Category Archives: Diets

High LDL on Paleo Revisited: Low Carb & the Thyroid

Posted by on September 1, 2011 352 comments

One of the more mysterious conditions afflicting low-carb Paleo dieters has been high serum cholesterol. Two of our most popular posts were about this problem: Low Carb Paleo, and LDL is Soaring – Help! (Mar 2, 2011) enumerated some cases and asked readers to suggest answers; Answer Day: What Causes High LDL on Low-Carb Paleo? (Mar 4, 2011) suggested one possible remedy.

On the first post, one of the causes suggested by readers was hypothyroidism – an astute answer. Raj Ganpath wrote:

Weight loss (and VLC diet) resulting in hypothyroidism resulting in elevated cholesterol due to less pronounced LDL receptors?

Kratos said “Hypothyroidism from low carbs.” Mike Gruber said:

I’m the guy with the 585 TC. It went down (to 378 8 months or so ago, time to check again) when I started supplementing with iodine. My TSH has also been trending up the last few years, even before Paleo. So hypothyroidism is my primary suspect.

Those answers caused me to put the connection between hypothyroidism and LDL levels on my research “to do” list.

Chris Masterjohn’s Work on Thyroid Hormone and LDL Receptors

Chris Masterjohn has done a number of blog posts about the role of LDL receptors in cardiovascular disease. His talk at the Ancestral Health Symposium was on this topic, and a recent blog post, “The Central Role of Thyroid Hormone in Governing LDL Receptor Activity and the Risk of Heart Disease,” provides an overview.

His key observation is that thyroid hormone stimulates expression of the LDL receptor (1). T3 thyroid hormone binds to thyroid hormone receptors on the nuclear membrane, the pair (a “dimer”) is then imported into the nucleus where it acts as a transcription factor causing, among other effects, LDL receptors to be generated on the cell membrane.

So higher T3 = more LDL receptors = more LDL particles pulled into cells and stripped of their fatty cargo. So high T3 tends to reduce serum LDL cholesterol levels, but give cells more energy-providing fats. Low T3, conversely, would tend to raise serum cholesterol but deprive cells of energy.

Other Pieces of the Puzzle

Two other facts we’ve recently blogged about help us interpret this result:

We can now assemble a hypothesis linking low carb diets to high LDL. If one eats a glucose and/or protein restricted diet, T3 levels will fall to conserve glucose or protein. When T3 levels fall, LDL receptor expression is reduced. This prevents LDL from serving its fat transport function, but keeps the LDL particles in the blood where their immune function operates.

If LDL particles were being taken up from the blood via LDL receptors, they would have to be replaced – a resource-expensive operation – or immunity would suffer. Apparently evolution favors immunity, and gives up the lipid-transport functions of LDL in order to maintain immune functions during periods of food scarcity.

High LDL on Low Carb: Good health, bad diet?

Suppose LDL receptors are so thoroughly suppressed by low T3 that the lipid transport function of LDL is abolished. What happens to LDL particles in the blood?

Immunity becomes their only function. They hang around in the blood until they meet up with (bacterial) toxins. This contact causes the LDL lipoprotein to be oxidized, after which the particle attaches to macrophage scavenger receptors and is cleared by immune cells.

So, if T3 hormone levels are very low and there is an infection, LDL particles will get oxidized and cleared by immune cells, and LDL levels will stay low. But if there is no infection and no toxins to oxidize LDL, and the diet creates no oxidative stress (ie low levels of omega-6 fats and fructose), then LDL particles may stay in the blood for long periods of time.

If LDL particles continue to be generated, which happens in part when eating fatty food, then LDL levels might increase.

So we might take high LDL on Paleo as a possible sign of two things:

  • A chronic state of glucose deficiency, leading to very low T3 levels and suppressed clearance of LDL particles by lipid transport pathways.
  • Absence of infections or oxidative stress which would clear LDL particles by immune pathways.

The solution? Eat more carbs, and address any remaining cause of hypothyroidism, such as iodine or selenium deficiency. T3 levels should then rise and LDL levels return to normal.

Alternatively, there is evidence that some infections may induce euthyroid sick syndrome, a state of low T3 and high rT3, directly. And these infections may not oxidize LDL, thus they may not lead to loss of LDL particles by immune pathways. So such infections could be another cause of high LDL on Paleo.

Gregory Barton’s Experience

Gregory Barton is an Australian, 52 years old, living in Thailand, where he keeps goats, makes goat cheese and manages a large garden which can be seen on http://www.asiagoat.com/.

Gregory left a comment with an intriguing story, and I invited him to elaborate in a post. Here’s Gregory’s story. – Paul

Gregory’s Writing Begins Here

One of the claims of low carb dieting is that it will normalize the symptoms of metabolic syndrome. Blood pressure, blood sugar and blood lipids, it is claimed, will all come down on a low carb diet, in addition to weight. For most people this happens. But there is a significant minority of people on Paleo and other low carb diets whose blood lipids defy this claim. (See the list of low-carb celebrities with high LDL in this post.)

Why should this happen? Why should some people’s lipids fall on low carb while other people’s lipids rise? Suboptimal thyroid might be the proximate cause for lipids rising on a low carb or paleo diet. Broda Barnes and Lawrence Galton have this to say about thyroid disorders:

“Of all the problems that can affect physical or mental health, none is more common than thyroid gland disturbance. None is more readily and inexpensively corrected. And none is more often untreated, and even unsuspected.”  — Hypothyroidism: The Unsuspected Illness

I went very low carb in April in an effort to address metabolic issues, eating as little as 15grams carbohydrate per day. I had great results with blood pressure, sleeping, blood sugar and weight loss. But lipids bucked the trend.

I had expected triglycerides and cholesterol to drop when I cut the carbs, but they did the opposite: They surged. By July my total cholesterol was 350, LDL 280, and triglycerides bobbed around between 150 and 220.

I did some research and found several competing theories for this kind of surge:

  1. Saturated fat: The increase in saturated fat created a superabundance of cholesterol which the liver cannot handle. Also, Loren Cordain has claimed that saturated fat downregulates LDL receptors.
  2. Temporary hyperlipidemia: The surge in lipids is the temporary consequence of the body purging visceral fat. Jenny Ruhl has argued that within a period of months the situation should settle down and lipids should normalize.
  3. Hibernation: The metabolism has gone into “hibernation” with the result that the thyroid hormone T4 is being converted into rT3, an isomer of the T3 molecule, which prevents the clearance of LDL.
  4. Malnutrition: In March, Paul wrote that malnutrition in general and copper deficiency in particular “… is, I believe, the single most likely cause of elevated LDL on low-carb Paleo diets.”
  5. Genetics: Dr. Davis has argued that some combinations of ApoE alleles may make a  person “unable to deal with fats and dietary cholesterol.”

I could accept that saturated fat would raise my cholesterol to some degree. However, I doubted that an increase in saturated fat, or purging of visceral fat, would be responsible for a 75% increase in TC from 200 to 350.

There are two basic factors controlling cholesterol levels: creation and clearance. If the surge was not entirely attributable to saturated fat, perhaps the better explanation was that the cholesterol was not being cleared properly. I was drawn to the hibernation theory.

But what causes the body to go into hibernation? According to Chris Masterjohn, a low carb diet could be the cause. Although he does not mention rT3, he warns,

“One thing to look out for is that extended low-carbing can decrease thyroid function, which will cause a bad increase in LDL-C, and be bad in itself. So be careful not to go to extremes, or if you do, to monitor thyroid function carefully.”

If low carb is the cause, then higher carb should be the cure. Indeed, Val Taylor, the owner of the yahoo rT3 group, commented that “it is possible that the rT3 could just be from a low carb diet.” She says, “I keep carbs at no lower than 60g per day for this reason.”

Cortisol and Getting “Stuck” in Hibernation

So what about temporary hyperlipidemia? Bears hibernate for winter, creating rT3, but manage to awaken in spring. Why should humans on low carb diets not be able to awaken from their hibernation? There are many people who complain of high cholesterol years after starting low carb.

A hormonal factor associated with staying in hibernation is high cortisol. It has been claimed that excessively high or low cortisol, sustained over long periods, may cause one to get “stuck” in hibernation mode. One of the moderators from the yahoo rT3 group said:

High or low cortisol can cause rT3 problems, as can chronic illness. It would be nice if correcting these things was all that was necessary. But it seems that the body gets stuck in high rT3 mode.

James LaValle & Stacy Lundin in Cracking the Metabolic Code: 9 Keys to Optimal Health wrote:

When a person experiences prolonged stress, the adrenals manufacture a large amount of the stress hormone cortisol. Cortisol inhibits the conversion of T4 to T3 and favours the conversion of T4 to rT3. If stress is prolonged a condition called reverse T3 dominance occurs and lasts even after the stress passes and cortisol levels fall. (my emphasis)

What I Did

First, I got my thyroid hormone levels tested. A blood test revealed that I had T4 at the top of the range and T3 below range. Ideally I would have tested rT3, but in Thailand the test is not available. I consulted Val Taylor, the owner of the yahoo rT3 group, who said that low T3 can cause lipids to go as high as mine have and, “as you have plenty of T4 there is no other reason for low T3 other than rT3.”

I decided to make these changes:

  1. Increase net carbs to ~50 grams per day. Having achieved my goals with all other metabolic markers I increased carbs, taking care that one hour postprandial blood sugar did not exceed 130 mg/dl.
  2. Supplement with T3 thyroid hormone.
  3. In case the malnutrition explanation was a factor, I began supplementing copper and eating my wife’s delicious liver pate three times per week.

I decided to supplement T3 for the following reasons:

  • The surge in TC was acute and very high. It was above the optimal range in O Primitivo’s mortality data.
  • I increased carbs by 20-30g/day for about a month. TC stabilized, but did not drop.
  • The rT3 theory is elegant and I was eager to test my claim that the bulk of the cholesterol was due to a problem with clearance rather than ‘superabundance’.

What happened?

I started taking cynomel, a T3 supplement, four weeks ago. After one week triglycerides dropped from 150 to 90. After two weeks TC dropped from 350 to 300 and after another week, to 220. Last week numbers were stable.

Based on Paul’s recent series on blood lipids, especially the post Blood Lipids and Infectious Disease, Part I (Jun 21, 2011), I think TC of 220 mg/dl is optimal. As far as serum cholesterol levels are concerned, the problem has been fixed.

I believe that thyroid hormone levels were the dominant factor in my high LDL. Saturated fat intake has remained constant throughout.

My current goal is to address the root causes of the rT3 dominance and wean myself off the T3 supplement. I hope to achieve this in the next few months. My working hypothesis is that the cause of my high rT3 / low T3 was some combination of very low carb dieting, elevated cortisol (perhaps aggravated by stress over my blood lipids!), or malnutrition.

Another possibility is toxins: Dr Davis claims that such chemicals as perchlorate residues from vegetable fertilizers and polyfluorooctanoic acid, the residue of non-stick cookware, may act as inhibitors of the 5′-deiodinase enzyme that converts T4 to T3. Finally, Val Taylor claims that blood sugar over 140 mg/dl causes rT3 dominance. I couldn’t find any studies confirming this claim, and don’t believe it is relevant to my case. Val recommends low carb for diabetics to prevent cholesterol and rT3 issues but warns not to go under 60g carb per day.

Issues with T3 Supplementation

There are some factors to consider before embarking upon T3 supplementation:

  1. Preparation: In order to tolerate T3 supplement you have to be sure that your iron level and your adrenals are strong enough. This requires quite a bit of testing. I’ve read of people who cut corners with unpleasant results.
  2. Practicalities: T3 supplementation requires daily temperature monitoring in order to assess your progress. People who are on the move throughout the day would find this difficult.
  3. Danger: Once you get on the T3 boat you can’t get off abruptly. Your T4 level will drop below range and you will be dependent on T3 until you wean yourself off. If you stopped abruptly you could develop a nasty reaction and even become comatose.

My advice for anyone doing very low carb

As Chris Masterjohn said, in the quote above, if you are going to do very low carb, check your thyroid levels. I would add: Increase the carbs if you find your free T3 falling to the bottom of the range. It might be a good idea to test also for cortisol. A 24-hour saliva test will give you an idea whether your cortisol levels are likely to contribute to an rT3 issue. It might also be a good idea to avoid very low carb if you are suffering from stress – such as lipid anxiety!

Gregory Barton’s Conclusion

I also think my experience may help prove thyroid hormone replacement to be an alternative, and superior, therapy to statins for very high cholesterol. Statins, in the words of Chris Masterjohn,

“… do nothing to ramp up the level of cholesterol-made goodies to promote strength, proper digestion, virility and fertility.  It is the vocation of thyroid hormone, by contrast, to do both.”

Paul’s Conclusion

Thanks, Gregory, for a great story and well-researched ideas. The rapid restoration of normal cholesterol levels with T3 supplementation would seem to prove that low T3 caused the high LDL levels.

However, I would be very reluctant to recommend T3 supplementation as a treatment for high LDL on Paleo.  If the cause of low T3 is eating too few carbs, then supplementing T3 will greatly increase the rate of glucose utilization and aggravate the glucose deficiency.

The proper solution, I think, is simply to eat more carbs, to provide other thyroid-supporting nutrients like selenium and iodine, and allow the body to adjust its T3 levels naturally. The adjustment might be quite rapid.

In Gregory’s case, his increased carb consumption of ~50 g/day was still near our minimum, and he may have been well below the carb+protein minimum of 150 g/day (since few people naturally eat more than about 75 g protein). So I think he might have given additional carbs a try before proceeding to the T3.

Gregory had a few questions for me:

GB: What if one is glucose intolerant and can’t tolerate more than 60 grams per day without hyperglycemia or weight gain?

PJ: I think almost everyone, even diabetics, can find a way to tolerate 60 g/day dietary carbs without hyperglycemia or weight gain, and should.

GB: What if raising carbs doesn’t normalize blood lipids and one finds oneself ‘stuck in rT3 mode’?

PJ: I’m not yet convinced there is such a thing as “stuck in rT3 mode” apart from being “stuck in a diet that provides too few carbs” or “stuck in a chronic infection.” If one finds one’s self stuck while eating a balanced diet, I would look for infectious causes and address those.

Finally, if I may sound like Seth Roberts for a moment, I believe this story shows the value of a new form of science: personal experimentation, exploration of ideas on blogs, and the sharing of experiences online. It takes medical researchers years – often decades – to track down the causes of simple phenomena, such as high LDL on low carb. We’re on pace to figure out the essentials in a year.

Water Weight: Does It Change When Changing Diets? Does It Matter?

Posted by on January 14, 2011 54 comments

We’re now up to the final topic in the series reviewing experiences on the diet. Our final topic is the issue of weight gain and loss. This will take a few posts to explore. Next week will be “fat loss week.” This week, let’s look at the question of water weight.

Overweight people who come to the Perfect Health Diet from a high-carb diet seem to lose weight from the beginning. Here is a recent comment from Robert:

I started PHD a few weeks ago, after finding the blog, and then reading the book. I have only positive experiences to report…. I had been overweight in the past, and lost weight by low-calorie dieting on processed foods, along with strength training. After a while I would revert to some degree of overeating, and have to diet again. I’m mildly overweight now but I have been losing 2 lbs. per week on the PHD. Keep in mind this is before any calorie counting. I keep telling myself I will plug things in to Fitday, but so far my hunger is autoregulating itself and the weight is coming off.

However, some of our readers who came from very low-carb diets experienced immediate weight gains. One commenter on Amazon seemed to think this experience would be universal:

[I]f you are coming to the diet from a zero-carb or very-low-carb regimen, you can count on an immediate and substantial weight gain if you suddenly adopt the recommended intake of “400 carb calories [100 grams] per day of starchy tubers, rice, fruit, and berries.” (K. Hix)

Commenter Maggy reported a gain of 5 pounds in her first week:

Following your advice, I added back a bit of “safe starch” last week, and decreased protein intake, keeping sat fat and MCF pretty high. Well, I got on the scale today and have managed to put on 5 pounds! I’m trying to figure out what is going on and what I need to tweak. I do need to lose a good 20-30 lbs, and while I don’t want to compromise health, I also don’t want to put back on what I managed to lose doing a VLC diet.

Is this an adjustment period I need to get through? Maybe I’m one of those broken metabolism folks who has to stick with VLC?

Commenter Bill also experienced a quick gain of a few pounds, and wondered if it could be due to water weight:

After experimenting with adding modest amounts of “safe starches” to my much lower-carb routine, I have noticed a modest weight gain of 3-5 lbs. I wonder if it’s merely glycogen and water repletion.

Beth Mazur of WeightMaven.org agreed:

I also wouldn’t be surprised about weight gain. Presumably these folks are normally running on fairly low glycogen stores. Add some starchy carbs back, and the resulting water weight gain could be a handful of pounds presumably.

That’s an interesting question, so I thought I’d look into the matter.

Background: Glycogen, Glycoproteins, and Water Weight

Sugars are hydrophilic. If you put some water next to some sugar, the sugar will soak it up. As a result, a person’s water weight depends in part on the weight of sugars in the body. More sugars, more water, more weight.

It’s commonly stated that each gram of glycogen is associated with four grams of water; let’s take that as a general ratio for organic sugars.

A typical adult has around 500 grams of glycogen, roughly one-third in the liver and two-thirds in muscle. With associated water, this would add about 2.5 kg or 5 pounds to body weight.

But there are also several pounds of glucose in glycoproteins throughout the body:

  • Mucus in the digestive tract and airways may be as much as 80% sugar by dry weight.
  • The glycocalyx, a protective polysaccharide coat around cells, is primarily composed of sugars.
  • Hyaluronan, glucosamine, and other compounds that enable joints to move freely have much of their weight as sugar-water associations.

These sugar-containing molecules with their associated water add a lot of weight to the body. Glycogen we’ve said accounts for as much as 5 pounds; mucus probably accounts for several pounds at least; and other glycoproteins must add at least a few pounds more.

Are Glycogen and Glycoproteins Lost on a Low-Carb Diet?

It’s commonly asserted that much of these sugar-containing molecules, and their associated water, are lost on a low-carb diet. From a review of Gary Taubes’ Why We Get Fat, linked today by CarbSane:

[B]etween 5-10lbs of weight are lost on a low-carb diet due to the mobilization of the water stored with glycogen …

I argued in my “zero-carb dangers” series that a danger of zero-carb dieting was that the body would downregulate production of glycoproteins; and that reduced production of these might be quite dangerous.

For instance, reduced production of mucus in the digestive tract might increase the risk of gastrointestinal cancers, bowel diseases, and entry of infectious pathogens through the gut.

If it’s true that low-carb diets reduce water weight by 5 to 10 pounds, there must be a substantial loss of sugar-containing molecules. This is hardly likely to be healthy. Glycoproteins are essential for good health. Indeed, the evolution of glycoproteins was a prerequisite for the evolution of multicellular life!

So I would find this kind of water-weight loss quite alarming.

Let’s look for some data to see if it actually happens.

From High-Carb Diet to Fasting

In our earlier post on fasting for migraines, commenter js290 linked to a very nice post by Ned Kock, in which he talked about the components of weight loss during starvation. Ned posted this picture, taken from a textbook [1]:

Over 30 days of fasting, almost half the weight lost is from fat and almost half from water; small amounts of protein and sugar are lost.

In the first few days, water loss dominates. In the first 48 hours, 3.4 kg are lost, of which roughly 0.35 kg are glycogen, 0.1 kg protein, 0.3 kg fat, and 2.65 kg water.

So in the first two days of fasting, fully 5.8 pounds of water are lost. That’s remarkable.

Presumably, if this person had been returned to his normal diet, that weight would have been regained in a few days.

If the water loss was triggered by a loss of carbohydrate (in glycogen and glycoproteins), then a very low-carb diet might have had the same effect as the fast.

From High-Carb to Low-Carb Diets

There are some metabolic ward studies looking at what happens when people adopt low-carb diets. Here’s one that looked at an Atkins-style diet. [2]

The subjects entered the metabolic ward but continued to eat their normal diet on days 1 through 7, to provide a baseline. Then they adopted an Atkins-style diet for 2 weeks. Carbohydrate was reduced to 21 g (80 calories) per day, and they could eat as much fat and protein as they wished.

The results:

During the low-carbohydrate diet, mean body weight decreased by 2.02 kg from 114.43 kg (last day of the usual diet) to 112.41 kg (last day of the low-carbohydrate diet) …

During the low-carbohydrate diet, mean body water decreased from 46.30 kg to 45.94 kg. Body water decreased in 6 patients, increased in 3 patients, and did not change in 1 patient. After subtraction of body water, mean body weight decreased from 68.13 kg to 66.48 kg. [2]

In other words, water weight hardly changed. The weight loss was accounted for by fat loss, which was understandable because the subjects reduced their calorie intake by 946 calories per day. [2]

So in this study, water weight loss averaged only 360 g (0.8 lb), and some patients actually gained water weight on the low-carb diet!

So it looks like going from a high-carb diet to a low-carb diet needn’t lead to much loss of water weight.

From Low-Carb Diet to Fasting

I looked for some papers on what happens when a low-carb dieter starts a fast. I found this:

In her book ‘Living on Light’, Jasmuheen tries to animate people worldwide to follow her drastic nutrition rules in order to boost their quality of life. Several deaths have been reported as a fatal consequence. A doctor of chemistry who believably claimed to have been ‘living on light’ for 2 years, except for the daily intake of up to 1.5 l of fluid containing no or almost no calories was interested in a scientific study on this phenomenon.

The 54-year-old man was subjected to a rigorous 10-day isolation study with complete absence of nutrition. During the study he obtained an unlimited amount of tea and mineral water but had no caloric intake….

[The man experienced] a mean weight loss of 0.26 kg/d … [3]

If his weight loss of 260 g/day consisted of 130 g protein and 130 g fat – a plausible mix – then he was expending about 1700 calories per day. This is very plausible, and leaves little room for water weight loss.

So when a low-carb dieter starts a fast, he may lose hardly any water weight at all!

Summary and My Own Experience

These studies are inconsistent. If going from a high-carb diet to a low-carb diet doesn’t produce water weight loss, and going from a low-carb diet to fasting doesn’t, then why would going from a high-carb diet to fasting?

I confess I was surprised by the level of water loss reported by Ned’s source. I fast moderately often, and I lose typically around 1 pound during a 36 hour fast. Shou-Ching’s experience is similar. That doesn’t leave much room for water weight loss.

But clearly, some people do experience large losses of water weight when they adopt a low-carb diet or a fast, and then regain it upon carb re-feeding.

I think we have to conclude that the phenomenon of water weight loss on low-carb diets, and water weight gain on carb re-feeding, is variable across persons. In some persons it happens, and in others it doesn’t.

Conclusion

I think those sugars serve important functional purposes. Glycoproteins are essential for health. Glycogen is a desirable reserve that helps the liver manage blood glucose and muscles exert force.

Maggy asked if she was metabolically broken because she gained 5 pounds in a week by adding carbs back in. Now, a lot can happen in a week, including significant changes in fat and protein mass, and water weight changes due to changes in sodium levels. Low-carb diets tend to lead to salt loss, so that may have been a factor.

But if the weight gain was entirely due to restoration of sugar and water levels, then I’m reluctantly led to the conclusion that Maggy may indeed be “metabolically broken.” The brokenness is not in the gain of bodily sugars when she eats the carbs; it’s in the loss of these important sugars on her very low-carb diet!

If it’s unhealthy to lose those sugars, and if a metabolically healthy person can sustain the body’s sugar and water levels through a fast, then the loss of sugars on either a low-carb diet or fast suggests a damaged metabolism.

As much as Maggy wishes to lose weight, it is important to lose weight from adipose cells, not from water and glycoproteins. Her rapid ~5 lb weight gain upon shifting from a very low-carb diet to the Perfect Health Diet might have been a very good thing.

UPDATE:

CarbSane has begun a series on water weight, and has interesting numbers on water weight in adipose tissue and lean tissue, and how water weight varies between obese and lean persons. This post introduced several papers, and a follow-up contributes an interesting analysis and suggests that movement of fatty acids between adipose and lean tissue may be involved in water weight changes.

I didn’t know that extracellular water weight in tissues was so variable. Thank you CarbSane! 

References

[1] Wilmore, J.H., Costill, D.L., & Kenney, W.L. (2007). Physiology of sport and exercise. Champaign, IL: Human Kinetics. Cited by Ned Kock, “The amounts of water, carbohydrates, fat, and protein lost during a 30-day fast,” http://healthcorrelator.blogspot.com/2010/10/amounts-of-water-carbohydrates-fat-and.html.

[2] Boden G et al. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Ann Intern Med. 2005 Mar 15;142(6):403-11. http://pmid.us/15767618. Full text: http://www.annals.org/content/142/6/403.full.pdf.

[3] Heusser P et al. Nutrition with ‘light and water’? In strict isolation for 10 days without food – a critical case study. Forsch Komplementmed. 2008 Aug;15(4):203-9. http://pmid.us/18787329.

Dangers of Zero-Carb Diets, IV: Kidney Stones

Posted by on November 23, 2010 123 comments

Kidney stones are a frequent occurrence on the ketogenic diet for epilepsy. [1, 2, 3] About 1 in 20 children on the ketogenic diet develop kidney stones per year, compared with one in several thousand among the general population. [4] On children who follow the ketogenic diet for six years, the incidence of kidney stones is about 25% [5].

A 100-fold odds ratio is hardly ever seen in medicine. There must be some fundamental cause of kidney stones that is dramatically promoted by clinical ketogenic diets.

Just over half of ketogenic diet kidney stones are composed of uric acid and just under half of calcium oxalate mixed with calcium phosphate or uric acid. Among the general public, about 85% of stones are calcium oxalate mixes and about 10% are uric acid.  So, roughly speaking, uric acid kidney stones are 500-fold more frequent on the ketogenic diet and calcium oxalate stones are 50-fold more frequent.

Causes are Poorly Understood

In the nephrology literature, kidney stones are a rather mysterious condition.

Wikipedia has a summary of the reasons offered in the literature for high stone formation on the ketogenic diet [4]:

Kidney stone formation (nephrolithiasis) is associated with the diet for four reasons:

  • Excess calcium in the urine (hypercalciuria) occurs due to increased bone demineralisation with acidosis. Bones are mainly composed of calcium phosphate. The phosphate reacts with the acid, and the calcium is excreted by the kidneys.
  • Hypocitraturia: the urine has an abnormally low concentration of citrate, which normally helps to dissolve free calcium.
  • The urine has a low pH, which stops uric acid from dissolving, leading to crystals that act as a nidus for calcium stone formation.
  • Many institutions traditionally restricted the water intake of patients on the diet to 80% of normal daily needs; this practice is no longer encouraged.

These are not satisfying explanations. The last three factors focus on the solubility of uric acid or calcium in the urine; the first on availability of calcium, one of the most abundant minerals in the body.

There is no consideration of the sources of uric acid, oxalate, or calcium phosphate.

Two of the factors focus on urine acidity, but alkalinizing diets have only a modest effect on stone formation. In the Health Professionals Study and Nurses Health Study I and II, covering about 240,000 health professionals, people with the lowest scores for a DASH-style diet (an alkalinizing diet high in fruits, vegetables, nuts, and legumes) had a kidney stone risk less than double that of those with the highest DASH-style scores. [6]

On ketogenic diets specifically, supplementation with potassium citrate to alkalinize the urine and provide citrate reduced the stone formation rate by a factor of 3. [3] They were still more than 30-fold more frequent than in the general population.

It seems the medical community is still unaware of some primary causes of stone formation.

Uric Acid Production

One difference between a ketogenic (or zero-carb) diet and a normal diet is the high rate of protein metabolism. If both glucose and ketones are generated from protein, then over 150 g protein per day is consumed in gluconeogenesis and ketogenesis. This releases a substantial amount of nitrogen. While urea is the main pathway for nitrogen disposal, uric acid is the excretion pathway for 1% to 3% of nitrogen. [7]

This suggests that ketogenic dieters produce an extra 1 to 3 g/day uric acid from protein metabolism. A normal person excretes about 0.6 g/day. [8]

In addition to kidney stones, excess uric acid production may lead to gout. Some Atkins and low-carb Paleo dieters have contracted gout.

Oxalate Production

Our last post (on scurvy) argued that very low-carb dieters are probably inefficient at recycling vitamin C from its oxidized form, dehydroascorbic acid or DHAA.

If DHAA is not getting recycled into vitamin C, then it is being degraded. Here is its degradation pathway:

The degradation of vitamin C in mammals is initiated by the hydrolysis of dehydroascorbate to 2,3-diketo-l-gulonate, which is spontaneously degraded to oxalate, CO(2) and l-erythrulose. [9]

Oxalate is a waste material that has to be excreted in the kidneys. Vitamin C degradation is a major – in infections, probably the largest – source of oxalate in the kidneys:

Blood oxalate derives from diet, degradation of ascorbate, and production by the liver and erythrocytes. [10]

Since the loss rate from vitamin C degradation can reach 100 g/day in severe infections, and most of that mass is excreted as oxalate, it is apparent that a very low-carb dieter who has active infections, as did I and KM in the scurvy post, or some other oxidizing stress such as injury or cancer, may easily excrete grams of oxalate per day, with the amount limited by vitamin C intake.

Dehydration and Loss of Electrolytes

Excretion of oxalate consumes both electrolytes, primarily salt, and water:

In mammals, oxalate is a terminal metabolite that must be excreted or sequestered. The kidneys are the primary route of excretion and the site of oxalate’s only known function. Oxalate stimulates the uptake of chloride, water, and sodium by the proximal tubule through the exchange of oxalate for sulfate or chloride via the solute carrier SLC26A6. [10]

Salt and water are also needed by the kidneys to excrete urea and uric acid.

Personally, I found that my salt needs increased dramatically on a zero-carb diet. I needed at least a teaspoon per day of salt when zero-carbing, compared to less than a quarter-teaspoon when eating carbs.

As a result of loss of salt and water, low-carb dieters tend to become dehydrated. This is also a widely-observed side effect on ketogenic diets.

We’ve all seen what happens to urine when we’re dehydrated: it becomes colorful due to high concentrations of dissolved compounds.

As urine becomes saturated, it no longer possible for uric acid and oxalate to dissolve. They precipitate out and initial deposits nucleate further deposits to form kidney stones.

Polyunsaturated Fats and Kidney Stones

That brings us to another factor that promotes kidney stones: high omega-3 polyunsaturated fat consumption.

Here’s the data:

Older women (NHS I) in the highest quintile of EPA and DHA intake had a multivariate relative risk of 1.28 (95% confidence interval, 1.04 to 1.56; P for trend = 0.04) of stone formation compared with women in the lowest quintile. [11]

Eating omega-3 fats promotes calcium oxalate kidney stones about as much as eating oxalate. The top quintile of dietary oxalate intake has a relative risk of 1.22. [12]  (The top dietary source of oxalate is spinach, by the way.)

So what about EPA and DHA promotes kidney stone formation?  A clue comes from julianne of Julianne’s Paleo & Zone Nutrition Blog; she made a very interesting comment:

A few years ago I started taking a high dose of Omega 3, because of joint inflammation, and other issues. This made big difference for about 3 months, then seemed to not work any more. I talked to a nutritionist friend and she pointed out that according to Andrew Stoll (The Omega 3 Connection) you must take 1000 mg vit C and 500 iu vit E daily or the omega 3 becomes oxidised in your body (cell membranes) and ineffective. I started taking both and in days was back to the original anti-inflammatory effectiveness of omega 3. I have since talked to others about this – for example a psychiatrist whose clients did well on omega 3 for 3 months and then it became ineffective.

Paleo advice from many is to consume a high dose of omega 3, and at the same time reduce carbs. I am wondering if there are people suffering vit C depletion as a result of increased omega 3 consumption as well as too low carbs?

EPA and DHA have a lot of fragile carbon double bonds – 5 and 6 respectively – and are easily oxidized. It’s quite plausible that this lipid peroxidation can lead to oxidation and degradation of vitamin C.

If so, then higher EPA and DHA consumption would increase the flux of oxalate through the kidneys and raise the risk of calcium oxalate stones. It makes sense that the effect is strongest in the elderly, who tend to have the worst antioxidant status.

What Does This Tell Us About the Cause of Stones in the General Population?

Since most kidney stones afflicting the general public are calcium oxalate stones, it seems likely that vitamin C degradation may be the major source of raw material for kidney stones.

If so, then the risk of kidney stones can be greatly reduced by dietary and nutritional steps.

First, the rate of oxidation can be slowed by higher intake of antioxidants such as:

  • Glutathione and precursors such as N-acetylcysteine;
  • Selenium for glutathione peroxidase;
  • Zinc and copper for superoxide dismutase;
  • Coenzyme Q10 for lipid protection;
  • Alpha lipoid acid;
  • Colorful vegetables and berries.

Vitamin C supplementation has mixed effects: its antioxidant effect is beneficial but its degradation is harmful.

Second, electrolyte and water consumption are important. Salt is especially important.

Finally, alkalinizing compounds like lemon juice or other citrate sources can increase the solubility of uric acid.

Conclusion

Zero-carb dieters are at risk for

  • Excess renal oxalate from failure to recycle vitamin C;
  • Excess renal uric acid from disposal of nitrogen products of gluconeogenesis and ketogenesis;
  • Salt and other electrolyte deficiencies from excretion of oxalate, urea and uric acid; and
  • Dehydration.

These four conditions dramatically elevate the risk of kidney stones.

To remedy these deficiencies, we recommend that everyone who fasts or who follows a zero-carb diet obtain dietary and supplemental antioxidants, eat salt and other electrolytes, and drink lots of water.

Also, unless there is a therapeutic reason to restrict carbohydrates, it is best to obtain about 20% of calories from carbs in order to relieve the need to manufacture glucose and ketones from protein. This will substantially reduce uric acid excretion. If it also reduces vitamin C degradation rates, as we argued in our last post, then it will substantially reduce oxalate excretion as well.

Related Posts

Other posts in this series:

  1. Dangers of Zero-Carb Diets, I: Can There Be a Carbohydrate Deficiency? Nov 10, 2010.
  2. Dangers of Zero-Carb Diets, II: Mucus Deficiency and Gastrointestinal Cancers A Nov 15, 2010.
  3. Danger of Zero-Carb Diets III: Scurvy Nov 20, 2010.

References

[1] Furth SL et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol. 2000 Nov;15(1-2):125-8. http://pmid.us/11095028.

[2] Herzberg GZ et al. Urolithiasis associated with the ketogenic diet. J Pediatr. 1990 Nov;117(5):743-5. http://pmid.us/2231206.

[3] Sampath A et al. Kidney stones and the ketogenic diet: risk factors and prevention. J Child Neurol. 2007 Apr;22(4):375-8. http://pmid.us/17621514.

[4] “Ketogenic diet,” Wikipedia, http://en.wikipedia.org/wiki/Ketogenic_diet.

[5] Groesbeck DK et al. Long-term use of the ketogenic diet. Dev Med Child Neurol. 2006 Dec;48(12):978-81. http://pmid.us/17109786.

[6] Taylor EN et al. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol. 2009 Oct;20(10):2253-9. http://pmid.us/19679672.

[7] Gutman AB. Significance of uric acid as a nitrogenous waste in vertebrate evolution. Arthritis Rheum. 1965 Oct;8(5):614-26. http://pmid.us/5892984.

[8] Boyle JA et al. Serum uric acid levels in normal pregnancy with observations on the renal excretion of urate in pregnancy. J Clin Pathol. 1966 Sep;19(5):501-3. http://pmid.us/5919366.

[9] Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007 Jan;274(1):1-22. http://pmid.us/17222174.

[10] Marengo SR, Romani AM. Oxalate in renal stone disease: the terminal metabolite that just won’t go away. Nat Clin Pract Nephrol. 2008 Jul;4(7):368-77. http://pmid.us/18523430.

[11] Taylor EN et al. Fatty acid intake and incident nephrolithiasis. Am J Kidney Dis. 2005 Feb;45(2):267-74. http://pmid.us/15685503.

[12] Taylor EN, Curhan GC. Oxalate intake and the risk for nephrolithiasis. J Am Soc Nephrol. 2007 Jul;18(7):2198-204. http://pmid.us/17538185.

Danger of Zero-Carb Diets III: Scurvy

Posted by on November 20, 2010 207 comments

I started low-carb Paleo dieting in late 2005. I ate a lot of vegetables but no starches and hardly any fruit. In retrospect, I would call it a near zero-carb diet. At that time I was 12 years into a chronic illness that got a little worse each year and was quite mysterious to me. Adopting a low-carb diet brought immediate changes: it made what I would much later recognize as a chronic bacterial infection better (in parts of the body, not the brain) and made a chronic fungal infection worse.

Within about a year I had developed scurvy. It took me an embarrassingly long time to figure out what it was. By the time knew what it was, I had 3 cavities; had lost 25 pounds; had developed diverticulitis and an abdominal aorta that visibly swelled with every heartbeat; and had minor skin wounds – scrapes and scratches – that hadn’t healed in 6 months.

Developing scurvy was a surprise, because I was eating many vegetables plus taking a multivitamin containing 90 mg of vitamin C. I had never had any signs of vitamin C deficiency before adopting a low-carb diet.

Four grams a day of vitamin C for two months cured all the scurvy symptoms. It would be several more years before I figured out the infections, but this experience taught me the importance of micronutrition. The experience persuaded me that I needed to research diets and nutrition closely, and started us down the path of writing Perfect Health Diet.

Scurvy on a Ketogenic Diet

My experience is not unique. Here’s one case we mention in the book: the story of a young girl with epilepsy.

KM was a 9-year old girl … diagnosed with epilepsy at six months old. She started a ketogenic diet in October 2003, as her multiple antiepileptic drugs were proving to be less than effective; indeed she was having as many as 12 tonic seizures per day with prolonged periods of non-convulsive status epilepticus. After the diet was prescribed the seizure frequency reduced markedly and there were a number of long periods of time in which she had no seizures.

KM’s mother gave a history of her daughter having had bleeding gums since the beginning of September 2006; she described them as being very dark red, swollen and bleeding. In addition, she explained that her daughter had dry, crusted blood peri-orally. The family’s general dental practitioner had explained that this was probably caused by erupting teeth and instructed her to use 0.2% chlorhexidine gluconate gel and to continue her regular oral hygiene regimen; however this had no effect. About a month later the patient’s right arm became swollen. It was thought that she had sustained a fracture or a dislocation; however she was discharged from the local hospital’s fracture clinic because there was clinical improvement and radiographs showed no callus formation.

In early November KM inhaled a primary molar tooth while she was having her teeth cleaned (Fig. 1). This required an emergency bronchoscopy to retrieve it; at the same time the surgeons extracted her remaining primary teeth in order to avoid a recurrence of the problem….

At that time an appointment was made to attend a paediatric dentistry consultant clinic at the Leeds Dental Institute; however this was never kept as about three weeks after the extractions the patient was admitted to hospital with low grade fever, persistently bleeding gums, oedema of her hands and feet and a petechial rash on her legs. [1]

This girl was eating a typical amount of vitamin C: her dietary intake was calculated at 73 mg/day, well above the US RDA for 9-13 year olds of 45 mg/day. Yet her blood level was only 0.7 µmol/l. Scurvy is diagnosed at levels below 11 µmol/l.

The symptoms of scurvy are sufficiently insidious that it is easy to miss the diagnosis. In KM’s case, it happened that a “senior house officer” – a junior doctor in training – from India recognized the symptoms of scurvy. Otherwise, it might have never have occurred to the doctors to test her vitamin C level. [2]

What Is the Cause of Low-Carb Scurvy?

So what causes scurvy to develop on low-carb diets even with vitamin C intake well above the US RDA?

It seems to be a confluence of two factors:

  • An infection or some other stress (e.g. injury, cancer) leads to the oxidation of extracellular vitamin C; and
  • On a low-insulin or glutathione-deficiency-inducing diet, oxidized vitamin C is not recycled.

Infection and Vitamin C

The immune response to infections generates reactive oxygen species, which oxidize vitamin C. Oxidation removes a hydrogen atom from vitamin C, turning it into “dehydroascorbic acid,” or DHAA. If DHAA remains in the blood, it degrades with a half-life of 6 minutes. [3]

Infections can cause vitamin C deficiency on any diet. During the “acute phase response” to infection or injury, vitamin C often becomes deficient. Here is a nice paper in which French doctors surveyed their hospital patients for scurvy:

We determined serum ascorbic acid level (SAAL) and searched for clinical and biological signs of scurvy in 184 patients hospitalized during a 2-month period.

RESULTS: The prevalence of hypovitaminosis C (depletion: SAAL<5 mg/l or deficiency: SAAL<2 mg/l) was 47.3%. Some 16.9% of the patients had vitamin C deficiency. There was a strong association between hypovitaminosis C and the presence of an acute phase response (p=0.002). [4]

So half were at least depleted in vitamin C and 17% had outright deficiency, which if it persisted would produce scurvy.

We’ve previously written of how important it is to supplement with vitamin C during infections:

I might add here that in sepsis, an extremely dangerous inflammatory state brought on by bacterial infections, intravenous vitamin C reverses some of the worst symptoms. [5] If you have a loved one suffering from a dangerous infection, it might not be a bad idea to get them some vitamin C.

Insulin Dependence of Vitamin C Recycling

DHAA can be recycled back into vitamin C, but only inside cells.

In order to enter cells, DHAA needs to be transported by glucose transporters. GLUT1, GLUT3, and GLUT4 are the three human DHAA transporters; GLUT1 does most of the work. [6]

DHAA transport is crucial for brain vitamin C status. There is no direct transport of vitamin C into the brain, yet the brain is one of the most vitamin C-dependent tissues in the body. The brain relies entirely on GLUT1-mediated transport of DHAA from the blood for its vitamin C supply. Within the brain, DHAA is restored to vitamin C by glutathione.

Supplying DHAA to stroke victims (of the mouse persuasion) as late as 3 hours after the stroke can reduce the stroke-damaged volume by up to 95%:

DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). [7]

This is a fascinating reminder of the importance of vitamin C for wound repair and protection from injury.

Glucose transporters are activated by insulin. Thus, DHAA import into cells is increased by insulin, leading to more effective recycling of vitamin C [8]:

Insulin and IGF-1 promote recycling of DHAA into ascorbate. Source.

Confirming the role of insulin in promoting vitamin C recycling, Type I diabetics (who lack insulin) have lower blood levels of vitamin C, higher blood levels of DHAA, increased urinary loss of vitamin C metabolites, and greater need for dietary vitamin C. [9, 10]

Now we have a mechanism by which zero-carb diets reduce vitamin C recycling: by lowering insulin levels they inhibit the transport of DHAA into cells, preventing its recycling into vitamin C. Instead, DHAA is degraded and excreted. As a result, vitamin C is lost from the body.

Glutathione and Vitamin C Recycling

Once inside the cell, DHAA is recycled back to ascorbate, mainly by glutathione inside mitochondria:

Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. [11]

A GLUT1 transporter on the mitochondrial membrane is needed to bring DHAA into mitochondria, possibly squaring the effect of insulin on vitamin C recycling.

Since glutathione recycles vitamin C, glutathione deficiency is another possible cause of vitamin C deficiency.

Glutathione is recycled by the enzyme glutathione peroxidase, a selenium-containing enzyme whose abundance is sensitive to selenium status. One difficulty with zero-carb diets is that they seem to deplete selenium levels.

Selenium deficiency is a common side effect of ketogenic diets. Some epileptic children on ketogenic diets have died from selenium deficiency! [12]

So here we have a second mechanism contributing to the development of scurvy on a zero-carb diet. The diet produces a selenium deficiency, which produces a glutathione deficiency, which prevents DHAA from being recycled into vitamin C, which leads to DHAA degradation and permanent loss of vitamin C.

Conclusion

Zero-carb dieters are at high risk for vitamin C deficiency, glutathione deficiency, and selenium deficiency. Anyone on a zero-carb diet should remedy these by supplementation.

These deficiencies are exacerbated by chronically low insulin levels. Insulin helps recycle vitamin C, which supports glutathione status. Lack of insulin increases vitamin C degradation and loss.

The failure of the body to efficiently recycle vitamin C and maintain antioxidant stores on a zero-carb diet is evidence of an evolutionary maladaption to the zero-carb diet.

There was no reason why our ancestors should have become adapted to a zero-carb diet; after, all they’ve been eating starches for at least 2 million years. It seems a risky step to try to live this way.

Related Posts

Other posts in this series:

  1. Dangers of Zero-Carb Diets, I: Can There Be a Carbohydrate Deficiency? Nov 10, 2010.
  2. Dangers of Zero-Carb Diets, II: Mucus Deficiency and Gastrointestinal Cancers A Nov 15, 2010.
  3. Dangers of Zero-Carb Diets, IV: Kidney Stones Nov 23, 2010.

References

[1] Willmott NS, Bryan RA. Case report: Scurvy in an epileptic child on a ketogenic diet with oral complications.  Eur Arch Paediatr Dent. 2008 Sep;9(3):148-52. http://pmid.us/18793598.

[2] Willmott NS, personal communication.

[3] “Dehydroascorbate,” Wikipedia, http://en.wikipedia.org/wiki/Dehydroascorbate.

[4] Fain O et al. Hypovitaminosis C in hospitalized patients. Eur J Intern Med. 2003 Nov;14(7):419-425. http://pmid.us/14614974.

[5] Tyml K et al. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med. 2005 Aug;33(8):1823-8. http://pmid.us/16096461.

[6] Rivas CI et al. Vitamin C transporters. J Physiol Biochem. 2008 Dec;64(4):357-75. http://pmid.us/19391462.

[7] Huang J et al. Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11720-4. http://pmid.us/11573006.

[8] Qutob S et al. Insulin stimulates vitamin C recycling and ascorbate accumulation in osteoblastic cells. Endocrinology. 1998 Jan;139(1):51-6. http://pmid.us/9421397.

[9] Will JC, Byers T. Does diabetes mellitus increase the requirement for vitamin C? Nutr Rev. 1996 Jul;54(7):193-202. http://pmid.us/8918139.

[10] Seghieri G et al. Renal excretion of ascorbic acid in insulin dependent diabetes mellitus. Int J Vitam Nutr Res. 1994;64(2):119-24. http://pmid.us/7960490.

[11] Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007 Jan;274(1):1-22. http://pmid.us/17222174.

[12] Bank IM et al. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol. 2008 Dec;39(6):429-31. http://pmid.us/19027591. (Hat tip Dr. Deans.)