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?

Pho (Vietnamese Noodle Soup)

Posted by on February 27, 2011 33 comments

Pho is probably the most popular dish of Vietnam. Noodle soups are extremely popular throughout the Far East, but Vietnam is known for its distinctive flavors.

Beef Broth

To start, make a beef broth. You might want to refer back to this post: Ox Feet Broth, Miso Soup, and Other Soups. It’s not necessary to start from ox feet, any beef bones will do. It’s nice to choose bones that have a lot of collagen and fat, that makes a richer broth.

Beef bones are available at a wide range of stores these days. To make our broth, we picked up $3 of beef bones at BJ’s Wholesale Club yesterday and cooked them in water for 3 hours. Today, before dinner, we warmed up a portion. Here’s what it looks like:

Rice Noodles

You’ll also need some rice noodles. We discussed rice noodles in this post: Cranky Grouch’s Spaghetti. The chief difference from that recipe is that we used thinner noodles, so it took less than 3 minutes to cook the noodles. As before, it’s important to have the water reach a boil before adding the noodles, cook briefly, and then drain the water and cool the noodles in cold water to stop them from cooking further. Another difference is that we didn’t add olive oil at the end.

Here’s a picture of today’s rice noodles cooking:

Other Ingredients

The essential ingredients are thin-sliced beef, fish sauce, a lime, and basil leaves. (You can substitute cooked shredded chicken or shrimp for beef.)

Other standard ingredients are bean sprouts (which are legumes, but low in toxicity and more like a vegetable) and cilantro. We think red onions complement the other flavors.

Some spices may also be desired, but are not necessary. Chili sauce for those who like it hot, plum sauce for those who like it sweet. Black bean sauce, garlic, ginger, salt, and pepper are also commonly used.

Thin-sliced beef is readily available at Asian markets. It’s often labeled as beef for shabu-shabu, the Japanese version of hot pot:

Here is the fish sauce and chili sauce we used. We prefer lighter fish sauces, which are translucent in the bottle; stronger fish sauces are opaque.

Here are the ingredients we used:

The lime is cut into eighths, the beef thawed; that is fish sauce on the lower left.

Making Your Pho

You can arrange the ingredients to your taste in your own soup bowl. Paul starts with some noodles, onions, and thin-sliced beef:

The broth is added hot from the pot, and the thin beef slices change color to brown within seconds. Top with sprouts and basil, and it looks like this:

Add lime, fish sauce, and spices to taste, and you’re ready to go. Here Paul has lifted out a piece of collagen and fat from the broth – this adds great richness to the soup:

It was delicious! The lime and fish sauce flavor is unique to Vietnamese cuisine and makes a great change of pace from our regular cooking.

If Chef Anthony Bourdain had come to dinner with us tonight, he might have been even more delighted than he was in this video:

Around the Web; and Is There a Fat Mass Setpoint?

Posted by on February 26, 2011 15 comments

[1] CoQ10 and niacin not good for Top Gun pilots: You don’t get useful supplement information like this at other Paleo sites.

The case presented here details a Naval Aviator who experienced reduced G tolerance over two successive flights with a temporal relationship of starting a new supplement. Two components of the supplement, coenzyme Q10 and niacin, are highlighted here for their hemodynamic effects. After stopping the supplement the aviator regained his normal G tolerance and had no further issues in flight.

Barker PD. Reduced G tolerance associated with supplement use. Aviat Space Environ Med. 2011 Feb;82(2):140-3. http://pmid.us/21329031.

[2] Thank you, science, this is helpful:

[3] N-acetylcysteine and choline reverse insulin resistance in rats. This is for biology junkies. How does physiological insulin resistance get reversed? Feeding signals do it, and cysteine and choline may be primary signals. Also, there is liver and brain involvement, since denervation of the liver causes insulin resistance. A hypothesis: there is a “hepatic insulin sensitizing substance” (HISS).

Lautt WW et al. Bethanechol and N-acetylcysteine mimic feeding signals and reverse insulin resistance in fasted and sucrose-induced diabetic rats. Can J Physiol Pharmacol. 2011 Feb;89(2):135-42. http://pmid.us/21326345.

[4] Do eggs eliminate need for carbohydrates? Seth Roberts recounts an interesting n=1 experience:

Joseph Buchignani … discovered that a meat-only diet eliminated his IBS. However, it also caused craving for carbs. Because carbs caused IBS, he couldn’t simply eat carbs. He tried many ways of getting rid of the craving for carbs: eating more animal fat, eating less animal fat, eating oil, eating lard, and eating different kinds of animals and cuts of meat. He varied how he cooked the meat, eating especially fresh meat, and eating fresh whole fish. All of these attempts failed. He did not try taking a multivitamin pill.

Finally he tried adding egg to the meat. That eliminated his craving for carbs…

Sure, some cravings reflect nutrient deficiencies. (Not all cravings: An alcoholic craves alcohol.) But in the cases I know about, there is an obvious or semi-obvious connection between the craving and the deficiency. For example, people who chew too much ice (pagophagia) crave ice to chew. They are iron-deficient. Eating iron eliminates the pagophagia. Long ago, a craving to eat something crunchy would have led you to eat bones. Bone marrow is high in iron. So the craving makes sense. In contrast, there is no obvious or semi-obvious connection between carbs and eggs.

The explanation for Mr. Buchignani’s experience is not obvious to me either. However, here’s a hypothesis:  Eggs are rich in cysteine and choline, so maybe they give an especially strong feeding signal that over-rides the appetite signal generated by carbohydrate deficiency.

[5] We need a good mucus barrier to prevent self-digestion. Every once in a while I assert in the comments that we need a good mucus barrier to protect our own cells from digestive enzymes, and so people with bowel problems (hence a deficient mucus barrier) should be cautious about taking protease or lipase enzymes. Then somebody asks for a reference (tough crowd!).

Well, here’s a paper that came out this week. It’s about proteases. The new part to me was that NAC is mucolytic and aggravates the injury. So reversing your insulin resistance with NAC might damage your gut … trade-offs, trade-offs.

Qin X et al. The Mucus Layer is Critical in Protecting Against Ischemia-Reperfusion-Mediated Gut Injury and in the Restitution of Gut Barrier Function. Shock. 2011 Mar;35(3):275-281. http://pmid.us/20856173.

[6] Most pesticide-contaminated vegetable? Celery. “This stalky vegetable tops the dirty list. Research showed that a single celery stalk had 13 pesticides, while, on the whole, celery contained as many as 67 pesticides.”

[7] Paleo cavities and chronic infections: Rhodesian Man, dated to between 125,000 and 300,000 BC, had cavities in ten upper teeth and pitting in his skull indicates he was probably killed by a chronic dental or ear infection. Paleo diets were not a cure-all for infectious disease. Via Melissa McEwen.

[8] Love in nature:

(Via Yves Smith)

[9] Vegan recovers health by eating animal foods: That’s not news. But she wrote a beautiful essay:

I wanted desperately for it to be right, for my ethics to outweigh my physiology.

Then she got death threats.

(Via Newmark’s Door)

[10] Shows how out of touch I am: If Richard Nikoley hadn’t blogged about it, I wouldn’t have known he has detractors. Whatever for? Has he been teasing the vegans again?

[11] Does the body have a fat mass setpoint? Pål Jåbekk of Ramblings of a Carnivore has a discussion of why the word “setpoint” may mislead. I agree – fat mass “equilibrium” or leptin “target” would probably be better words.

Pål objects to the setpoint language because he thinks it has encouraged a simple fat in / fat out mechanistic view of weight gain, and promotes a therapy of “starve and do insane amounts of exercise.” Pål suggests instead a lake metaphor:

When it comes to the body fat setpoint, I rather like the lake comparison. A lake can for those less informed seem to have a set point of water level. Despite rather large fluctuations in temperature, evaporation and water going into and out of the lake, the lake maintains it water level because the factors mostly responsible for the level influence each other. This does not mean that it is difficult to change the level, nor does it mean the lake “attempts to defend against change.” Build a damn dam and the water level will go up. Drain it, and the level goes down. It’s not very hard, you just have to push the right buttons.

I like this metaphor because it expresses the equilibrium concept – fat mass is in equilibrium the way water in the lake is in equilibrium; the equilibrium can change. On the other hand, the way to adjust water level is to reduce water in and increase water out. Doesn’t this metaphor promote the calories in / calories out view? And isn’t that the view that suggested the failed “starve and do insane amounts of exercise” weight loss regimen?

My conclusion: Semantic disagreements can be hard to resolve!

(Note to readers: For our thoughts on how to lose weight, peruse the “Weight Loss” category).

[12] Weekly video: The Cleveland zoo discovers that gorillas get healthier when they eat natural foods instead of sugary biscuits. This is a revelation to zoology:

(Via John Durant)