Abstract

INTRODUCTION

The prevalence of low vitamin D status has increased in the general population [1]. This is concerning given the growing recognition of the association between vitamin D insufficiency and increased risk of cardiovascular disease, cancer, and pulmonary ailments [2–7]. Indeed, preliminary trials – although not uniform in their results – suggest that vitamin D supplementation may mitigate the incidence and adverse outcomes of these diseases and may reduce all-cause mortality [8–11, 12■]. Although its pleotropic effects on chronic diseases have received significant attention, the role of vitamin D in acute illness is less understood. In this review, we summarize current evidence and conclude that vitamin D status may play an important role in acute stress and critical illness.

MEASURING VITAMIN D STATUS

Vitamin D, a 27-carbon secosteroid, is unlike most other hormones. Differences in source (endogenous vs. exogenous prehormone), extensive need for tissue modification (skin vs. liver vs. kidney), an active intermediary prohormone {25-hydroxy-vitamin D [25(OH)D]}, and a critical set of modulators [parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 (FGF-23)] add to the complexity of vitamin D regulation [13]. Taken together, these factors complicate the direct measurement of vitamin D, as well as which parameter would best reflect overall vitamin D status [14].

Upon exposure to ultraviolet B irradiation, endogenous synthesis of vitamin D₃ starts with a photochemical reaction in the epidermis (Fig. 1). Alternatively, vitamin D₃ can be supplied exogenously as a nutrient or obtained through a dietary intake of fatty fish and vitamin D-enriched foods. Specially treated plant materials can also contribute to vitamin D intake in the form of vitamin D₂ (ergocalciferol). Although their metabolic pathways are identical and both may contribute to vitamin D adequacy, vitamin D₃ appears to be more efficiently metabolized [12■, 15, 16].

FIGURE 1

Synthetic pathway of the major vitamin D metabolites. (1) Reaction catalyzed by UVB (290–310 nm). (2) Isomerization reaction catalyzed by heat. (3) Reaction catalyzed by 25-hydroxylase. (4) Reaction catalyzed by renal 1-a-hydroxylase. (5). Reaction catalyzed by tissue 1-a-hydroxylase. 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; 25(OH)D₃, 25-hydroxyvitamin D₃; DBP, vitamin D-binding protein.

Vitamin D traverses the systemic circulation after binding to vitamin D-binding protein (DBP) and is hydroxylated in the liver to 25(OH)D. 25(OH)D is rapidly released by the liver into the circulation, where under normal circumstances, it exhibits a biological half-life of approximately 2–3 weeks [17]. In the kidney, 25(OH)D is enzymatically converted to the vitamin D hormone calcitriol {1,25-dihydroxyvitamin D [1,25(OH)₂D]}, which is the most biologically active metabolite of the vitamin D synthesis pathway. This final step is rigidly controlled by the stimulus of PTH, inhibition by FGF-23, and circulating levels of calcium, phosphorus, and 1,25(OH)₂D itself [13]. Circulating 25(OH)D levels are, however, approximately 500–1000 times higher than 1,25(OH)₂D levels, and both 25(OH)D and 1,25(OH)₂D are predominantly protein-bound in circulation. Indeed, only 0.03% of 25(OH)D is free, with close to 88% bound to DBP and the remainder to albumin [18■].

Serum 25(OH)D levels reflect overall vitamin D body stores from sunlight exposure and dietary intake [14]. Under normal circumstances, it is the best indicator of vitamin D status [19■, 20]. This is unusual in the sense that a metabolite one step removed from the most biologically active form is used to assess adequacy. Nonetheless, 25(OH)D is the most abundant vitamin D metabolite and its relative stability in the systemic circulation makes it a good indicator of vitamin D stores in the general population. However, recent evidence suggests that significant variation in 25(OH)D levels may occur from hour to hour in acutely ill patients and that single-point assessments may be inaccurate estimates of vitamin D status in such patients [21■■]. On the contrary, 1,25(OH)₂D is present in picomolar concentrations and, because it is tightly regulated, the concentration can remain normal or even be elevated, despite evidence of deficiency [17]. Moreover, in stark contrast to 25(OH)D, the half-life of 1,25(OH)₂D is only a few hours [18■]. Furthermore, measurement of 1,25(OH)₂D maybe confounded by the greater technical difficulty in performing the assay and by conditions such as renal insufficiency or advanced aging that reduce 1-a-hydroxylase activity, which is a major cause of low levels of 1,25(OH)₂D independent of vitamin D stores [14, 22].

25-HYDROXYVITAMIN D AS A BIOMARKER

The role of 25(OH)D levels as a biomarker for disease is controversial. Widespread utilization of thresholds to define disease risk has led to multiple issues from both a clinical and research perspective [23]. To date, there is no consensus about the optimal definitions of either vitamin D deficiency or insufficiency, and diverse cut points for 25(OH)D levels have been suggested, ranging from 16 to 48 ng/ml [19■, 24–26]. This uncertainty is likely to be multifactorial, including inadequate standardization of vitamin D assay methodologies [14] and differences in the measured functional endpoints used by various investigators, which arise from the classic and nonclassic effects of vitamin D.

The classic function of vitamin D is the control of extracellular calcium metabolism by regulating absorption in epithelia involved in calcium transport. Consequently, the traditional ‘low normal’ level for 25(OH)D was 10ng/ml (to convert to nmol/l, multiply by 2.496), as this threshold had the advantage of high specificity for rickets and osteomalacia [13, 17]. Since low vitamin D status stimulates PTH secretion to increase intestinal calcium absorption and bone resorption to maintain calcium balance, it has been proposed that vitamin D sufficiency be described as the concentration of 25(OH)D which achieves maximal PTH suppression [27]. In this regard, vitamin D sufficiency is defined by a 25(OH)D level of 28ng/ml [28]. On the basis of studies on fracture prevention, most investigators have adopted the definition of vitamin D insufficiency as 25(OH)D concentrations less than 30ng/ml and deficiency below 20ng/ml [17, 27, 29]. However, the 2011 report from the Institute of Medicine defined vitamin D adequacy as 25(OH)D levels between 20 and 50ng/ml, on the basis of an estimate that 25(OH)D levels of 20ng/ml would protect 97.5% of the healthy population from skeletal disorders and the higher risk of vitamin D toxicity at 25(OH)D levels above 50ng/ml [19■, 30■].

The nonclassic function of vitamin D includes regulation of cell proliferation and differentiation, regulation of hormone secretion, and the regulation of immune function [20, 31]. These effects take place on a cellular level and are directly dependent on 25(OH)D levels [32]. Indeed, cells of the neuromuscular, cardiovascular, endocrine, and immune system express the vitamin D receptor (VDR) [33]. Furthermore, most of these cells express the 25(OH)D-1-a-hydroxylase, to produce 1,25(OH)₂D for autocrine and paracrine use within the target cell itself [13, 34]. The discovery of VDRs in activated immune cells has particularly stimulated research into the role of vitamin D in immune function [35■]. It is now recognized that vitamin D plays a critical role in the regulation of the innate and the adaptive immune systems [36, 37]. 1,25(OH)₂D inhibits adaptive immunity by attenuating the proliferation and differentiation of both T and B lymphocytes, which is thought to ameliorate the severity of autoimmune diseases [38]. In contrast to its inhibitory role in adaptive immunity, 1,25(OH)₂D is a potent activator of the innate immune system [39]. Innate immunity represents the first line of defense against microbial invasion and constitutes both epithelial and mucosal cells, as well as polymorphonuclear leukocytes, monocytes, and macrophages [38]. The central mechanism underlying microbial eradication is the activation of toll-like receptors in the host cell, which induces formation of potent antimicrobial peptides, such as cathelicidin [40]. Macrophages and epithelial cells respond to both circulating and local 1,25(OH)₂D synthesized by 1-a-hydroxylase activity on 25(OH)D. Recent evidence suggests that 25(OH)D levels of approximately 30–35ng/ml might be sufficient for vitamin D to optimize its cathelicidin effects [41■].

25-HYDROXYVITAMIN D LEVELS AND ACUTE ILLNESS

Seasonal variations in influenza and pneumococcal community-acquired pneumonia suggest that vitaminD, through its antimicrobial, anti-inflammatory, and/or immunomodulatory actions, may play an important role in disease risk [42, 43]. Although a number of early clinical studies suggested anassociation between 25(OH)D levels below 10ng/ml and acute respiratory tract infections (ARIs) [44, 45], recent studies have furnished more compelling evidence (Table 1). Two large retrospective studies demonstrated that 25(OH)D levels below 30ng/ml are associated with increased risk for upper respiratory tract infections (URIs) [46, 47■■]. This evidence is further strengthened by a prospective, observational cohort study, which demonstrated an almost twofold reduction inviral URI risk when serum 25(OH)D levels were at least 38ng/ml [48]. Low 25(OH)D levels have also been shown to significantly increase the risk of work absenteeism owing to URIs [49]. Evidence from randomized clinical trials (RCTs) is limited, but in general, suggests that improved vitamin D status through supplementation is associated with a lower incidence of ARIs [50].