Our study identified vitamin D deficiency in 34.6% of children and young adults with IBD. This prevalence of vitamin D deficiency is higher than has been reported previously,18–20
higher than that among healthy New England adolescents (24.1% ≤15 ng/mL),38
and similar in patients with CD and UC. Low serum albumin concentration was a significant independent predictor of low serum 25OHD concentration, a finding that has not been reported previously in patients with IBD, to our knowledge. Other risk factors for hypovitaminosis D included winter season, dark skin complexion, low BMI, high ESR, new diagnosis, no vitamin D supplementation, and UGI involvement in patients with CD.
Our finding of higher-than-previously-reported prevalence of vitamin D deficiency among young patients with IBD could be attributed to several factors. Assay-related underrepresentation of serum 25OHD concentrations in subjects taking vitamin D supplements was considered, and is possible, in view of the recently reported Nichols’ Advantage assay’s inadequacy in measuring exogenous sources of vitamin D2
Nevertheless, our screened subjects were not receiving therapeutic doses of vitamin D2
(>800 IU of vitamin D2
) when their serum 25OHD concentration was measured. Two of the 3 studies in pediatric subjects with IBD to report vitamin D status used a serum 25OHD concentration <15 ng/mL as the cutoff value for vitamin D deficiency and could have, as a result, underestimated the prevalence of this condition.19,20
Naturally occurring seasonal variation in serum 25OHD concentrations may also lead to differences in reporting the prevalence of vitamin D deficiency among studies, depending on clustering of sampling during certain seasons. The sampling distribution across seasons was not reported in 2 studies,19,20
but it was roughly uniform in our study.
We also compared our findings with those of a study performed at our institution, examining the prevalence of vitamin D deficiency (serum 25OHD concentration ≤15 ng/mL) among healthy New England adolescents.38
This study used the same method and assay for serum 25OHD concentration determination as ours. Prevalence of vitamin D deficiency according to this study was 39.4% during the winter, 44.4% during spring, 12.1% during the summer, and 16.9% during fall. We found a prevalence of vitamin D deficiency of 55.3%, 19.4%, 30.3%, and 28.6% during the respective seasons.
The current literature seems to support the concept that the prevalence of vitamin D insufficiency and deficiency is higher in patients with CD than UC. The only pediatric study to examine vitamin D status of UC patients reports mean serum 25OHD concentrations similar and within normal limits in patients with CD and UC but without using a cutoff value to define vitamin D deficiency.19
Our findings suggest that pediatric patients with CD and UC do not differ significantly in their vitamin D status and that, after adjusting for other factors, diagnosis becomes less significant. This may be of importance in clinical practice, because it suggests that certain risk factors predispose pediatric patients with IBD to low serum 25OHD concentrations regardless of diagnosis and that both patients with CD and UC may benefit from frequent monitoring of their vitamin D status.
In accordance with findings of other studies in children with IBD,18
we found a higher prevalence of vitamin D deficiency during winter and among subjects with darker skin complexion and lower serum 25OHD concentrations in patients with CD and UGI involvement. In accordance with findings in adults with IBD,24
we found a negative relationship between ESR and serum 25OHD concentration and lower serum 25OHD concentrations in our patients with lower zWt and zBMI. In contrast to findings in adults with IBD,24
we found lower serum 25OHD concentrations in newly diagnosed patients. Our finding of a positive association of serum 25OHD concentration with vitamin D supplementation has not been observed by other investigators of either adults18,22
IBD could lead to vitamin D deficiency, because patients may have decreased exposure to sunlight, decreased intake, malabsorption, and gastrointestinal loss. Regarding exposure of patients with IBD to sunlight, some investigators have found significantly decreased serum 25OHD concentration in patients with IBD during both winter and summer in the Northern Hemisphere,23
and others report a tendency toward lower sun exposure in patients with CD compared with healthy controls even in the summer.27
Decreased oral vitamin D intake in patients with IBD compared with healthy individuals has been neither consistently documented27
nor linked with low serum 25OHD concentrations.18,22
Intestinal absorption of vitamin D was found to be normal in the majority of patients with IBD, regardless of the severity of disease.27,43
Protein-losing enteropathy frequently complicates the course of IBD44
resulting in hypoalbuminemia. Vitamin D and its metabolites are bound to plasma vitamin D binding protein (DBP) regardless of their origin (endogenous or exogenous).3
Only 0.04% of the total 25OHD and 0.4% of the 1,25-hydroxy-vitamin D are encountered as “free” unbound sterols in the circulation.3
DBP is an α
-globulin, which belongs to the albumin superfamily of binding proteins.45
The loss of albumin and immunoglobulins into the gut lumen is well documented in patients with IBD.37,46
Loss of DBP, and with it vitamin D, has not been studied in patients with IBD, but it is a likely mechanism.
To our knowledge, we are the first to report albumin concentration as an independent predictor of serum 25OHD concentration in pediatric patients with IBD. Based on the strong relationship between serum 25OHD and albumin concentration, we hypothesize that protein-losing enteropathy is a leading mechanism of hypovitaminosis D. This has important implications for treatment, because both enteral and parenteral supplementation of this vitamin may prove inadequate, at least in the usual dose, and in patients with active disease.
The significance of hypovitaminosis D among pediatric patients with IBD is unclear and deserves further study. In healthy adolescents and adults, serum 25OHD concentration has been negatively correlated with serum PTH concentration.4,6,38,47
This relationship between serum 25OHD and PTH concentrations has not been consistently reproduced in patients with IBD. In accordance with findings in healthy subjects, some investigators found a negative association of serum 25OHD concentration with serum PTH concentration in IBD patients.21,31
Others have observed an increased prevalence of secondary hyperparathyroidism only after intestinal resection25,26,48
and in undernourished patients with CD.29
In contrast to findings in healthy subjects, serum PTH concentrations similar to those of healthy controls were found in patients with IBD despite their lower serum concentrations of 25OHD,22,49
and serum PTH and 25OHD concentrations actually lower than those of healthy controls were found by others in patients with IBD.50
Two studies report PTH status in pediatric patients with IBD. In one of these studies,19
lower PTH concentrations occurred in patients with CD than in those with UC, despite lower serum 25OHD concentrations. In the other,20
an increase in serum PTH concentration was seen after treatment of CD. We found no relationship between serum PTH and 25OHD concentrations. This finding could not be explained solely by assay-related underrepresentation of serum 25OHD concentration in subjects taking vitamin D supplements, because a relationship between PTH and 250HD was absent in subjects not taking supplements as well. We speculate that in patients with IBD, bone resorption is independent of vitamin D deficiency and likely a result of their increased underlying inflammatory state. Adequate supplementation and/or bone resorption probably maintain serum calcium at appropriate concentrations, thus alleviating the occurrence of secondary hyperparathyroidism in these patients, even when they are vitamin D deficient. It remains to be examined whether secondary hyper-parathyroidism will eventually occur if serum 25OHD concentration remains low during a quiescent phase of the disease, when inflammation-induced bone resorption is less likely. This would imply that vitamin D supplementation may be of greater benefit during disease remission.
The relationship between serum 25OHD concentration and BMD is controversial in studies of patients with IBD. Serum 25OHD concentration correlated positively with BMD of the forearm in unselected patients with CD,26
and lower serum 25OHD concentration correlated significantly with low hip and spine BMD in patients with small intestinal resections.48
On the other hand, many investigators found that BMD was not related to vitamin D status in either adults22,25
with IBD. Moreover, BMD was found to be low despite normal serum 25OHD concentration in many studies of patients with IBD.33,34,50,51
We found no significant association between serum 25OHD concentration and zLSBMD among our subjects, although there was a high prevalence of low zLSBMD. We selected a time interval of 6 months before or after BMD measurement to assess the vitamin D status of our patients, because our goal was to capture in a cross-sectional manner a serum 25OHD concentration that would be most representative and reflective of the vitamin D status of the patients around the time of their BMD measurement. Some investigators reported seasonal variation in BMD and bone turnover of the same subjects with loss of bone mass or high bone turnover during the winter months and gain of bone mass or lower bone turnover during the summer months, which could be reflective of seasonal variation in vitamin D status.5,23
We did not assess BMD and vitamin D status during the same season in our subjects, but we found that mean zLSBMD did not differ between winter/spring and summer/fall, whereas serum 25OHD concentration had a clear seasonal variation. To better evaluate the relationship between vitamin D status and BMD in pediatric patients with IBD, prospective longitudinal studies relating several measurements of serum 25OHD concentration throughout the year with BMD measurements are needed.
The findings in this study must be considered in light of acknowledged limitations. Some limitations stem from the retrospective nature of this study. For example, additional factors that may have influenced vitamin D status in our subjects may have not been considered. Sunlight exposure among our patients was not studied in detail. Nevertheless, seasonal variation was considered and found significant. Dietary vitamin D intake was not measured. However, although the total amount of daily vitamin D intake through diet and supplements is unknown, vitamin D supplementation seems to place the subjects in an advantageous position regarding their vitamin D status, according to our findings. In this study, the number of available patients with UC was lower than that of patients with CD. Nevertheless, reporting vitamin D status and risk factors for hypovitaminosis D separately in these 2 groups of patients was one of the objectives of our study, based on current concepts, now challenged, of their differences in regard to vitamin D status.