In the 30 years since I took Nutrition 101, few changes compare in magnitude to the ones we have seen in vitamin D research. Back then, vitamin D was for rickets. Now, it's good for almost everything.
Hallmarks of D Deficiency
There are two hallmarks to vitamin D-related conditions - disease incidence varies by latitude and with season. This certainly is true with the conditions we already associate with D deficiency. Heart attacks are more common in the winter months.2,3 Multiple sclerosis, the classic example of latitude variability, increases in frequency with distance from the equator. And, of course, MS now is associated with D deficiency.4 Other autoimmune disorders also are linked to low D levels.5 Diabetes is so closely affected by D that blood sugar levels fluctuate by month of the year, hitting their highest point in the late winter and spring, when D status is lowest.6,7 Onset of diabetes also varies seasonally, with the fewest cases diagnosed in August and the most cases diagnosed in March.8 I've been ruminating what other conditions might be related to D deficiency that are not yet on my list. The easiest way to gather data for these ruminations is to rummage on PubMed under the rudimentary headings of "season" and "latitude." It's surprising what comes to light.
Everything Cardio
It's not just heart attacks that fluctuate by season. Apparently, anything that has to do with a person's cardiovascular plumbing is at risk in the winter. This includes atrial fibrillation,9 heart failure,10 DVT,11 pulmonary embolism,12,13 aortic rupture,14,15 cervical artery dissection17 and blood pressure.18 (Though there is an argument that aortic ruptures can be triggered by low air pressure, which is probably more frequent in the winter.16 If this were true, we'd probably hear more about people having serious problems driving west up Interstate 70 from Denver toward the Continental Divide.)
One suggested explanation for these elevated cardiovascular problems in winter is that blood gets thicker because of the higher incidence of colds and flu, triggering hypercoagubility. It turns out this isn't true. When a long list of blood parameters were monitored for seasonal variability, only HDL cholesterol and cortisol showed inverse seasonal patterns, with a maximum during summertime. No statistically significant seasonal variations were seen for red blood cell aggregation, complement factor C4, total cholesterol, ceruloplasmin, haptoglobin, white blood cell count and plasminogen. The researchers who originally posed this question concluded, "These data do not support the hypothesis that increased morbidity and mortality from cardiovascular diseases during winter may be mainly attributable to increased synthesis of acute-phase proteins due to infections."19 So, perhaps it is wintertime decreases in vitamin D levels that trigger all of these cardio problems.
There are two hallmarks to vitamin D-related conditions - disease incidence varies by latitude and with season. This certainly is true with the conditions we already associate with D deficiency.
Most Inflammatory Stuff
Many inflammatory conditions fluctuate with season. Pancreatitis20 is seasonal, as it is more common in the spring. So, too, is gout. Frequency of gout attacks vary by season,21 peaking in the spring.22-24 Appendicitis also varies by season but peaks in the summer, July to be exact.25 It's rare for me to treat appendicitis so I'll hold off trying to rationalize how it can be related to D deficiency. But there is no question my gout patients now take extra vitamin D. Myofascial pain varies with season, peaking during the dark months.26
Inflammatory Bowel Diseases
The inflammatory bowel diseases appear linked to vitamin D. In an Italian study, the onset of Crohn's disease is most common in spring and summer.27 With Crohn's disease, it matters what time of year you were born. If born in May and June, you have less of a chance of developing Crohn's, but being born from September to January increases your chance of getting Crohn's.28-30 Wonder why? Either this has to do with one's mother's vitamin D level just prior to delivery, or the kid's vitamin D level in the first months of life. Maybe it's not the summer low incidence of Crohn's that's important, but the winter increase. Infants born in the winter start out with a lower maternal D donation and will find it difficult to produce their own D during their first months of life. The developing immune system might be handicapped by this early deficiency for the rest of life. What about latitude? Aside from the fact that Crohn's disease incidence is higher in northern Scotland than in southern Scotland,31 not much else came to light. Whatever the explanation, making sure pregnant patients have adequate D when they give birth might change an infant's fate. We already know that supplementing vitamin D to pregnant women lowers the incidence of diabetes in their children.32-33
Ulcerative colitis (UC) also has a seasonal variability, with attacks occurring most often from December to January.34 Curiously, this seasonal variation is not seen on the inside; diagnosing UC via endoscopic exams doesn't show variability with season. Only symptom onset varies.35 Vitamin D supresses bowel inflammation in animal models. Creating mice missing receptor sites for vitamin D only creates mice incredibly susceptible to inflammatory bowel disease.36 In an experiment using these mice bred to develop inflammatory bowel disease (IBD), vitamin D prevented disease development.37 This might have something to do with vitamin D's interaction with interleukin-2. In another one of these animal model experiments, in which mice were bred without the IL-2 gene, D was no longer effective at suppressing ulcerative colitis. D-3 nonetheless did lower the mortality rates of these poor mice.38
Mice bred to get UC do much better if given both D and calcium. Either one of these supplements prevents or reduces the symptoms of disease by inhibiting TNF-alpha, which then suppresses the IBD.39 TNF-alpha is one of those big important things in medicine we are supposed to understand these days and inhibiting it generally is considered a very useful thing to do. The National Institutes of Health Web site (www.nih.gov) links elevated TNF-alpha to a host of conditions, including psoriasis, tuberculosis, insulin resistance, diabetes, obesity, hyperadrogenism, cerebral malaria, alopecia areata, rheumatoid arthritis, ankylosing spondylitis, osteoporosis, osteopenia, asthma, inflammatory bowel disease and hepatitis.40 Drugs such as infiiximab (Remicade) and etanercept (Enbrel), which block TNF-alpha, are all the rage. If vitamin D lowers TNF-alpha, it might help any of these conditions. There is one difference we already are aware of: Blocking TNF-alpha via drugs increases the risk of tuberculosis41 while vitamin D is useful at preventing and treating tuberculosis.42 Inflammatory bowel disease is a disease of the Western world. Perhaps our higher rates simply are due to more time spent indoors and resulting lower vitamin D levels.
Fertility and Related Topics
Vitamin D plays a role in fertility. This should seem rather obvious, as most plants and animals time their reproductive cycle with the seasons. The season of a woman's birth influences how old she will be when she enters menopause. Women born in March have the latest menopause, while women born in October have the earliest. On average, there is about a 15-month difference: Women born in October reach menopause at over 50 years of age, compared with less than 49 years for women born in March.43
Although we usually don't think about it in humans, there is a seasonal variation to our conception. Conception rates are lowest during the dark winter months and peak during the summer months.44 Even human artificial insemination is more successful during the winter months, October through March, with the best results in November.45 When male rats are made Vitamin D deficient in experiments, they become infertile. Fertility can be restored by supplementing with vitamin D or calcium.46
Late luteal-phase dysphoric disorder (LPDD), which I suspect is a fancy descriptive for PMS-related depression, gets worse during the winter. Pain and swelling associated with menses don't appear to change with the season,47 but depressive symptoms surely do.48
Early Puberty
There is an unexplained tendency for young girls to reach puberty at progressively earlier ages. This is most noticeable in girls in Western countries and most pronounced in girls of African descent in these countries. Though many theories suggest exogenous estrogen exposure, consider that vitamin D deficiency is more common in African-American girls than Caucasian girls. It would be easy to jump to the assumption that vitamin D deficiency played a role in this earlier puberty. Yet, at least one study points out that living further north delays the onset of puberty.49 Could lowered fertility rates in industrialized countries be related to increasing levels of D deficiency as people get less sun exposure? Perhaps.
Immune Function
White blood cell counts fluctuate with the seasons and this might be part of the reason for seasonal infectious disease variability.50 It isn't clear whether this variability is caused by fluctuating D levels. In rats, the leukocyte count and absolute lymphocyte content are highest in spring, while eosinophils peak in autumn and neutrophils and monocytes peak in winter.51
Colds, Flu and Other Winter Cooties
Colds and flu are more prevalent in the winter. I don't need PubMed to notice that. Could this seasonality be a D deficiency? Does vitamin D status help people fight infection? Perhaps. Several studies have shown vitamin D triggers the human cathelicidin antimicrobial peptide gene, better known as the CAMP gene. This CAMP gene is part of the innate immune system and provides the rapid response used to repel assaults from numerous infectious organisms, including bacteria, viruses, fungi and parasites.52-53
A March 2006 study showed that by triggering this CAMP gene and stimulating these antibiotic-like chemicals, vitamin D is useful for fighting tuberculosis (TB). Blood from African-Americans contains less D and is less capable of mounting this type of defense. This explains why they are more susceptible to TB.54 While vitamin D deficiency is common among African-American children in our country, it isn't as common in Africa. Sure, they get rickets - not from D deficiency, but instead from calcium deficiency.55
In Europe, massive single doses of vitamin D are given in what is called Stoss therapy. Used initially to treat D-deficiency rickets, these are jumbo, several hundred thousand IU of vitamin D at a time. Despite the absence of published clinical data, Stoss therapy is becoming popular for acute infectious disease. An Internet search finds multiple Web sites promoting Stoss therapy for anything from the common cold to bird flu.
On his Web site, John Cannell, MD, the vitamin D guru, summarizes a 1994 study written by Dr. P.K. Rehman:56
"In 1994, Dr. Rehman gave 60,000 units of vitamin D a week to 27 children (ages 3-12) with frequent childhood infections and compared them to controls. The children also had elevated alkaline phosphatase, which usually indicates vitamin D deficiency. He gave the kids vitamin D for six weeks along with calcium. Within a few weeks, ‘infections were fully controlled and no recurrences were reported for six months.' The kids just stopped getting sick! … 9,000 units a day of vitamin D for six weeks should bring most vitamin-D-deficient children to 50 ng/ml, probably higher."57
It's not just heart attacks that fluctuate by season. Apparently, anything that has to do with a person's cardiovascular plumbing is at risk in the winter.
Perhaps the reason people get colds and flu in the winter is not because it's cold, rainy and snowy. Perhaps it's because, like many of these other seasonal illnesses, vitamin D levels are lower during that time of the year, weakening our defenses against infection.
Asthma and T-helper Cells
In Greece, more young kids get hospitalized during the winter through spring months with asthma, but then there is a clear peak in admissions in May.58-59 Could this just be lousy air quality in the winter and allergies in the spring? There is no question asthma is triggered by air pollution60 and air particulates.61
Current opinion seems to be that although vitamin D is useful for some autoimmune diseases, it doesn't help asthma. At this time, the link between D and IBD, RA, MS and DM is pretty much accepted. The theory is that D is useful for these autoimmune diseases because it inhibits the development and function of Th-1 cells and induces other T-helper cells, including Th-2 cells.62 The idea of downregulating Th-1 cells and inducing Th-2 cells is another one of those big concepts in medicine that came along after I graduated school; this gives me an excuse to omit further discussion about it. Suffice to say, add vitamin D to your lists of things useful in shifting from Th-1 to Th-2 predominance.
SAD: The Obvious Link to D Deficiency
The most obvious condition that begs mention is seasonal affective disorder (SAD). By definition, SAD is seasonal, getting worse as vitamin D levels decline with decreasing sun exposure in the winter as people get depressed.63
In one study, supplementation with 800 IU per day of vitamin D didn't help.64 But, in another study, doses of 400 to 800 IU made a difference.65 Yet another study used 100,000 IU and this dose definitely helped. This later study compared vitamin D supplementation against light therapy. "All subjects receiving vitamin D improved in all outcome measures. The phototherapy group showed no significant change in depression scale measures."66 Eating disorders, particularly bulimia, also worsen in the winter and perhaps similar doses of vitamin D should be considered for these patients.67
Here in Denver, sunny as it might be, come late winter, a great many people like to fly down to Mexico for a week to get some sun. Given the estimate that a day on the beach might generate 10,000-20,000 IU of vitamin D, I figure a week at the beach is equivalent to about 100,000 IU. Thus, the study that used the 100,000 IU dose has a certain charm to it. I have little doubt that these returning vacationers look happier than anyone else in town.
OK, So It's Guesswork
Some of these links are weak; some on the verge of acceptance. Given the low toxicity profile of vitamin D, I find myself more and more often looking a patient in the eye and telling them, "Vitamin D won't hurt, and it just might help you feel better."
Resources
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