link between hypothyroidism and elevated LDL. As one cause of hypothyroidism is iodine or selenium deficiency, this is another pathway by which mineral deficiencies can elevate LDL.

UPDATE: Mike Gruber reduced his LDL by 200 mg/dl by supplementing iodine. Clearly iodine can have big effects!

Other commenters brought up fish oil. They may be interested to know that fish oil not only balances omega-6 to modulate inflammatory pathways, it also suppresses endothelial lipase and thus moderates the LDL-raising and HDL-lowering effect of vascular damage:

On the other hand, physical exercise and fish oil (a rich source of eicosapentaenoic acid and docosahexaenoic acid) suppress the activity of EL and this, in turn, enhances the plasma concentrations of HDL cholesterol. [7]

Whether this effect is always desirable is a topic for another day.

My December Advice to Larry

So what was my December advice to Larry?

It was simple. In adopting a low-carb Paleo diet, he had implemented Steps One and Two of our book. My advice was to implement Step Three (“Be well nourished”) by taking our recommended supplements. Eating egg yolks and beef liver for copper and choline is a good idea too.

Just to cover all bases, I advised to include most of our “therapeutic supplements” as well as all the “essential supplements.”

Since December, Larry has been taking all the recommended supplements and eating 5 ounces per week of beef liver. As I noted yesterday, Larry’s LDL decreased from 295 mg/dl to 213 mg/dl, HDL rose from 74 mg/dl to 92 mg/dl, and triglycerides fell from 102 to 76 mg/dl since he started Step Three. This is all consistent with a healthier vasculature and reduced production of endothelial lipase.

Conclusion

Some people think there is something wrong with a diet if supplements are recommended. They believe that a well-designed diet should provide sufficient nutrition from food alone, and that if supplements are advised then the diet must be flawed.

I think this is quite mistaken. The reality is that Paleolithic man was often mildly malnourished, and modern man – due to the absence of minerals from treated water and agriculturally produced food, and the reduced diversity and higher caloric density of our foods – is severely malnourished compared to Paleolithic man.

We recommend eating a micronutrient-rich diet, including nourishing foods like egg yolks, liver, bone broth soups, seaweed, fermented vegetables, and so forth. But I think it’s only prudent to acknowledge and compensate for the widespread nutrient depletion that is so prevalent today. Even when nutrient-rich food is regularly eaten, micronutrient deficiencies are still possible.

Eating Paleo-style is not enough to guarantee perfect health. Luckily, supplementation of the key nutrients that we need for health and that are often missing from foods will often get us the rest of the way.

References

[1] Dobreva I et al. LDLs induce fibroblast spreading independently of the LDL receptor via activation of the p38 MAPK pathway. J Lipid Res. 2003 Dec;44(12):2382-90. http://pmid.us/12951358.

[2] Paradis ME, Lamarche B. Endothelial lipase: its role in cardiovascular disease. Can J Cardiol. 2006 Feb;22 Suppl B:31B-34B. http://pmid.us/16498510.

[3] Giulian D et al. The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J Neurosci. 1989 Dec;9(12):4416-29. http://pmid.us/2480402.

[4] Tosco A et al. Molecular bases of copper and iron deficiency-associated dyslipidemia: a microarray analysis of the rat intestinal transcriptome. Genes Nutr. 2010 Mar;5(1):1-8. http://pmid.us/19821111.

[5] Harvey LJ, McArdle HJ. Biomarkers of copper status: a brief update. Br J Nutr. 2008 Jun;99 Suppl 3:S10-3. http://pmid.us/18598583.

[6] Aliabadi H. A deleterious interaction between copper deficiency and sugar ingestion may be the missing link in heart disease. Med Hypotheses. 2008;70(6):1163-6. http://pmid.us/18178013.

[7] Das UN. Long-chain polyunsaturated fatty acids, endothelial lipase and atherosclerosis. Prostaglandins Leukot Essent Fatty Acids. 2005 Mar;72(3):173-9. http://pmid.us/15664301.

Low Carb Paleo, and LDL is Soaring – Help!

Posted by on March 2, 2011 59 comments

To Kindy, Zach’s parents, and the NBIA/PKAN kids: I’ve been reading papers on the disease and trying to figure out the best diet for the disease. But the biochemistry is a bit complex, more complex than I realized last week, and I want to make sure my advice is sound. So I’m delaying my NBIA/PKAN/ketogenic diet posts until next week.

My sincere apologies for the delay!

I’m a little busy this week – busy with work, busy with learning about NBIA/PKAN, and eager to spend time with my brother who is visiting from Germany – and so I thought I’d do a “You be the doctor” quiz.

Here’s the puzzle. Someone adopts a low-carb Paleo diet. Very healthy diet, right? But their LDL cholesterol level starts to rise. And rise. And rise.

Larry Eshelman emailed me last December with this problem. His LDL history:

  • 103 mg/dl (1990-2002, eating a low fat diet)
  • 115 mg/dl (2002-2007, eating a low carb diet)
  • 195 mg/dl (2007-2009, after reading Gary Taubes and adding saturated fat)
  • 254 mg/dl (Dec 2009, very low-carb Paleo for 5 weeks)
  • 295 mg/dl (Jun 2010, very low-carb Paleo for 7 months)

(SI system readers, convert to mmol/l by dividing by 38.67.)

A common problem

This is not a terribly uncommon problem in the Paleo community; it afflicts famous and brilliant bloggers as well as ordinary folks. It’s been discussed by Richard Nikoley in several posts:

Some examples of high LDL on a Paleo diet, with links – most of these provided to me by Larry (thanks Larry!):

OK, that’s enough: this is a minority phenomenon, but it’s definitely not an exceptional n=1 phenomenon.

Larry’s Progress

Larry wrote me at the beginning of December asking for advice. He implemented everything I suggested. I just heard back from him this week with new data.

His LDL decreased from 295 mg/dl to 213 mg/dl in a recent test. His HDL rose from 74 mg/dl to 92 mg/dl. His triglycerides fell from 102 to 76 mg/dl.

LDL is still high, but improving; the others are excellent and improving.

So, quiz questions:

  • Can you guess what my December advice to Larry was?
  • What causes these cases of soaring LDL on Paleo? (Of course, there are multiple possible causes of high LDL, but I think among Paleo dieters one explanation is more likely than others, and that’s what I’m looking for.)

My answers tomorrow night.

UPDATE: Answers here: Answer Day: What Causes High LDL on Low-Carb Paleo?

Choline Deficiency and Plant Oil Induced Diabetes

Posted by on November 12, 2010 70 comments

I’m going to deviate from my original plan for the “Dangers of a Zero-Carb Diet” series to discuss a topic that came up in the comments to the first post.

Leonie’s Diabetes and the Rose Corn Oil Trial

What prompted this diversion is Leonie’s interesting comment from Wednesday’s post:

I developed diabetes several years after being on a low carb diet. Continuing low carb to manage the diabetes did not halt its progress. It has taken about 18 months of adding more carbs (60 – 100 gr/day) to my diet to bring my fasting glucose down by a couple of mmol and eating more carbs has also lowered my Hba1c and post meal spikes significantly. I wonder if the liver is another organ that may be affected by carbohydrate deficiency.

I had not heard of such cases before, or so I thought, but Dr. Deans in the comments reminded us that Peter at Hyperlipid had noticed two similar cases in the Rose Corn Oil trial. [1] (The Rose Corn Oil trial, of course, figures prominently in our book’s discussion of PUFA toxicity.)

In the Rose Corn Oil trial, there were three arms – a normal diet arm, a high corn oil arm, and a high olive oil arm. The normal dieters were expected to eat “fried foods, fatty meat, sausages, … ice cream, cheese, … milk, eggs, and butter” while the oil arms were supposed to restrict these foods and replace them with corn or olive oil.

Here’s what happened:

Four patients were removed from the trial for other reasons. Two developed non-cardiac thromboembolism and were given anticoagulant therapy. The other two were removed because of diabetes mellitus. One of them already had mild diabetes, but glycosuria increased considerably soon after he started oil. Oil was stopped and glycosuria disappeared. Oil was restarted, but was stopped a month later because heavy glycosuria recurred. The other patient, not a previously recognized diabetic, developed glycosuria with a diabetic glucose-tolerance test a few weeks after starting oil. [1]

The patients who developed diabetes came one from the corn oil arm and one from the olive oil arm. Likewise, the patients who developed thromboembolisms came one from the corn oil arm and one from the olive oil arm. No such disasters occurred on the “fatty meat” arm.

Since all three diets were similarly fatty, it doesn’t appear to be the quantity of fat that was the issue. Rather it was the type of lipid, or some micronutrient that was present in the animal and dairy foods but lacking in the plant oils.

For insight into what the problem might be, let’s look at how scientists poison lab animals.

Insights from Diet Animal Poisoning Research

You have to pity diet researchers. It takes 60 years for bad diets to poison humans enough to significantly raise mortality rates. Yet a diet researcher is supposed to gain a Ph.D. in 4 years (or in 5 while simultaneously obtaining an MD!), do a postdoc in 2 years, win a grant in the first years of an entry-level position with PI status, and then demonstrate productive results within the term of a 2-to-5 year grant. Deadlines are pressing: A study needs to start rats or mice on two diets, and have one diet produce much better health than the other, in considerably less than a two-year time frame.

Just comparing McDonald’s fast food with a Mediterranean diet won’t do. Two years later both sets of mice will die happily of old age, with no significant differences between groups. Peer reviewers judge you to have discovered no new results. No new results means no paper, no grant, no job.

So “diet” researchers first have to become experts at quickly inducing disease in rats and mice. Find a diet that poisons animals in a few months, compare it to another diet that doesn’t, and you have a paper. Look for variations that slow or hasten the poisoning, and you have more papers. To be a highly productive scientist, one must be a skilled animal poisoner.

Various techniques have been developed for this purpose, including: knocking out some crucial gene; breeding a mutant strain that naturally develops disease; giving the animals poison with their food; or depriving them of crucial nutrients. Almost every study of diet in mice or rats uses one of these techniques.

If a missing nutrient can cause diabetes within a few years for Leonie and 12 to 18 months for the Rose Corn Oil trial volunteers, it’s likely to be pretty good at inducing disease in animals too. There’s a good chance diet animal poisoning researchers have already stumbled upon it in rats or mice.

Choline Deficiency Diseases

One of the most popular deficiency diets among researchers is the choline-deficient diet. A useful paper by Dutch scientists [2] gives a nice look at the impact of choline deficiency on rats.

Choline deficiency (CD) by itself induces metabolic syndrome (indicated by insulin resistance and elevated serum triglycerides and cholesterol) and obesity.

A combined methionine and choline deficiency (MCD) actually causes weight loss and reduces serum triglycerides and cholesterol, but induces more severe liver damage. The MCD diet prevents the body from manufacturing choline from methionine, vitamin B12, and folate, so MCD diets severely reduce choline levels; and without choline VLDL particles are not produced. Without VLDL particles, fats and cholesterol are trapped in the liver and never reach the blood and adipose cells.

Here is a measure of insulin resistance on the two diets:

The induction of insulin resistance by the CD diet is very rapid, requiring less than a week.

Induction of insulin resistance is thought to be mediated by elevated TNF-alpha production by adipose cells and by hypertriglyceridemia. Since the MCD diet neither raised serum triglycerides nor caused obesity which induces TNF-alpha production in adipose cells, it did not cause insulin resistance.

What Does This Have to Do With Diabetes?

Insulin resistance is a key step in the development of diabetes:

  • Insulin resistance in the liver causes the liver to release more glucose into the blood (since insulin inhibits glucose release by the liver). This is discussed in a nice paper [3] found by LynMarie Daye and cited in the comments by CarbSane.
  • Peripheral insulin resistance means that the rest of the body is less sensitive to insulin. The pancreas has to produce more insulin to dispose of the excess glucose that the liver is releasing.

This elevation of insulin and glucose levels is a crucial step toward diabetes; it is “pre-diabetes.”

Persistently elevated glucose levels can then poison the beta cells of the pancreas, diminishing insulin secretion capability and causing diabetes. [4]

The Rose Corn Oil trial was not a low-carb diet, so postprandial glucose levels could easily have risen to toxic levels.

If a CD diet can cause insulin resistance in a week, it’s plausible that it might cause diabetes in 12 to 18 months, which is when the Rose Corn Oil trial patients developed it.

What About the Thromboembolism Cases?

MCD diets induce fibrinogenesis. In the blood, excess fibrin formation leads to clotting, and clots can block vessels to cause thromboembolisms. It may be that the thromboembolism cases in the Rose Corn Oil trial had methionine, folate, or B12 deficiencies to go with their choline deficiency.

Why Do Plant Oils Induce Diabetes But Not Animal Fats?

So why did diabetes develop in the corn and olive oil arms of the Rose Corn Oil trial but not the “fatty meat and dairy” arm?

Well, look at the choline content of these foods:

Choline content of one cup (~200 g) oil or fat or 227 g (1/2 lb) meat

Beef liver 968.0 mg
Cube steak (beef) 290.0 mg
Beef tallow 164.0 mg
Butter 42.7 mg
Olive oil 0.6 mg
Corn oil 0.4 mg

Source: http://nutritiondata.com.

Take away meat and dairy and replace them with plant oils, and it’s very easy to have a choline deficiency.

What Does This Have to Do With Zero-Carb Diets?

Maybe nothing … without carb consumption, postprandial glucose levels are not as high, and beta cell poisoning is less likely … but it may be that a zero-carb diet aggravates a choline deficiency in some fashion. I will leave this as a topic for further research.

UPDATE: Leonie in a new comment gives us more information: she has PCOS, goiter with nodules, and auto-antibodies. This suggests autoimmunity as a more likely explanation for her zero-carb diabetes.

Conclusion

In the book, we recommend the use of animal fats such as beef tallow for cooking, and recommend that pregnant women and vegetarians supplement with choline. We thought seriously about recommending that everyone supplement choline, but were reluctant to recommend too many supplements.

In retrospect, we should have recommended choline supplements for everyone who is overweight, has elevated blood glucose or lipids, or has elevated liver enzymes.

We have been using beef tallow as our cooking oil for several months now. It might be good practice for everyone to favor animal fats like beef tallow over plant oils for cooking.

References

[1] Rose GA et al. Corn oil in the treatment of ischaemic heart disease.  Br Med J. 1965 Jun 12;1(5449):1531-3. http://pmid.us/14288105.

[2] Veteläinen R et al. Essential pathogenic and metabolic differences in steatosis induced by choline or methione-choline deficient diets in a rat model. J Gastroenterol Hepatol. 2007 Sep;22(9):1526-33. http://pmid.us/17716355.

[3] Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth. 2000 Jul;85(1):69-79. http://pmid.us/10927996.

[4] Leibowitz G et al. Glucose regulation of ?-cell stress in type 2 diabetes. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:66-75. http://pmid.us/21029302.