Tuesday, November 10, 2009

Malocclusion: Disease of Civilization, Part V

Prenatal Development of the Face and Jaws

The structures of the face and jaws take shape during the first trimester of pregnancy. The 5th to 11th weeks of pregnancy are particularly crucial for occlusion, because this is when the jaws, nasal septum and other cranial structures form. The nasal septum is the piece of cartilage that forms the structure of the nose and separates the two air passages as they enter the nostrils.

Maternal Nutritional Status Affects Fetal Development

Abnormal nutrient status can lead to several types of birth defects. Vitamin A is an essential signaling molecule during development. Both deficiency and excess can cause birth defects, with the effects predominantly targeting the cranium and nervous system, respectively. Folic acid deficiency causes birth defects of the brain and spine. Other nutrients such as vitamin B12 may influence the risk of birth defects as well*.

The Role of Vitamin K

As early as the 1970s, physicians began noting characteristic developmental abnormalities in infants whose mothers took the blood-thinning drug warfarin (coumadin) during the first trimester of pregnancy. These infants showed an underdevelopment of the nasal septum, the maxilla (upper jaw), small or absent sinuses, and a characteristic "dished" face. This eventually resulted in narrow dental arches, severe malocclusion and tooth crowding**. The whole spectrum was called Binder's syndrome, or warfarin embryopathy.

Warfarin works by inhibiting vitamin K recycling, thus depleting a nutrient necessary for normal blood clotting.
It's now clear that Binder's syndrome can result from anything that interferes with vitamin K status during the first trimester of pregnancy. This includes warfarin, certain anti-epilepsy drugs, certain antibiotics, genetic mutations that interfere with vitamin K status, and celiac disease (intestinal damage due to gluten).

Why is vitamin K important for the development of the jaws and face of the fetus? Vitamin K is required to activate a protein called matrix gla protein (MGP), which prevents unwanted calcification of the nasal septum in the developing fetus (among
other things). If this protein isn't activated by vitamin K during the critical developmental window, calcium deposits form in the nasal septum, stunting its growth and also stunting the growth of the maxilla and sinuses. Low activity of MGP appears to be largely responsible for Binder's syndrome, since the syndrome can be caused by genetic mutations in MGP in humans. Small or absent sinuses are common in the general population.

One of the interesting things about MGP is its apparent preference for vitamin K2 over vitamin K1.
Vitamin K1 is found predominantly in green vegetables, and is sufficient to activate blood clotting factors and probably some other vitamin K-dependent proteins. "Vitamin K2" refers to a collection of molecules known as menaquinones. These are denoted as "MK", followed by a number indicating the length of the side chain attached to the quinone ring.

Biologically important menaquinones are MK-4 through MK-12 or so. MK-4 is the form that animals synthesize from vitamin K1 for their own use. Certain organs (brain, pancreas, salivary gland, arteries) preferentially accumulate K2 MK-4, and certain cellular processes are also selective for K2 MK-4 (
MGP activation, PKA-dependent transcriptional effects). Vitamin K2 MK-4 is found almost exclusively in animal foods, particularly pastured butter, organs and eggs. It is always found in foods designed to nourish growing animals, such as eggs and milk.

Humans have the ability to convert K1 to K2 when K1 is ingested in artificially large amounts. However, due to the limited absorption of normal dietary sources of K1 and the unknown conversion efficiency, it's unclear how much green vegetables contribute to K2 status. Serum vitamin K1 reaches a plateau at about 200 micrograms per day of dietary K1 intake, the equivalent of 1/4 cup of cooked spinach (see figure 1 of this paper). Still, I think eating green vegetables regularly is a good idea, and may contribute to K2 status.
Other menaquinones such as MK-7 (found in natto) may contribute to K2 status as well, but this question has not been resolved.

Severe vitamin K deficiency clearly impacts occlusion. Could more subtle deficiency lead to a less pronounced form of the same developmental syndrome? Here are a few facts about vitamin K relevant to this question:
  • In industrial societies, newborns are typically vitamin K deficient. This is reflected by the fact that in the US, nearly all newborns are given vitamin K1 at birth to prevent potentially fatal hemorrhage. In Japan, infants are given vitamin K2 MK-4, which is equally effective at preventing hemmorhage.
  • Fetuses generally have low vitamin K status, as measured by the activity of their clotting factors.
  • The human placenta transports vitamin K across the placental barrier and accumulates it. This transport mechanism is highly selective for vitamin K2 MK-4 over K1.
  • The concentration of K1 in maternal blood is much higher than its concentration in umbilical cord blood, whereas the concentration of K2 in maternal blood is similar to the concentration in cord blood. Vitamin K2 MK-7 is undetectable in cord blood, even when supplemented, suggesting that MK-7 is not an adequate substitute for MK-4 during pregnancy.
  • In rat experiments, arterial calcification due to warfarin was inhibited by vitamin K2 MK-4, but not vitamin K1. This is probably due to K2's ability to activate MGP, the same protein required for the normal development of the human face and jaws.
  • The human mammary gland appears to be the most capable organ at converting vitamin K1 to K2 MK-4.
Together, this suggests that in industrial societies, fetuses and infants are vitamin K deficient, to the point of being susceptible to fatal hemorrhage. It also suggests that vitamin K2 MK-4 plays a critical role in fetal and early postnatal development. Could subclinical vitamin K2 deficiency be contributing to the high prevalence of malocclusion in modern societies?

An Ounce of Prevention

Vitamin A, folic acid, vitamin D and vitamin K2 are all nutrients with a long turnover time. Body stores of these nutrients depend on long-term intake. Thus, the nutritional status of the fetus during the first trimester reflects what the mother has been eating for several months
before conception.

Dr. Weston Price noted that a number of the traditional societies he visited prepared women of childbearing age for healthy pregnancies by giving them special foods rich in fat-soluble vitamins. This allowed them to gestate and rear healthy, well-formed children.
Nutrient-dense animal foods and green vegetables are a good idea before, during and after pregnancy.

* Liver is the richest source of vitamin A, folic acid and B12.

** Affected individuals may show class I, II, or III malocclusion.


TedHutchinson said...

For those new to the topic of Vitamin K2 here is a useful free full text review Alternative Medicine Review Vitamin K2

lightcan said...

I know this is off topic and it might be more suitable in the comments section for omega 3 eggs but maybe people who read the blog are going to look at the last post and not at the comments of the previous post.
I got too excited when I found this and thought of sharing. A video lecture with dr. Lands that maybe you know about Stephan.


Dr. B G said...

WOW Stephan,

I hope is not the conclusion of this mind enlightening series?

OMG so B**BIES make MK4??!

u rock.


Scott Miller said...

Superb series!

I've been posting links to it all over the place.

Matt Stone said...

Awesome again. This has definitely been one of my favorite blog series I've ever read. No doubt about it.

This MGP sounds interesting.

One of my conclusions on abnormal facial and jaw development has been that folic acid is a primary factor. Since folic acid is found to be pivotal in the neural tube formation that completes facial development (and can cause cleft palate for example if there is extreme deficiency), it seems likely that it is somehow involved.

When I came across a study showing that those suffering from fructose malabsorption always had low levels of serum folic acid (as well as zinc and tryptophan), I certainly began to wonder.

Anyway, MGP here I come.

Anonymous said...

My pregnant sister-in-law picked up some K2, and promptly noted that there was a warning on the bottle against pregnant women taking it!

Of course given the long time of turnover, maybe it would be "too late" anyway.

Helen said...

Thanks again for the great series, Stephan. I also am glad you aren't anti-vegetable. The anti-vegetable stuff makes me crazy, as though there were no safe haven in this world. And I like vegetables.

R K @ Health Matters To Me said...

Awesome stuff, Stephan. Speaking of prenatal development, Vitamin K1 and K2, I'm trying to figure out how a family of raw vegans -- the Boutenkos -- appear to be in good health (read: beautiful facial structure) while avoiding animal foods. My suspicion is their inclusion of a ridiculous amount of leafy greens (K1) in their diet and their Russian background.

Blog post to come soon ...

Stephan Guyenet said...

Hi Matt,

Interesting observation about the fructose malabsorption. Maybe bacterial overgrowth is reducing folate absorption. Obese people typically have multiple nutritional deficiencies. I'd like to know if the obesity is cause or effect.

Hi Justin,

I don't recommend taking K2 supplements during pregnancy, simply because the effects of an unnaturally high K2 intake on the fetus are unknown. If she wants to supplement, best to keep it in the natural range: 500 micrograms per day or less. In my opinion, the ideal source of K2 is food.

There's another issue with K2 supplements that I haven't discussed yet. Natural K2 is all trans, while synthetic K2 MK-4 may contain some of the unnatural cis form. I don't know what effect cis MK-4 has on the body. I e-mailed Thorne to find out how much cis MK-4 is in their supplement, but never heard back from them. I should try again.

Hi Helen,

I'm not anti-vegetable, but I also don't subscribe to the popular notion that eating an immoderate quantity of vegetables every day will solve our health problems.

StephenB said...

Folate in supplemental form can be had as folic acid, folinic acid, or 5-Methyltetrahydrofolate. Anyone know what form of folate is in liver?

Helen said...

Stephan -

Agreed. Vegetables aren't a panacea, but they aren't altogether toxic either. :)

Anonymous said...

Ryan Koch,

I wonder about plant only diets too. But two thing come to mind: breastfeeding and bodyfat consumption.

On any diet you'll consume bodyfat and protein—that's animal food with fat-soluble vitamins. Many people have large stores from past diet. Also any mother hip to health will breastfeed.

I don't want to theorize further. Speculating on other people feels awkward.

Unknown said...

Do humans have the ability to taste K2 or tell if a food has more K2 than another food?

Richard Nikoley said...


Regarding the Boutenkos, perhaps we're not far enough along in our genetic evolution -- only 4 million years -- that's it's impossible to revert to being an all-day-eating primate and enjoy good health.

Personally, I'd rather die young than eat that way.

Don Matesz said...

@ Ryan,

From the Boutenko website:

"The four of us embarked on a diet of entirely raw foods in 1994.."

That is 15 years ago. According to the bios on the site, the youngest (Valya) was 8 years old when they started the raw diet. The basic bone structure development had taken place well before they started eating the raw vegan diet.

Also note that the children were both born well before the family adopted the raw vegan diet.

Drs. Cynthia and David said...

Thanks for another great post Stephan!

Re raw vegan diets, see Stan's post from last summer http://stan-heretic.blogspot.com/2009/06/fuhrmans-diet-repeat-of-natural.html . There is a link in that post to an article discussing the long term health consequences of this diet. (hint- not pretty).

Anna said...

Stephan, I read this fantastic post via Google Reader on my phone while waiting in line (for the 2nd time) for the Simpson's ride at Universal Studios Hollywood (we finally succumbed to a long-ago promise to take our son and friends to USH).

I've never been a Simpson's follower, but I think Matt Groening, knowingly or not, was onto something when he drew the Simpson's characters with essentially no chin! Looking at all the chinless images around me while I waited got me thinking about what the Simpsons ate. I was quite sure it probably wasn't a lot of Vitamin A & K2-rich grass fed butter and pastured egg yolks.


Stephan Guyenet said...

Ha, good observation about the Simpsons.

Gabriella Kadar said...

Stephan, in regards the quantity of spinach you mention: how much of the K1 is bioavailable? If it's 3 to 13% depending on whether or not oil is added, then how could 1/4 cup of spinach provide adequate daily K1?

We've got to keep the bioavailability issue in mind when we look at K1 content of vegetables and fruits (avocados).

Matt Stone: Folate supplementation results in a decrease in the incidence of cleft lip but not cleft palate.

I'm wondering if 'morning sickness' (which begins in the morning and continues for the rest of the waking hours... being optimistic I thought morning sickness was only a morning phenomenon :() is the cause of some of the midface underdevelopment. The sorts of foods which contain enough vitamin K for mother and fetus are not terribly appetizing during the first trimester. Possibly the degree of nausea and vomiting during the first trimester may influence vitamin K availability to the developing fetus. Vitamin K containing foods are seasonal and there are seasonal variations in content of these foods as well. If a mother's first trimester is during the winter or early spring and she experiences morning sickness, then possibly this places the fetus at more risk.

Ken said...

Binders syndrome tends to have "relatively protruding lower jaw (mandible) and/or a “reverse overbite” (or class III malocclusion" It's pretty unusual.

I'd be concerned about pregnant or intending to become pregnant women eating liver as it can contain 50,000 IU per serving.

Polar bear liver contains a lot of vitamin A eating one big serving will make your skin fall off. There are always those who take things to extremes on the basis that the more the better.

Vitamin D poisoning of babies by mothers who made up milk by adding too much powdered concentrate is a case in point.

I agree that "the 5th to 11th weeks of pregnancy are particularly crucial for occlusion", fluctuating asymmetry due to fetal stress could explain why people adapted to the glycemic load of a hunter gatherer diet who suddenly start eating a modern or even just neolithic agricultural diet have some kinds of dental irregularities.

"such features as plagiocrany (asymmetry of the skull), which may occur merely from cradling habits and other causes (Wells, 1967a) or on irregularities of the teeth, which probably result from many adverse factors in foetal life as well as in infancy.(Wells, C. (1975). Prehistoric and historical changes in nutritional diseases and associated conditions, Progress in Food and Nutrition Science, 1(11), 729-779)

Nonetheless I would maintain that some ethnic groups have an edge to edge bite and some don't and some have wide zygomatic arches and flaring gonial angles, some don't. The genetic factors in the shape of the face will be most affected by factors that directly infuence attractiveness to the opposite sex. Having crowded wonkey teeth would be selected against for sure, the straight teeth that most people have are the result, but most people have naturally straight teeth for genetic reasons not from chewing stress.

Anna said...


I think your concerns about lack of nutrition due to morning sickness is addressed in this line of Stephan's post:

"Thus, the nutritional status of the fetus during the first trimester reflects what the mother has been eating for several months before conception."

Being fat soluble, Vitamins A, D, & K can be drawn from the mother's reserves, assuming there is a reserve.

Stephan Guyenet said...

Hi Gabriella,

I agree with your point about bioavailability. The study I cited looked at the relationship between ingested K1 and serum K1 level, rather than absorbed K1 and serum K1. So basically, if you eat 1/4 cup of spinach a day, you're maxing out absorption, even though as a percentage of the K1 ingested, absorption is low.

So if we have our 200 micrograms, and we absorb 15% of it because we ate it with butter (I'm being generous), that gives us 30 micrograms in the bloodstream. Even if we have a really good K1-K2 conversion rate of let's say 25%, that's 7 micrograms K2 per day. We get more than that amount of K2 in our normal diet. I think that shows that dietary K2 is in fact nutritionally important relative to K1 in humans.

Hi Ken,

Binder's patients can have class I or II malocclusion as well. I can't seem to find the paper I read that in though.

Gabriella Kadar said...

Anna, vitamin K storage is low in humans even though it is a fat soluble. Studies done by Sara Booth et. al. where study subjects were given only 5 micrograms vitamin K1 per day showed a decrease in body levels after three weeks and a large increase in PIVKA levels. This was counteracted by providing them with 45 microgams per day.

Dietary analysis studies, again by Sara Booth's group at Tufts, indicated that the demographic group in the United States least likely to be consuming adequate amounts of vitamin K were women in their prime reproductive years.

Anonymous said...

You stated that the question of whether other menaquinones such as MK-7 contribute to K-2 status has not been resolved.

A study by Yamaguchi, M., et al found that when ovariectomized rats were fed MK-7, bone loss was prevented. Further, it was found that feeding rats MK-7 alone produced significant elevation of serum MK-4 and MK-7. It was concluded "this effect may be partly caused by MK-4 which is formed by degradation of MK-7 to MK-4."

Studies have demonstrated that MK-7 has greater efficacy than vitamin K1 in carboxylating both liver and bone Gla proteins. Other studies have shown that MK-7 in natto greatly reduces risk of fracture independent from BMD.

Perhaps ther menaquinones from fermented foods such as aged cheese would, in similar manner, "degrade" or otherwise convert to MK-4.

Aged raw milk cheese from grass fed A2 cows is a great substitute for raw milk, particularly in areas where raw milk is very difficult to come by. Fortunately I live near Sweet Home Farm in Elberta Alabama where excellent raw milk cheese is made of milk of their grass fed Guernsey cows. Hopefully it provides benificial vitamin K2 as well.

Stephan Guyenet said...

Hi Jack,

Thanks. What I meant, but did not express clearly, is that no one knows whether MK-7 contributes to MK-4 status or not in humans. MK-7 can clearly carboxylate osteocalcin, but can it do all the other things vitamin K2 MK-4 normally does in the body? If it gets converted to MK-4, then the answer would undoubtedly be yes, but to my knowledge, no one has demonstrated that in humans.

Anonymous said...

Hi Stephan,

While it is true that it has not been proven that MK-7 contributes to the MK-4 status in humans, the fact that MK-7 converts to MK-4 in rats suggests that MK-7 would convert to MK-4 in humans as well. Many studies have been conducted in Japan regarding the effect of MK-7 from natto on bone health, and it would seem that it would be easy, as a part of one of their studies,to determine whether MK-7 increases serum MK-4 in humans.

In the Yamaguchi study on rats, it was concluded that the protection against bone loss in ovariectimized rats was due "in part" to conversion of MK-7 to MK-4. In my opinion it is probable that the protection against bone loss was entirely due to MK-4 and that MK-7 played no part other than to increase availabel MK-4. Further, the carboxylation of osteocalcin attributed to MK-7 in humans could be entirely due to conversion of MK-7 to MK-4.

In the Rotterdam study on heart disease in which a strong correlation between K2 intake and CHD mortality was found, more than half the K2 intake was from cheese and was other than MK-4. If MK-n does not contribute to MK-4 status in humans than the results of the study should be considered flawed. The same is true of the Heidelberg study on prostate cancer risk.

Well, that is my opinion as of today. It could change tomorrow.

Pensive said...

In general, well done. One of the best health blogs around. That's the bouquet.

I don't normally respond to blogs, since most people aren't amenable to the sort of input us long term breastfeeders might contribute :) but you seem a lot more open to discussion.

Now the brickbat:

You said: "•In industrial societies, newborns are typically vitamin K deficient."

" This is reflected by the fact that in the US, nearly all newborns are given vitamin K1 at birth to prevent potentially fatal hemorrhage."

Part one, partly true. Part two, the "fact" is a sweeping assumption.

Does the "fact" that the medical profession is heading to mass medicate everyone with a polypill, reflect an incontrovertible "fact" that everyone today has an inherent defect which will always result in strokes or heartattacks?

Or does it reflect a quick fix mentality, disinterested in more rounded solutions?

1) A study of medical history is useful to see that vitamin K primarily became a necessity for some babies, particularly those "medically" born, traumatically and with drugs. Remember twilight sleep? There are quite a few birth drugs which have the potential to disrupt clotting factors.

2) Have you also studied the effects of the twentieth century obsession with immediate cord clamping on blood volume; clotting factors; ideal circulation and the impact on the immune system?

You might find it interesting if you do. It might change your thinking in other areas as well.

3)It could be said that for some babies, acute vitamin K deficiency is caused by multiple unnecessary iatrogenic interventions.

4) Studies on vitamin K levels in pregnant woman vary wildly, from more than adequate to totally inadequate. All that reveals is that some deficient women rely on a standard american diet, which leads to wholesale sub-nutrition which can impact on their baby.

Other women, whose Vitamin K levels are much higher, reject totally, modern diet, and eat more than enough foods to provide the baby with more than enough vitamin K.

Yet the medical profession takes the lowest common denominator, and on the "just in case" scenario, inflicts that on everyone.

Which leads you perhaps, to the conclusion that application of a treatment for the "just in case" one in a thousand, means that the other 999 were inherently defective?

For the mothers with normal or high levels of nutritional vitamin K, their babies, (like babies born previously in history without the aid of traumatic ventouse delivery and unnecessary drugs) would be highly unlikely to have a vitamin K deficiency resulting in haemorrhage....

5) Therefore... the default position of the "normal" human neonate is NOT one of "bad design" or inate vitamin K deficiency, but of nutrition ignorance assisted by preventable medical error.

The reality is that an unthinking parent (and their child unfortunately) collective reaps from what is sown.

Garbage in, garbage out.

Caveat. I'm not saying that timely medical intervention is a bad thing.

What I'm saying is the medical assumption that the human design is inherently flawed, is itself, a dogma resulting from flawed thinking.

However, I recognise in today's world that it's much easier for doctors to convince mothers that babies are inherently defective and that vitamin K injections are always necessary.

It's nice to see that you are attempting to redress that imbalance.

Hopefully in the process, you will destroy a few more sweeping assumptions in the process.

Competing interests: I'm someone who breastfed her first child for two years, and the second for four and a half years (which helped vanquish allergies) and who believes that natural processes and good nutrition does actually have something to commend it. :)

phanamere said...

The other day I noticed that Whole Health Source blog received a rating on the blog-rating website Technorati. I'm not sure what their algorithm is but I was pleasantly stunned to note that of 1,200 health-issue blogs, Whole Health Source was rated among the top ten (7th). Since then it has moved up a couple of notches. I don't know exactly what it means but you're doing something right. Bravo! Here's the link:

Stephan Guyenet said...

Hi Pensive,

I think we agree. My point is that most fetuses/infants in affluent societies are K2 deficient, probably due to the mother's diet.

Hi Phanamere,


Nicole Handfield said...

Not sure if this post is still being updated, but I wanted to add my experience with Vitamin K. First, My family has been drinking raw milk from grass fed cows, supplementing with fermented cod liver oil, eating organ meats from pastured animals, etc., all in the Weston Price style, for several years now. My youngest child, now almost six months old, was born at home, with no medical interventions (no drugs of any kind) as well as delayed cord clamping. We declined Vitamin K injection as well as the other interventions (erythromycin and hep b vaccine). At one month of age, my son had a large intracranial hemmorhage which the medical professionals tell us is completely due to his vit k deficiency which would have been taken care of by the shot normally given to infants. He had a craniotomy, but large protions of his brain were killed by the stroke caused by the hemmorhage.
I am inclined to believe that God would not create children who are deficient and must receive an injection at birth in order to survive. However, I think industrial living does have natural consequences and even adhering as closely as possible to a Weston Price diet and delayed cord clamping, etc., aren't enough sometimes.
I am not trying to be argumentative, but simply offer my experience to people (my kindred) like Pensive who think that prophylactic measures like the vit K shot aren't necessary.