Vitamin D Deficiency and Supplementation in Critical Illness

The Known Knowns and Known Unknowns

Priya Nair; Balasubramaniam Venkatesh; Jacqueline R Center


Crit Care. 2018;22(276) 

In This Article

The Known Knowns

Pleiotropic Functions of Vitamin D

Vitamin D3 is produced in the skin from 7-dehydrocholesterol in a dual-stage process where the B ring is broken under ultraviolet rays (e.g. sunlight), and the pre-D3 formed in this process isomerises to D3 in a thermo-sensitive but non-catalytic process.[1]

The three main steps in vitamin D metabolism, 25-hydroxylation, 1a-hydroxylation, and 24-hydroxylation, are all performed by cytochrome P450 mixed-function oxidases (CYPs). The first step towards activation is conversion of vitamin D to 25 hydroxy-D. In addition to UV activation small amounts of vitamin D, either as D2 or D3, can enter the body from its intestinal absorption from dietary intake and progress towards activation by hydroxlyation. The next step toward full activation is into 1,25 dihydroxy-vitamin D (1,25(OH)2D) via CYP27B1 (also known as 1-alpha hydroxylase), a mitochondrial P450 enzyme in the proximal renal tubule of the kidney. 25-Hydroxyvitamin D 24 hydroxylase, also known as CYP24, can hydroxylate both 25 hydroxy-D and 1,25(OH)2D. In addition to 1,25(OH)2D, the kidney also produces 24,25 dihydroxyvitamin D, a relatively inactive metabolite.[2]

Figure 1 summarises the synthesis and metabolism of vitamin D as well as its classic and pleiotropic functions.

Figure 1.

Synthesis, metabolism and functions of vitamin D. PTH parathyroid hormone, FGF-23 fibroblast growth factor-23, RANKL receptor activator of nuclear kappa-B ligand

There is a growing appreciation for the many roles of vitamin D beyond its classic actions on calcium metabolism and musculoskeletal health. This has been driven by the finding that most body tissues have receptors for the active form of vitamin D, 1,25(OH)2D, known as vitamin D receptors (VDRs). Additionally, most of these tissues also contain the enzyme CYP27B1, which is responsible for the conversion of the major circulating form of vitamin D, 25-hydroxy-vitamin D (25 hydroxy-D), to its active metabolite 1,25(OH)2D. Regulation of this conversion at the tissue level differs from the conventional activation that occurs in the kidney in that it is more substrate dependent and hence more susceptible to vitamin D deficiency.[2]

The non-skeletal actions of vitamin D are mediated by the control of gene expression in a number of organs such as the brain, prostate, colon and immune cells, which may be of particular relevance in critical illness. These non-skeletal actions result in regulation of cellular proliferation, differentiation, apoptosis and angiogenesis.[3] In fact the mechanism of action of vitamin D in these contexts is analogous to the way in which steroid hormones act. As a result of this contemporary knowledge, vitamin D is considered more a hormone than a vitamin.[4]

1,25(OH)2D has been reported in animal models and in cultured cells to improve insulin production, modulate T-and B-cell activity, enhance phagocytic killing activity, improve vascular smooth muscle resistance, reduce risk of developing autoimmune diseases and inhibit cancer cell growth.[5]

Prevalence of Deficiency With Season and Latitude

Vitamin D deficiency is highly prevalent in all age groups. Depending on the definition used, approximately 1 billion adults (15% of the population) are vitamin D deficient. Prevalence is higher in Middle Eastern countries where sun exposure is limited by clothing, especially in girls and women.

This high prevalence may be related to several factors, such as decreased vitamin D photosynthesis in response to UVB in individuals with high skin melanin content, aging, use of extensive skin coverage and minimal exposure to sunlight. In addition, low vitamin D intake and high rates of obesity contribute.[6]

Season appears to be a small part of the problem worldwide, as countries with long winters appear to have lower deficiency rates overall compared to sunny countries, which is probably related to the fortification of staples, consumption of fatty fish and regular use of vitamin D supplements.[6] However, seasonal variation in vitamin D has been well documented with 25 hydroxy-D levels varying by 10–20 nmol/L between summer and winter.[7]

Although it has been hypothesised that influenza pandemics are associated with solar control of vitamin D levels in humans, which waxes and wanes along with solar cycle-dependent ultraviolet radiation,[8] other groups have refuted this.[9]

In a cohort study of critically ill adults in France, admission to the ICU in spring (following winter months) was found to be an independent predictor of severe vitamin D deficiency (level < 30 nmol/L).[10]

Association of Deficiency With Adverse Health Outcomes

A number of population studies have shown low vitamin D levels are associated with poor outcomes. However, causality is more difficult to establish given that a low vitamin D level in itself might be a marker of poor general health,[11] with deficiency observed in individuals with limited physical activity and sunlight exposure, advanced age, obesity, poor diet and other comorbid illnesses.

In the general population, mortality risk appears to decrease as 25 hydroxy-D levels increase, with optimal levels 75–87.5 nmol/l. A large meta-analysis of community-dwelling adults showed that the lowest 25 hydroxy-D quintile observed was associated with increased all-cause mortality (pooled risk ratio of 1.57; 95% CI 1.36 to 1.81).[12]

Conditions that have been associated with vitamin D deficiency include certain malignancies such as colon, breast, ovarian, prostate and lymphoma. Some studies also report increased mortality risk with these cancers in vitamin D-deficient individuals.[13–16] Similarly low vitamin D levels have been associated with cardiovascular conditions such as poor hypertension control and congestive cardiac failure.[17,18] Vitamin D deficient subjects who have multiple sclerosis, diabetes, depression and certain infections such as influenza, tuberculosis and other conditions have demonstrated similar association with adverse outcomes.[19–23]

Prevalence of Deficiency in Critical Illness and Association With Poor Outcomes

Several observational studies in critically ill patients have demonstrated an association between vitamin D deficiency/insufficiency and adverse outcomes.[10,24–32] These include higher illness severity scores and risk of death, longer stay in ICU, longer duration of mechanical ventilation, increased rates of ventilator-associated pneumonia, blood culture positivity and an increased incidence of organ dysfunction, particularly acute kidney injury. The associated ICU and hospital costs are also higher in vitamin D-deficient patients.[33]

A systematic review of 14 observational studies involving 9,715 critically ill patients reported an increased association with sepsis and increased risk of death and concluded that vitamin D deficiency was associated with an increased susceptibility for severe infections and risk of death in critically ill patients.[34] This suggests that vitamin D deficiency might serve as a predictor of these negative outcomes in the ICU.

Likewise in the paediatric intensive care unit (PICU) population, a recent systematic review and meta-analysis has reported a 50% prevalence of deficiency at the time of PICU admission. Deficiency was also determined to be associated with greater illness severity, multiple organ dysfunction, and mortality in the PICU setting.[35]

Supplementation of Vitamin D in Critically ill Patients is Safe

A handful of studies have investigated vitamin D supplementation in ICU patients.[36–42] These studies have predominantly used oral cholecalciferol in doses varying from 200 to 540,000 IU in either single or repeated doses. None of the studies reported any clinically relevant adverse effects. Transient hypercalcaemia not requiring any intervention was the only reported finding.[42]

In a randomised controlled trial (RCT) by Amrein et al.,[40] mild hypercalcaemia was the major adverse effect associated with high-dose vitamin D, but no serious adverse events were recorded. Mean calcium and phosphorus levels were similar between the placebo and vitamin D3 group. Serum ionised calcium levels were slightly higher in the vitamin D3 group only at the 6-month follow-up. The two highest 25 hydroxy-D levels recorded were below those considered to be acutely toxic (> 150 ng/mL). Individual hypercalcaemia did occur in some instances in the vitamin D3 group, but remained asymptomatic and did not require treatment. Renal parameters or the degree of hypercalciuria were not different between the groups.

This suggests that supplementation of vitamin D within these dose ranges is safe in the short term (up to 6 months) in critically ill patients, although none of the studies have published follow-up beyond that time period.