Vitamin D - Use In Clinical Practice
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The recent discovery from a meta-analysis of 18 randomized controlled trials that supplemental cholecalciferol (vitamin D) significantly reduces all-cause mortality emphasizes the medical, ethical, and legal implications of promptly diagnosing and adequately treating vitamin D deficiency. Not only are such deficiencies common, and probably the rule, vitamin D deficiency is implicated in most of the diseases of civilization. Vitamin D's final metabolic product is a potent, pleiotropic, repair and maintenance, seco-steroid hormone that targets more than 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. One of the most important genes vitamin D up-regulates is for cathelicidin, a naturally occurring broad-spectrum antibiotic.
Natural vitamin D levels, those found in humans living in a sun-rich environment, are between 40-70 ng/mL, levels obtained by few modern humans. Assessing serum 25-hydroxy-vitamin D (25(OH)D) is the only way to make the diagnosis and to assure treatment is adequate and safe. Three treatment modalities exist for vitamin D deficiency: sunlight, artificial ultraviolet B (UVB) radiation, and vitamin D supplementation. Treatment of vitamin D deficiency in otherwise healthy patients with 2,000-7,000 IU vitamin [D.sub.3] per day should be sufficient to maintain year-round 25(OH)D levels between 40-70 ng/mL. In those with serious illnesses associated with vitamin D deficiency, such as cancer, heart disease, multiple sclerosis, diabetes, autism, and a host of other illnesses, doses should be sufficient to maintain year-round 25(OH)D levels between 55-70 ng/ mL. Vitamin D-deficient patients with serious illness should not only be supplemented more aggressively than the well, they should have more frequent monitoring of serum 25(OH) D and serum calcium. Vitamin D should always be adjuvant treatment in patients with serious illnesses and never replace standard treatment. Theoretically, pharmacological doses of vitamin D (2,000 IU/kg/day for three days) may produce enough of the naturally occurring antibiotic cathelicidin to cure common viral respiratory infections, such as influenza and the common cold, but such a theory awaits further science. (Altern Med Rev 2008; 13(1):6-20)
Lappe et al recently reported the first RCT of vitamin D in preventing internal cancers and found a 60-percent reduction in such cancers by increasing baseline 25(OH)D levels from 29 ng/mL to 38 ng/mL with 1,100 IU (28 mcg) per day. (5) Baseline and treatment-induced serum 25(OH)D levels were strong and independent predictors of cancer risk. Lappe et al's study left open the possibility that higher doses and higher treatment-induced 25(OH)D levels might prevent even more cancers. (Note that 25(OH)D levels are reported in the literature as either ng/mL or nmol/L; 1.0 ng/mL equals 2.5 nmol/L.)
Besides cancer, vitamin D deficiency is associated with cardiovascular disease, hypertension, stroke, diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, osteoporosis, periodontal disease, macular degeneration, mental illness, propensity to fall, and chronic pain. (6-10) A recent review presented considerable evidence that influenza epidemics, and perhaps even the common cold, are brought on by seasonal deficiencies in antimicrobial peptides (AMP), such as cathelicidin, secondary to seasonal deficiencies in vitamin D. (11) Results of an RCT support the theory, finding 2,000 IU of vitamin D/day for one year virtually eliminated self-reported incidence of colds and influenza (Figure 1). (12) Even the current triple childhood epidemics of autism (13) (Figure 2), asthma, (14) and type 1 diabetes, (15) all of which blossomed after sun-avoidance advice became widespread, might be the tragic and iatrogenic sequela of gestational or early childhood vitamin D deficiencies brought on by medical advice to avoid the sun. (Most sun screens are absorbed into the skin and blood and are quite likely toxic. Use of coconut oil is ideal, it protects skin from burning and does not block the crucially beneficial ultra-violet A and B. ed)
Claims that vitamin D may help prevent such a wide variety of diseases seem incredible until one realizes vitamin D is not a vitamin; rather, it is the only known substrate for a potent, pleiotropic, repair and maintenance, seco-steroid hormone with a single endocrine function, but multiple autocrine functions. Previously, many practitioners thought vitamin D's activity was principally its endocrine function--the regulation of serum calcium--and was thus mainly involved in bone metabolism. Indeed, the classic endocrine function of vitamin D begins when the kidney hydroxylates 25(OH)D into 1,25[(OH).sub.2]D, which then acts, both directly and indirectly, to maintain serum calcium.
However, in the last ten years, it has become clear the vitamin D steroid hormone system includes more than the classic endocrine pathway used to preserve calcium economy. (16) The enzyme that further hydroxylates 25(OH)D to 1,25[(OH).sub.2]D (activated vitamin D, the steroid hormone) is present in a wide variety of human tissues other than kidney. 1,25[(OH).sub.2]D is autonomously made in tissues and directly affects numerous cells via its autocrine, and presumed paracrine, functions. (17) Most organs show evidence of end organ responsiveness to 1,25[(OH).sub.2]D. (18) Like all steroid hormones, 1,25[(OH).sub.2]D acts as a molecular switch, activating more than 200 target genes, thereby regulating gene expression. Thus, locally produced 1,25[(OH).sub.2]D exists in most tissues of the body, is under autonomous autocrine control, and has as many mechanisms of action as genes it targets. This explains why the same substance may have a role in preventing cancer, influenza, autism, asthma, multiple sclerosis, and cardiovascular disease, not just curing rickets and osteomalacia (Figure 3).
Such claims leave practitioners with understandable skepticism and multiple questions. Is vitamin D a cure-all? When should I recommend vitamin D? How much should I prescribe? What form of vitamin D should I use? How much do children need? How much do pregnant or breastfeeding women need? Is it appropriate to use higher doses of vitamin D as adjuvant treatment for any of the above diseases? How do I interpret vitamin D blood tests and which tests should I order? What is the risk of toxicity?
Another way to ask many of these questions is, "What is an ideal 25(OH)D level?" Levels needed to optimize intestinal calcium absorption (34 ng/mL) (19) are lower than those needed to optimize neuromuscular performance (38 ng/mL). (20) Recent pooled meta-analyses estimate 25(OH)D levels of 52 ng/mL are needed to effect a 50-percent reduction in the incidence of breast cancer. (21) Although some experts believe the lower limit of adequate 25(OH)D levels is in the low 30s, (22,23) others recommend a lower limit of 40 ng/mL; (24,25) there is certainly no scientific consensus.
Ideal levels are unknown but are probably close to levels present when the human genome evolved in sub-equatorial Africa. Natural levels, such as those found at the end of summer in 30 young men who spent the summer working outdoors, were around 50 ng/mL; (26) however, these levels are obtained by only a small fraction of people. (27) Furthermore, despite such summertime levels, at the end of winter 25(OH)D levels in 50 percent of these men dropped to less than 30 ng/mL, indicating a sun-induced level of 50 ng/mL at the end of summer is inadequate to maintain such a level during wintertime.
Another way to ask the "ideal 25(OH)D" question involves understanding vitamin D's unique pharmacokinetics. Unlike any other steroid hormone system, the substrate concentrations for the liver production of 25(OH)D are absolutely rate limiting. This means the liver enzymes that initially hydroxylate vitamin D to form 25(OH)D and the enzyme in tissue that generates 1,25[(OH).sub.2]D operate below their Michaelis-Menten constants throughout the full range of modern human substrate concentrations; i.e., the reactions follow first-order mass action kinetics. (28) The more vitamin D that is ingested, the more is converted into 25(OH)D, and the more is converted into 1,25[(OH).sub.2]D in the tissues. The reaction appears to be uncontrolled; an aberrant, totally unique, and potentially dangerous situation for a steroid hormone system. Imagine, for example, if cortisol, testosterone, progesterone, or estradiol levels were entirely dependent on the intake of their substrate, cholesterol.
Hollis et al recently explained this conundrum and concluded very few humans obtain enough vitamin D even if they take several thousand units per day. (29) Hollis et al studied the pharmacokinetics of the parent compound, vitamin D, and its first metabolic product, 25(OH)D, in two groups; Hawaiians with significant sun exposure and lactating women receiving 6,400 IU of supplemental vitamin D per day. They found 25(OH)D levels had to exceed a minimum of 40 ng/ mL, and often 50 ng/mL, to begin to detect the parent compound in the blood and begin to normalize the kinetics of 25(OH)D production. In other words, when 25(OH)D levels > 40 ng/mL were achieved, the parent compound began to be detectable in the blood, the reactions became saturable and controlled (like other steroid hormone systems), and thus levels above 40 ng/mL appear to represent the lower limit of "normal" 25(OH) D levels.
This implies virtually everyone has a chronic 25(OH)D substrate deficiency, at least in the winter, and the absence of the parent vitamin D compound (cholecalciferol) in the blood means all available vitamin D is used for metabolic needs and none of it is stored. Because of this, most individuals have chronic substrate starvation, functional vitamin D deficiency, and thus, perhaps, higher risk for the "diseases of civilization."
The ideal 25(OH)D level continues to be debated in scientific circles and consensus awaits further science. However, do we wait for science to complete its work with highly seasonal 25(OH)D levels (Figure 4) that reflect sunlight deprivation, levels where vitamin D steroid pharmacokinetics are aberrant, or is it safer to wait with levels normally achieved by humans in a sunrich environment, levels where vitamin D's kinetics are normalized (>40 ng/mL)?
Once a practitioner is comfortable with ideal 25(OH)D levels being above 40 ng/mL, the answers to the questions posed above become fairly simple. Healthy humans should be supplemented with enough vitamin D or exposed to enough ultraviolet B (UVB) radiation to achieve natural 25(OH)D levels (40-70 ng/mL) year-round, whether they are infants, children, pregnant women, lactating women, healthy young adults, or the elderly.
What role vitamin D has in treating--rather than preventing--disease is largely unknown, but given vitamin D's genetic mechanism of action, it may have a significant role. For example, vitamin D reduces cellular proliferation, induces differentiation, induces apoptosis, and prevents angioneogenesis, each a laudable goal in cancer treatment. A simple risk-versus-benefit analysis suggests patients with a potentially fatal cancer (see below) may think it wise to maintain 25(OH)D levels in the high end of natural ranges (55-70 ng/mL), ranges that assure vitamin D's kinetics are normalized. While the RCTs needed to clarify vitamin D's role in the treatment of disease are being conducted, a strong case already exists for adequately diagnosing and aggressively treating vitamin D deficiency. (22,25,30)
Adult vitamin D deficiency is the rule rather than the exception in industrialized nations. (31-33) A high number of otherwise healthy children and adolescents are also vitamin D deficient. (34,35) Rickets, a disease of the industrial revolution, is being diagnosed more frequently, (36) especially in breast-fed infants. (37) Alarmingly, given mounting animal data that gestational vitamin D deficiency causes subtle but irreversible brain damage in mammalian offspring, (38,39) severe deficiencies are common in newborn infants and pregnant women, especially African-Americans. (40) A population-based study of 2,972 U.S. women of childbearing age found 42 percent of African-American women had 25(OH)D levels below 15 ng/mL, and 12 percent had levels below 10 ng/mL. (41)
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Furthermore, the definition of vitamin D deficiency changes almost yearly as research shows the low end of ideal 25(OH)D ranges are higher than were previously thought. The aforementioned prevalence studies used outdated reference values for low-end 25(OH) D ranges and therefore underestimate the incidence of vitamin D deficiency. Obviously, the higher the low end of the 25(OH)D cutoff point, the higher the percentage of the population defined as deficient. Only 10 percent of the subjects in any of the above studies had 25(OH) D levels > 40 ng/mL.
Vitamin D Metabolism and Physiology
Perhaps because the term "vitamin D" contains the word "vitamin" most people wrongly assume they can obtain adequate amounts by eating a healthy diet. The natural diets most humans consume, however, contain minimal vitamin D, unless those diets are rich in wild-caught fatty fish, sun-dried Shitake mushrooms, or wild reindeer meat. Small amounts of vitamin D are contained in fortified foods, such as fortified milk, some orange juices, and cereals, but such sources are minor contributors to vitamin D stores. Traditionally, the human vitamin D system began in the skin, not in the mouth.
Vitamin D normally enters the circulation after UVB from sunlight strikes 7-dehydro-cholesterol in the skin, converting it to vitamin [D.sub.3] or cholecalciferol (vitamin D). When taken by mouth, the body metabolizes vitamin D similarly to that generated in the skin. No matter how it arrives in the circulation, the liver readily hydroxylates vitamin D to 25(OH)D, the circulating form of vitamin D. Hundreds of tissues in the body use 25(OH)D as a substrate to make the end-product, 1,25[(OH).sub.2]D, known as activated vitamin D, a pleiotropic seco-steroid. If enough 25(OH)D substrate is available, multiple tissues are free to autonomously produce and locally regulate the amount of steroid needed for any particular disease state.
The skin's manufacture of vitamin D is extraordinarily rapid and remarkably robust; production after only a few minutes of sunlight easily exceeds dietary sources by an order of magnitude. Incidental sun exposure, not dietary intake, is the principal source of vitamin D stores and is a function of skin surface area exposed. (42,43) For example, when fair-skinned people sunbathe in the summer (one, full-body, minimal erythemal dose of UVB), they produce about 20,000 IU of vitamin D in 30 minutes, (44) the equivalent of drinking 200 glasses of milk (100 IU/8 oz. glass) or taking 50 standard multivitamins (400 IU/tablet) to obtain the same amount orally.
The fact that 20,000 IU vitamin D can be produced in the skin in 30 minutes of sun exposure, combined with vitamin D's basic genomic mechanism of action, raises profound questions. Why did nature develop a system that delivers huge quantities of a steroid precursor after only brief periods of sun exposure? Would natural selection evolve such a system if the remarkably high input that system achieved were unimportant? As humans evolved in a sun-rich environment (sub-equatorial Africa), is modern sunlight deprivation--and the resultant routinely low levels of this repair- and--maintenance steroid in tissues--a possible common cause of the diseases of civilization?
Factors Affecting Vitamin D Levels
Factors that can affect UVB exposure, and thus the skin's production of vitamin D, include latitude, season of the year, time of day, air pollution, cloud cover, melanin content of the skin, use of sunblock, age, and the extent of clothing covering the body. When the sun is low on the horizon, ozone, clouds, and particulate air pollution deflect UVB radiation away from the earth's surface. Therefore, cutaneous vitamin D production is effectively absent early and late in the day and for the entire day during several wintertime months at latitudes above 35 degrees, and impaired anytime the skies are polluted or cloudy.
Thus, vitamin D deficiency is more common the further poleward the population. For example, Boston, Massachusetts (latitude 42 degrees), has a four-month "vitamin D winter" centered around the winter solstice, when insufficient UVB penetrates the atmosphere to trigger skin production. This becomes an even longer period when the fall and late winter months are included, when sufficient UVB only penetrates around solar noon. In northern Europe and Canada, the "vitamin D winter" can extend for six months. Furthermore, properly applied sunblock, common window glass in homes and cars, and clothing all effectively block UVB radiation--even in the summer. Those who avoid sunlight--at any latitude--are at risk of vitamin D deficiency any time of the year. For example, a surprisingly high incidence of vitamin D deficiency exists in Miami, Florida, despite its sunny weather and subtropical latitude. (45)
African-Americans, the elderly, and the obese face added risk. Because melanin in the skin acts as an effective and ever-present sunscreen, dark-skinned people need much longer UVB exposure times to generate the same 25(OH)D stores as fair-skinned individuals. (46) The elderly make much less vitamin D than 20-year-olds after exposure to the same amount of sunlight. (47) Body fat absorbs vitamin D, thus obesity is a major risk factor for deficiency, with obese African-Americans at an even higher risk. (48) Anyone who works indoors, lives at higher latitudes, wears excessive clothing, regularly uses sunblock, is dark-skinned, obese, aged, or who consciously avoids the sun is at high risk for vitamin D deficiency.
In the absence of a metabolic bone disease such as rickets, osteomalacia, or osteoporosis, most practitioners assume vitamin D deficiency is asymptomatic, although that may be changing. Complaints endemic to every practitioner's office, such as muscular weakness, a feeling of heaviness in the legs, chronic musculoskeletal pain, fatigue, or easy tiring may be symptoms of vitamin D deficiency. (49) Such complaints are extremely common, difficult to treat, and easy to dismiss, but they may indicate symptomatic vitamin D deficiency.
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Physical examination is usually unremarkable but may reveal undue pain on sternal or tibial pressure if deficiency is severe. The vast majority of cases appear normal on exam, although frequent infections, autoimmune illness, diabetes, cancer, heart disease, major depression, and a host of other "diseases of civilization" may be warning signs that deficiency has been present for many years. (22,25)
The aged may be wheelchair-bound secondary to vitamin D deficiency-induced myopathy, yet they typically recover mobility after treatment. (50) The recent strong association of low mood and cognitive impairment in the aged with vitamin D deficiency (51) suggests depressed mood and/or impaired cognition may be presenting symptoms. A blinded intervention trial found 4,000 IU vitamin D per day improved the mood of endocrinology outpatients, (52) but there are no interventional studies of its effects on cognition.
Even without physical signs or symptoms, the physician should screen those at risk. Obtaining and properly interpreting a serum 25(OH)D level is the only way to make the diagnosis. A 25(OH)D level should be obtained at least twice yearly on any patient at risk, once in the early spring for the nadir and once in the late summer for a peak level. (53) We recommend 25(OH)D levels be kept above 40 ng/mL year-round (Figure 5).
It is crucial to remember that serum 1,25[(OH).sub.2]D levels play no role in diagnosing vitamin D deficiency. The kidney tightly controls serum 1,25[(OH).sub.2]D levels, which are often normal or even elevated in vitamin D deficiency. Therefore, a patient with normal or high 1,25[(OH).sub.2]D serum levels but low 25(OH)D levels is vitamin D deficient despite high serum levels of the active hormone. Practitioners who rely on serum 1,25[(OH).sub.2]D levels to make the diagnosis of vitamin D deficiency will routinely miss it. (25)
Treatment of Vitamin D Deficiency