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.

Gluten Sensitivity: Celiac Disease is the Tip of the Iceberg

Celiac disease is a degeneration of the lining of the small intestine caused by a sensitivity to gluten. Gluten is the protein portion of wheat, rye, barley, and wheat relatives (spelt, kamut, emmer, einkorn and triticale). I found an interesting paper recently on the impact of celiac disease on nutrient status and bone density. Researchers compared 54 Northern Italian children with untreated celiac disease to 60 presumably healthy children. The celiac patients had extremely poor vitamin D status, with a deficiency rate of 35.18% compared to 5% in the control group. This was using the lenient cut-off point of 20 ng/mL. Average serum 25(OH)D3 in celiac patients was less than half the level of the control group. The celiac patients also had low serum calcium and magnesium, and elevated parathyroid hormone. Celiac children had lower bone mineral density. All parameters returned to normal after 6 months on a gluten-free diet.

This confirms what has been shown numerous times before: celiac disease interferes with nutrient status, including the all-important fat-soluble vitamins. It's not surprising, since it flattens the villi, finger-like structures necessary for efficient nutrient absorption in the small intestine. But wait, the overwhelming majority of our vitamin D comes from the effect of sunlight on our skin, not through our small intestine! So gluten sensitivity must be doing something besides just flattening villi. Perhaps it does. Feeding wheat bran to "healthy" volunteers caused them to burn through their vitamin D reserves at an accelerated rate. I think this underlines what I've come to believe about wheat: it's problematic for a large proportion of the population, perhaps the majority.

Approximately 12% of Americans can be diagnosed as gluten sensitive using blood antibody tests (anti-gliadin IgA or IgG). A subset of these have full-blown celiac disease. The vast, vast majority are undiagnosed. Gluten sensitivity associates with a dizzying array of diseases, including autoimmune disorders, cancer, and neurological problems. The problem with the blood tests is they aren't very sensitive. The most common blood tests for celiac disease look for a class of antibody called IgA. IgA is produced by the mucosa, including the gut. Unless gut damage is already extensive, the majority of IgA stays in the gut. This may cause the assay to overlook many cases of gluten sensitivity. A negative blood antibody test does not rule out gluten sensitivity!

I recently discovered the work of Dr. Kenneth Fine of EnteroLab. He has developed an assay that detects anti-gliadin IgA in stool. Gliadin is one of the problematic proteins in gluten that is implicated in gluten sensitivity. Dr. Fine has been conducting informal research using his fecal anti-gliadin IgA test (data here). He has found that:

• 100% of untreated celiac patients are antigliadin IgA positive by fecal test, compared to only 76% by blood (n= 17).
• 76% of microscopic colitis (a type of chronic diarrhea) patients are positive by the fecal test, compared to 9% by blood (n= 57).
• 57% of symptomatic people (digestive problems?) are positive by the fecal test, compared to 12% by blood (n= 58).
• 62% of people with autoimmune disease are positive by the fecal test.
• 29% of asymptomatic (healthy) people are positive by the fecal test, compared to 11-12% by blood (n= 240).
• Baby and cow feces are 0% positive by the stool assay.

It gets worse. Gluten sensitivity is determined in large part by genetics. A gene called HLA-DQ is intimately involved. It encodes a protein that is expressed on the surface of cells, that serves to activate immune cells when certain foreign substances are present. Different versions of the gene are activated by different substances. HLA-DQ2 and HLA-DQ8 are classically associated with celiac disease. Roughly 42% of the US population carries DQ2 or DQ8. According to Dr. Fine, every allele except DQ4 has some association with gluten-related problems! Only 0.4% of the U.S. population carries HLA-DQ4 and no other allele.

Not everyone who is genetically susceptible will end up developing health problems due to gluten, but it's impossible to estimate how many of the problems we attribute to other causes are in fact caused or exacerbated by gluten.

The immune system can be divided into two parts: innate and adaptive. The innate immune system is a nonspecific, first-line reaction to a perceived threat. The adaptive immune system is a more sophisticated, but slower system that produces a powerful response by particular cell types to a very specific threat. Antibody production is part of the adaptive immune system. Thus, if your gluten sensitivity test is looking for antibodies, it could still be missing an immune reaction to gluten mediated by the innate immune system!

This question has been addressed in a preliminary study. Researchers took gut biopsies from celiac patients and asymptomatic controls. Five out of six asymptomatic controls showed elevated interleukin-15, a marker of innate immune activation, upon exposure to gliadin. An activated innate immune system (commonly called 'inflammation') is associated with a wide array of chronic diseases, from obesity to cancer to cardiovascular disease. Inflammatory cytokines are elevated in celiac patients and may play a role in their bone pathology. What I would like to see is some negative controls-- would the gut biopsies have produced interleukin-15 in response to benign foods or is it truly specific to gluten?

I don't intend to imply that everyone has gluten sensitivity, but I do think the totality of the data are thought-provoking. They also include the association between the introduction of wheat to non-industrial populations and the development of widespread health problems. Another thing to keep in mind is that traditional sourdough fermentation breaks down a portion of gluten, possibly explaining the rise in gluten sensitivity that has paralleled a shift to quick-rise yeast breads. I believe that gluten sensitivity is behind many modern ills, and should be on the short list of suspects in the case of unexplained health problems. This is particularly true of digestive, autoimmune and neurological disorders. Gluten sensitivity is easy to address: stop eating gluten for a few weeks. See how you feel. Reintroduce gluten and see what happens. You might learn something about yourself.

Book Review: Dangerous Grains

Dangerous Grains is about the health hazards of gluten grains. It's co-written by James Braly, an M.D. who specializes in food allergies, and Ron Hoggan, a celiac patient who has written widely on the subject.

Celiac disease is a degeneration of the intestinal lining caused by exposure to gluten. Gluten sensitivity is a broader term that encompasses any of the numerous symptoms that can occur throughout the body when susceptible people eat gluten. The term gluten sensitivity includes celiac disease. Gluten is a protein found in wheat, its close relatives (kamut, spelt, triticale), barley and rye. Wheat is the most concentrated source.

Dangerous Grains is a good overview of the mountain of data on celiac disease and gluten sensitivity that few people outside the field are familiar with. For example, did you know:

• An estimated one percent of the U.S. population suffers from celiac disease.
• Approximately 12 percent of the US population suffers from gluten sensitivity.
• Gluten can damage nearly any part of the body, including the brain, the digestive tract, the skin and the pancreas. Sometimes gastrointestinal symptoms are absent.
  
• Both celiac and other forms of gluten sensitivity increase the risk of a large number of diseases, such as type 1 diabetes and cancer, often dramatically.
• The majority of people with gluten sensitivity are not diagnosed.
• Most doctors don't realize how common gluten sensitivity is, so they rarely test for it.
  
• Celiac disease and other symptoms of gluten sensitivity are easily reversed by avoiding gluten.

Twelve percent of Americans have gluten sensitivity! That's an enormous disease burden coming from a single type of food. I suspect the true incidence may actually be higher. There are preliminary data suggesting that most people may mount an immune response to gluten that does not require antibodies (through the innate immune system). This type of gluten sensitivity would be overlooked by the typical antibody tests, but could still result in damage.

Dangerous Grains also discusses the opioid-like peptides released from gluten during digestion. Opioids are powerful drugs, such as heroin and morphine, that were originally derived from the poppy seed pod. They are strong suppressors of the immune system and quite addictive. There are no data that conclusively prove the opioid-like peptides in gluten cause immune suppression or addiction to wheat, but there are some interesting coincidences and anecdotes. Celiac patients are at an increased risk of cancer, particularly digestive tract cancer, which suggests that the immune system is compromised. Heroin addicts are also at increased risk of cancer. Furthermore, celiac patients often suffer from abnormal food cravings. From my reading, I believe that wheat causes excessive eating, perhaps through a drug-like mechanism, and many people report withdrawal-like symptoms and cravings after eliminating wheat.

I know several people who have benefited greatly from removing gluten from their diets. Anyone who has digestive problems, from gas to acid reflux, or any other mysterious health problem, owes it to themselves to try a gluten-free diet for a month. Gluten consumption has increased quite a bit in the U.S. in the last 30 years, mostly due to an increase in the consumption of processed wheat snacks. I believe it's partly to blame for our declining health. Wheat has more gluten than any other grain. Avoiding wheat and all its derivatives is a keystone of my health philosophy.

Another notable change that Sally Fallon and others have pointed out is that today's bread isn't made the same way our grandparents made it. Quick-rise yeast allows bread to be fermented for as little as 3 hours, whereas it was formerly fermented for 8 hours or more. This allowed the gluten to be partially broken down by the microorganisms in the dough. Some gluten-sensitive people report that they can eat well-fermented sourdough wheat bread without symptoms. I think these ideas are plausible, but they remain anecdotes to me at this point. Until research shows that gluten-sensitive people can do well eating sourdough wheat bread in the long term, I'll be avoiding it. I have no reason to believe I'm gluten sensitive myself, but through my reading I've been convinced that wheat, at least how we eat it today, is probably not healthy for anyone.

I'm not aware of any truly healthy traditional culture that eats wheat as a staple. As a matter of fact, white wheat flour has left a trail of destruction around the globe wherever it has gone. Polished rice does not have such a destructive effect, so it's not simply the fact that it's a refined carbohydrate. Hundreds, if not thousands of cultures throughout the world have lost their robust good health upon abandoning their traditional foods in favor of white flour and sugar. The medical and anthropological literature are peppered with these stories. I'm aware of one healthy culture that traditionally ate sourdough-fermented whole grain rye bread, the Swiss villagers of the Loetschental valley described in Nutrition and Physical Degeneration.

Overall, the book is well written and accessible to a broad audience. I recommend it to anyone who has health problems or who is healthy and wants to stay that way!

Celiac and Fat-Soluble Vitamins

One of the things I've been thinking about lately is the possibility that intestinal damage due to gluten grains (primarily wheat) contributes to the diseases of civilization by inhibiting the absorption of fat-soluble vitamins. If it were a contributing factor, we would expect to see a higher incidence of the common chronic diseases in newly-diagnosed celiac patients, who are often deficient in fat-soluble vitamins. We might also see a resolution of chronic disease in celiac patients who have been adhering faithfully to a long-term, gluten-free diet.

One thing that definitely associates with celiac disease is bone and tooth problems. Celiac patients often present with osteoporosis, osteopenia (thin bones), cavities or tooth enamel abnormalities (thanks Peter).

An Italian study showed that among 642 heart transplant candidates, 1.9% had anti-endomyosal antibodies (a feature of celiac), compared with 0.35% of controls. That's more than a 5-fold enrichment! The majority of those patients were presumably unaware of their celiac disease, so they were not eating a gluten-free diet.

Interestingly, celiac doesn't seem to cause obesity; to the contrary. That's one facet of modern health problems that it definitely does not cause.

The relationship between cancer and celiac disease is very interesting. The largest study I came across was conducted in Sweden using retrospective data from 12,000 celiac patients. They found that adult celiac patients have a higher overall risk of cancer, but that the extra risk disappears with age. The drop in cancer incidence may reflect dropping gluten following a celiac diagnosis. Here's another study showing that the elevated cancer risk occurs mostly in the first year after diagnosis, suggesting that eliminating gluten solves the problem. Interestingly, celiac patients have a greatly elevated risk of lymphoma, but a lower risk of breast cancer.

There's a very strong link between celiac and type I diabetes. In a large study, 1 in 8 type I diabetic children had celiac disease. This doesn't necessarily tell us much since celiac and type I diabetes are both autoimmune disorders.

One last study to add a nail to the coffin. Up to this point, all the studies I've mentioned have been purely observational, not able to establish a causal relationship. I came across a small study recently which examined the effect of a high-fiber diet on vitamin D metabolism in healthy (presumably non-celiac) adults. They broke the cohort up into two groups, and fed one group 20g of bran in addition to their normal diet. The other group got nothing extra. The bran-fed group had a vitamin D elimination half-life of 19.5 days, compared to 27.5 for the control group. In other words, for whatever reason, the group eating extra bran was burning through their vitamin D reserves 30% faster than the control group.

Unfortunately, the paper doesn't say what kind of bran it was, but it was probably wheat or oat (**Update- it's wheat bran**). This is important because it would determine if gluten was involved. Either way, it shows that something in grains can interfere with fat-soluble vitamin status, which is consistent with the staggering negative effect of wheat products on healthy non-industrialized cultures.

Add to this the possibility that most people may have some degree of gluten sensitivity, and you start to see a big problem. All together, the data are consistent with gluten grains interfering with fat-soluble vitamin status. As I discussed earlier, this could strongly contribute to the diseases of civilization. These data don't prove anything conclusively, but I do find them thought-provoking.

Thanks to Dudua for the CC photo