Vitamin D and the goldilocks principle: Too little, too much, or just right?

Vitamin D has long been recognized for its central role in calcium homeostasis and in the maintenance of skeletal health due to its effects on intestinal calcium absorption. More recently, however, an ever expanding array of studies have suggested that vitamin D may play a pivotal role across much of the human health and disease spectrum—including in such diverse conditions as cancer, cardiovascular disease, depression, dementia, diabetes, fall risk, immune disorders, infections, and pregnancy, among others (1). Although vitamin D is found in low levels in some foods, dietary intake alone of nonfortified foods provides only limited amounts of vitamin D (2). In some countries, including the United States, food fortification with vitamin D is now commonplace, and it has significantly stemmed the development of skeletal abnormalities (rickets in children and osteomalacia in adults) that can occur in those with very low vitamin D levels. Beyond ingestion of dietary sources, however, most humans obtain most their vitamin D via endogenous production from skin exposed to UVB irradiation. Given increasing concern for sun exposure as a risk factor for skin cancer, combined with lifestyles in which most time—particularly in developed countries—is spent indoors, decreased cutaneous production with resultant low levels of vitamin D is now commonplace in patients of all ages. Accordingly, vitamin D supplementation as performed under the care of a physician or, as is commonly seen in clinical practice, resulting from the purchase of readily available over-the-counter supplements (3) by individuals making their own care decisions under the influence of the popular press has become widespread. Vitamin D obtained from ingestion of food or supplements, or via skin exposure to UVB, is biologically inactive and must be modified to form 25-hydroxyvitamin D [25(OH)D; the storage form of vitamin D]. A small fraction of 25(OH)D is then converted to the physiologically active form of vitamin D (1,25-dihydroxyvitamin D) (2). 25(OH)D is the best test for assessment of vitamin D status due to both its approximately 1000-fold higher circulating concentration and its substantially longer circulating half-life when compared to 1,25-dihydroxyvitamin D. As such, 25(OH)D levels reflect an integrated measure of gastrointestinal absorbed sources and cutaneous synthesis. Given the plethora of purported roles for vitamin D, it is perhaps not surprising that over the past several years, few topics in medicine have generated as much passionate debate as has the question of what represents an “optimal” level of vitamin D in health vs disease. Thus, in 2010, the Institute of Medicine provided recommendations on optimal serum concentrations of 25(OH)D, concluding that serum 25(OH)D concentrations of > 20 ng/mL (50 nmol/L) are not required for maximum skeletal benefit (4). In contrast, however, are guidelines published shortly thereafter by a panel convened by The Endocrine Society, in which a serum 25(OH)D level of 30 ng/mL (75 nmol/L) was provided as a target for optimization of skeletal health (5). Notably, both sets of recommendations were based primarily on skeletal health outcomes, with both acknowledging that there were limited data of sufficient quality available to make recommendations for optimal vitamin D levels for other health outcomes (5, 6). Whereas much attention has focused on the association of low levels of vitamin D with health and/or disease, comparatively little effort has centered on the potential deleterious impact of high vitamin D levels. Although excess vitamin D supplementation can lead to hypercalcemia, vitamin D toxicity is believed to be very rare and to occur only after prolonged ingestion of large vitamin D doses (>10 000 IU/d) in patients with normal gastrointestinal absorption or in those consuming large amounts of dietary calcium. Thus, a high 25(OH)D level in the absence of hypercalcemia is not generally considered to be of significant clinical concern. Whether there exists a safe upper limit for 25(OH)D levels beyond hypercalcemia as an endpoint, however, remains largely unknown. Emerging data from several sources, however, suggest that supplementation with high doses of vitamin D (7), or high measured serum levels of 25(OH)D (8, 9), may have deleterious health effects that may or may not be related to effects on serum calcium levels. It is in this context that the study in this issue of the JCEM by Amrein et al (10) is of significant interest. In their retrospective study, the authors analyzed the association between serum 25(OH)D levels measured in the year preceding hospital admission with all-cause mortality after hospitalization in > 24 000 adults admitted for acute care to two large teaching hospitals in Boston. After adjustment for multiple potential confounding variables, patients who had a 25(OH)D level measured before hospitalization, which was either < 30 ng/mL or ≥ 60 ng/mL, had a significantly increased risk for all-cause 90-day mortality when compared to subjects with vitamin D levels between 30 and 60 ng/mL. When placed in the context of recent studies that have reported higher mortality rates in community-dwelling subjects at both the lower and upper ends of the 25(OH)D spectrum (8, 9), the results of Amrein et al (10) strengthen the notion that a U-shaped optimal 25(OH)D range exists in humans that—to paraphrase Goldilocks—is not “too little or too much, but just right.” U-shaped distributions abound in medicine. As an example, between the leftmost edge of cachexia and the rightmost edge of morbid obesity lies the healthy range for body mass index. Similarly, euthyroidism is preferred to hypothyroidism and hyperthyroidism; likewise eucalcemia is biologically more tenable than either hypocalcemia or hypercalcemia. Indeed, for almost any measurable physiological parameter, staying within a “normal range” is usually associated with a survival advantage. Given this then, it is perhaps not surprising that a U-shaped curve was found for the relationship between 25(OH)D levels and 90-day mortality in the study of Amrein et al (10), although based upon the data presented and the retrospective observational nature of the study, a causal relationship between either low or high 25(OH)D levels and mortality cannot be inferred. Nevertheless, it is interesting to note that indigenous Africans living near the equator, for whom sun exposure is the principal determinant of vitamin D levels, have serum 25(OH)D levels at exactly the midpoint (46 ng/mL [115 nmol/L]) (11) of the optimal range defined by Amrein et al (10), suggesting that maintenance of circulating 25(OH)D levels within this range may be of evolutionary advantage. It is important to recognize, as the authors do in their discussion, that the study as presented is not without significant limitations. These include those inherent to the retrospective cohort design study used; the absence of knowledge as to why 25(OH)D levels were measured in the year before hospitalization, which may have led to selection bias; the fact that multiple different assays for 25(OH)D measurements were used over the 18-year period of the study; and the fact that comparatively few (2.8% of total) patients had 25(OH)D levels ≥ 60 ng/mL (150 nmol/L). Accordingly, these findings cannot by themselves be used to guide clinical decisions in the hospitalized patient. However, they are consistent with emerging data from other recent studies (8, 9) and therefore raise the specter that high 25(OH)D levels may relate to mortality. Finally, given the widespread availability and comparatively lower expense of vitamin D over-the-counter supplementation, it appears increasingly prudent that we as clinicians urge our patients to use vitamin D judiciously, recognizing that high 25(OH)D levels are unlikely to be a panacea, and in some cases may be associated with more harm than good. Unfortunately, at this point there appear to be far more “unknowns” than “knowns” regarding optimal levels of vitamin D in all patients across all possible diseases or health states, with most available data coming from observational studies, as does this study of Amrein et al (10). As such, there is much work to be done, amid hope that currently ongoing randomized trials (12) will help us identify that “just right” spot for all of our patients.