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Monday, October 25, 2010

The Vitamin D Story

Vitamin D

by JP Saleeby, MD
**To be published in an upcoming issue of American Fitness magazine

In the past half-decade, the importance of Vitamin D in western medicine has reached a new found echelon.  Interest in this vitamin’s effects, not only on bone health, but on immune function and the neurological system have caused the assessment of serum levels to become a standard practice during annual physical exams.  It is now routine to have your Vitamin D (25-OH-Vitamin D) level checked by your primary care physician.  The interest is in part due to the large body of evidence in the last ten years showing that this once esoteric fat-soluble vitamin is in fact an important player in wellness.

Vitamin D is a group of fat soluble secosteroids of which there are five known forms.  A secosteroid is a molecule that is similar in structure to a steroid, except two of its four B-ring carbon atoms are open.  Cholesterol is a common example of a steroid molecule and happens to be the substrate of which Vitamin D is made.  Vitamin D1 through D5 are the designations of the known forms of Vitamin D, as they were the 4th group of "vitamins" discovered and named; hence the fourth letter in alphabet designation.  I need to point out that while not exactly a vitamin in the strictest sense, since humans do produce them endogenously and by definition a vitamin is a substance necessary for survival of an organism that is required to be consumed or ingested, it is still worthy of the categorization.  Nevertheless, Vitamin D is a constituent nutrient where deficiencies are known to lead to illness and disease and supplementation is known to reduce illness, extend and enhance quality of life.

Of the five secosteroids in the class, only two, Vitamin D2 and Vitamin D3 have physiologic properties and are important to human (and other organisms) health.  The D2 form is also referred to as ergocalciferol and is produced by plants, fungi and invertebrates.  Like all forms of Vitamin D, it is produced as a result of irradiation of those life forms by ultraviolet-B wavelength (UV-B) radiation from the sun.  Vitamin D3, also known as cholecalciferol, is produced by our bodies in the inner most layers of our epidermis (skin) again by direct contact with UV-B radiation.  Vertebrates are the only know producers of Vitamin D3.  The two skin layers, stratum granulosum and spinosum, contains the substrate 7-dehydrocholesterol and when irradiated by sunlight wavelengths between 270-300nm, an enzymatic conversion occurs changing it to the pre-active form of Vitamin D3.  Sunscreen and even glass will block the sun’s UV wavelength’s ability to make vitamin D naturally. Even the pigmentation of our skin plays a factor.  It should be noted that this may be the reason African-American men have a significantly higher risk for prostate cancer than do Caucasian men.  Fair skinned people produce more of this vitamin than those of darker complexions containing more melanin.  The angle and time under the sun is also a determinant; equatorial inhabitants fare better with vitamin D production than do those living in higher latitudes. 

In man, the newly produced pre-Vitamin D goes through some additional changes in the liver to produce calcidol and from there further metabolism to the bioactive calcitriol by the kidneys and immune system’s monocytes-macrophages.  Calcitriol is responsible for maintaining balanced concentrations of calcium and phosphorus in our serum as well as healthy growth and remodeling of bone.  On the immune side, calcitriol converted by the macrophage system acts as a cytokine (think chemical immune-messenger) to help modulate immune function against microbes like bacteria and viruses.  Having renal (kidney) disease or liver damage can greatly impair circulating vitamin D as conversion of the pro-Vitamin D to its active forms is limited.

Experiments show that Vitamin D2 absorbs UV-B radiation in fungi, plants and invertebrates and acts as a natural sunscreen against the damage sun’s rays can cause on DNA and cells.  While more easily available and less expensive to produce, Vitamin D2 is not as bioactive in humans as is D3.  Much of what has been used to fortify cow’s milk and other food products, however, has been Vitamin D2 prior to 2006.  As our knowledge of Vitamin D grows and with the current research trends, the food and supplement industry is pushing to utilize better preparations for supplements and fortifying foods.  Preparations utilizing the Vitamin D3 are becoming more common, as the use of D2 is falling by the wayside.

Common maladies from a deficiency in Vitamin D are Rickets, osteomalacia, and osteoporosis.  The recommended daily allowance (RDA) of Vitamin D will keep you out to trouble with Rickets, but supplementing with higher doses of Vitamin D3 has added health and wellness benefits.  Vitamin D3 has been shown to reduce inflammation, influence genes that regulate proliferation, differentiation and apoptosis in cells, thus playing a major role in cancer prevention.  There have been studies showing benefit not only in bone health, immune function and cancer prevention, but also the delaying of the onset of dementia, multiple sclerosis and even schizophrenia.  A recently published peer-reviewed report demonstrated a reduction by almost 50% in stroke when low Vitamin D levels were corrected in the study population.

Even in history Vitamin D plays a significant roll.  For example, Dr. Adolf Windaus won the 1928 Nobel Prize in chemistry for his work with Vitamin D.  Dr. Harry Steenbock discovered, in the 1920’s, that irradiated foods produced higher levels of Vitamin D and that fortifying foods in this way would reduce Rickets.  By 1945 with Dr. Steenbock’s work recognized, the fortifying of milk and some staple foods was common practice; Rickets was all but eradicated in America.

Along with producing Vitamin D naturally with sun exposure, dietary intake is the only other practical way of receiving this beneficial nutrient.  Intake can be measured in terms of micrograms (mcg) or International Units (IU), where 1 mcg of Vitamin D is equivalent to 40 IU.  More often times foods and supplements are labeled using IU.  The National Academy of Sciences (now know as the National Academies) recommends 200IU for those under the age of 50-years and 400IU for those 50 to 70-years, and 600IU for those over 70-years of age.  The typical American diet averages 100 IU/day, but this is not saying much, as the “typical” American diet is rather poor when considering the fast foods we generally eat on the run and the processed foods we buy at market.  The combination of this type of dietary intake and average sun exposure may allow us to reach these USDA RDA levels without supplementation.  However, longevity and nutritional medicine physicians and organizations recommend quite a higher daily dose for wellness and health.

Foods where higher levels of Vitamin D3 are achieved are found in fatty fish, eggs and lean meat.  For example, a 3.5 oz piece of salmon will give you 360 IU, tuna (3.5 oz) will give you 235 IU, catfish is a great source having 425 IU per 3 oz and it should be noted 15cc (a tablespoon) of cod liver oil is worth 1360 IU of Vitamin D3.  We witness again the intuitive wisdom of our grandparents as they made us choke down cod liver oil when we were sick.  A whole egg by the way gives us 20 IU of the vitamin.  Fortified milk (historically containing D2) will give on average only 98 IU per 8 oz glass.  Consuming milk as our only source of Vitamin D, a person would have to consume ten glasses of fortified milk daily to get minimum effective levels.  It is good to fortify foods do not get me wrong, but don’t believe all the advertising, that milk is the one.  The only vegan source; the mushroom will confer about 14 IU (un-irradiated) and 500 IU (irradiated) per 100 grams of edible fungi.

How much sun exposure is necessary to achieve levels of Vitamin D3?  Experiments range in levels depending on ethnic groups and level of sun exposure (altitude and latitude), but in general for whole body irradiation without sun blockers in a Caucasian person a dose of UV-B likely to just about induce a sunburn will yield a comparative dose equivalent to between 10,000 and 25,000 IU taken orally.  To put it more simply and practically, a fair skinned man wearing shorts and a t-shirt in mid-day sun at the equator for 10-minutes can produce 10,000 IU of Vitamin D3.  You cannot produce toxic doses of Vitamin D (hypervitaminosis) with sun exposure, as there is an equilibrium state that is reached in the skin.  As you reach this equilibrium point Vitamin D3 is degraded as quickly as it is produced, thus prohibiting overproduction and toxicity. 

Obviously, from a pedantic perspective, sun exposure trumps dietary supplements as an inexpensive and practical way of achieving levels in the health range, however, skin cancer and photo-aging issues arise.  Studies observing surfers in Hawaii noted quite a variance in Vitamin D production, so there is a good bit of variability with sun exposure, time of day, region, ethnicity and skin pigmentation.  This makes difficult giving standard recommendations for sun exposure.

Dosages of upward of 5000IU daily are recommended in certain instances.  For the most part a range between 1000 IU to 2000 IU is the general recommendation by the Linus Pauling Institute and other organizations with a focus on prevention and nutrition.  These quantities are best achieved by pharmaceutical grade dietary supplements or prescriptions.

As alluded to earlier, Vitamin D3 makes for better supplementation than D2, as D3 binds with greater affinity to the Vitamin D Binding Protein (VDBP) which is responsible for carrying Vitamin D in the blood stream without degradation.  This allows the metabolites of 25-OH-Vitamin D (inactive pro-vitamin), specifically 1,25-OH-Vitamin D, which is the bioactive form to attach to Vitamin D Receptors (VDR) on cells and at the nucleus, much more so than Vitamin D2 metabolites.  Vitamin D3 also has a longer shelf-life and is more stable than Vitamin D2 when placed in tablet or capsule form as a supplement or in fortified foods for that matter.  In recent years the supplementation and fortification industry is swinging over to Vitamin D3 more exclusively in higher-end products.

We can practically and efficiently measure our body’s stores of Vitamin D in the clinical setting, as mentioned earlier it is becoming a standard annual reimbursable test for many.  Measuring serum levels of 25-OH-Vitamin D is by convention the best way to assess levels, as this metabolite has a longer (15-day) half-life than other forms and assays serum and tissue levels quite well.  Levels of > 30 ng/ml are desirable while >200 ng/ml are nearing the toxic (hypercalcemia, hyperphosphatemia) range.  Levels below 30 are considered too low for optimum health.  While “normal” ranges vary rather considerably from one reference lab to another the widely accepted normal range for 25-OH-Vit. D is between 30.0 and 74.0 ng/ml. A person's fat content (obesity) is linked with lower Vitamin D levels, not that fat blocks UV-B rays from doing their thing, but rather adipose tissue can store Vitamin D and take it our of serum circulation. 

Children born to women with lower levels of Vitamin D while pregnant have been shown to be at higher risk for Multiple Sclerosis (MS) and psychiatric disorders.  Researchers have noticed that women with low Vitamin D tend to have children with twice the risk for schizophrenia.  Some studies have shown that Vitamin D supplementation can lower the doses of anti-psychotropic medication and have witnessed a drop in frequency of symptoms of schizophrenia in those patients.  

Low Vitamin D levels can cause a drop in hair follicle growth, increase risk for peripheral vascular disease, cancers (breast, colon, prostate) and neurological disorders.  Rheumatoid Arthritis (RA) and other immune disorders, juvenile Diabetes (DM), Parkinson’s and Alzheimer’s disease have also been implicated in low levels.  It is estimated that forty (40%) percent of the US population has a known Vitamin D deficiency.  In our nursing home patient population it has been demonstrated that some eighty (80%) percent have a deficiency.  It is an unfortunately statistic that some seventy-six (76%) percent of pregnant mothers show levels of deficiency, and the repercussions on their offspring are worrisome.  It should be noted that in the medical literature, all deaths (due to all causes) rise when Vitamin D levels are less than 18 ng/ml.  When correcting a long standing Vitamin D deficiency, one must be patient, as it can take months to correct low levels with proper supplementation.

How Vitamin D is important to our immune system is theorized as conversion occurs of pre- (inactive) Vitamin D to active 25-OH-Vitamin D metabolites.  The active metabolite will bind to Vitamin D Receptors (VDR) located on Natural Killer Cells (NKC), enhance phagocytosis in macrophages, increase T- and B- Cell function, and increase cathelicidine, a natural antimicrobial peptide (yet another downstream metabolite of Vitamin D).  All of these properties together have a pretty big impact on our immune system.

Researchers have found and published reports that doses of Vitamin D in the range of 1000 IU/d will reduce colon cancer risk by 50%, breast and ovarian cancer by 30% and as little as 400 IU/d has shown in at least one study to reduce pancreatic cancer by 43%.  Studies conducted on dementia, Alzheimer’s disease and Parkinson’s disease have shown some promise with regards to Vitamin D therapy.  Scientists have found that Vitamin D binds to receptors on the HLA-DRB1 gene and reduces MS expression in susceptible individuals.  The importance of Vitamin D in neuropsychiatric disorders continues to be realized as new research is published.

Every fall season we worry about the impact of Influenza on our lives.  What is Vitamin D’s link to the Flu?  It has been noted that with lower endogenous production due to decreased sun exposure in winter, in theory, a drop in Vitamin D affects immune system function to the point that we are more susceptible to Influenza.  There are other cofounding factors that may prove this theory incorrect with further research.  However, it is recommended that higher doses of daily Vitamin D be taken when exposed to the flu, or during the flu season.

Vitamin D has also been linked to lowering elevated blood pressure and cholesterol, as well as helping with Peripheral Vascular Disease (PVD).  VDRs in the renin system, which is integral in blood pressure control can regulate the ACE- Angiotensin II conversion process that affects blood pressure.  Low Vitamin D can cause Non-Insulin Dependent Diabetes Mellitus patients to produce less insulin secretion from the pancreas, thus worsening their serum glucose levels. 

With regard to drug interactions, there are some medications that block or interfere with production, others that interfere with the vitamin’s ability to bind with VDRs and block metabolism in the liver.  Steroids impair Vitamin D metabolism, Xenical® (Orlistat) and Cholestyramine reduce Vitamin D absorption in the gut.  And with lower Vitamin D levels, this affects the way calcium and magnesium is absorbed by the intestines.  Phenobarbital and Dilantin® (Phenytoin) (both seizure medications) reduce absorption and metabolize Vitamin D into less active compounds.

While Vitamin D is not the end all, be all of dietary supplements, it nonetheless holds a pretty lofty position.   Unrecognized and untreated low levels of this vitamin have pervasive effects on our health and morbidity.

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JP Saleeby, MD is an integrative and nutritionally minded physician, for more information visit www.saleeby.net


References:

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Based on an interview with Dr. Michael Holick, author, The UV Advantage, http://www.naturalnews.com/003069.html,  Accessed November 21, 2010.


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