AIM: To describe the relationship between vitamin D levels and inflammatory bowel disease (IBD) characteristics in northeastern Romanian patients.

METHODS: This was a prospective study of 47 consecutive IBD patients admitted to The Institute of Gastroenterology and Hepatology in Iasi, Romania between March 2011 and June 2012. The diagnosis of IBD was established based on endoscopic, histologic and radiologic findings. Demographic data, disease characteristics, ongoing treatments and biological parameters of patients (including markers of inflammation: C-reactive protein level, fibrinogen level, and erythrocyte sedimentation rate) were recorded. Serum vitamin D levels were measured and compared with age- and sex-matched healthy volunteers from the same geographic area. Vitamin D levels were defined as sufficient (> 30 ng/mL), insufficient (20-30 ng/mL), or severely deficient (< 20 ng/mL).

RESULTS: Thirty-three of the IBD patients included in this study had ulcerative colitis (UC) and 14 had Crohn’s disease (CD). Only 24% of the UC patients and 21% of the CD patients had sufficient vitamin D levels. The vitamin D levels were significantly lower in the CD patients with moderate to severe disease activity compared to the CD patients in remission or with mild disease activity (16 ± 6 ng/mL vs 26 ± 7 ng/mL; 16 ± 6 ng/mL vs 31 ± 9 ng/mL, respectively, P < 0.05). Vitamin D levels in the UC patients were not influenced by disease activity and no correlation was observed with the inflammation markers tested (C-reactive protein, fibrinogen, and erythrocyte sedimentation rate). No association was observed between vitamin D levels and smoking status or ongoing medication (5ASA, steroids, and anti-TNFα). Newly diagnosed IBD patients had lower vitamin D levels than patients with established cases, though these differences were not significant (UC: 22 ± 9 ng/mL vs 26 ± 12 ng/mL; CD: 18 ± 6 ng/mL vs 27 ± 11 ng/mL, respectively). Although no association was found between the season during which the visit was scheduled and vitamin D levels, the UC patients assessed during the winter tended to have lower levels than those assessed during the summer (22 ± 9 ng/mL vs 28 ± 13 ng/mL, respectively).

CONCLUSION: Vitamin D levels are significantly reduced in IBD patients in northeastern Romania, with the lowest levels occurring in CD patients with moderate to severe disease activity.

Inflammatory bowel disease (IBD) is a debilitating condition characterized by a dysregulated mucosal immune response to intestinal microorganisms in a genetically susceptible host. While its pathogenesis is only partially understood, studies have shown that a complex combination of genetic, immune, environmental and microbial factors contribute to IBD. It is thought that IBD results from an inappropriate immune response to luminal antigens in the gut[1]. This disease is an important public health problem, affecting up to 0.5% of the population in developed countries and with increasing incidence in developing nations[2-4].

Recent studies describing the immunomodulatory function of vitamin D have suggested that vitamin D activity could play an extenuating role in the occurrence and progression of these autoimmune diseases[5-7]. Epidemiological studies suggest that the prevalence of vitamin D deficiency is high in patients with Crohn’s disease (CD). Vitamin D deficiency is associated with a decreased exposure to sunlight, decreased oral vitamin D intake, malabsorption of vitamin D due to short gut syndrome or small bowel disease, bacterial overgrowth, and the use of cholestyramine for IBD symptom management[8]. Although patients with IBD are known to have an increased incidence of vitamin D deficiency, it remains unclear whether the deficiency contributes to and/or results from the disease. In this study, the vitamin D levels of northeastern Romanian IBD patients were compared with age- and sex-matched control subjects to assess the association between vitamin D levels and disease characteristics.

A total of 47 IBD patients and 94 healthy volunteers were included in this study. Thirty-three of the IBD patients had UC and 14 had CD. Demographic data and disease characteristics from these patients are presented in Table 1. Vitamin D levels were significantly lower in IBD patients compared to healthy controls (24 ± 10 ng/mL vs 31 ± 13 ng/mL, P < 0.05). However, IBD type did not influence this decrease, as no difference was found between the CD and UC patients. A significantly greater proportion of the male healthy controls had a sufficient vitamin D level than the male IBD patients (56% vs 25%, P < 0.05), but the difference between the female healthy controls and the female UC patients and respectively female CD patients did not reach the threshold of statistical significance (43% vs 24% vs 17%, P = 0.16). Additionally, while vitamin D levels in the healthy control group were significantly associated with the season (P < 0.05), this trend was not observed in the IBD patients. Although the vitamin D levels were lower in the winter compared to those during the summer in UC patients (22 ± 9 ng/mL vs 28 ± 13 ng/mL) and higher in CD patients (25 ± 8 ng/mL vs 21 ± 11 ng/mL, respectively), these differences were not significant.

In the UC patients, a lower serum vitamin D level was detected in a subgroup with extensive colitis (20 ± 7 ng/mL) compared to patients with left side colitis (30 ± 14 ng/mL); however, the difference was not significant. Similarly, a moderately reduced serum vitamin D level was observed in CD patients with involvement of only the colon compared to patients with additional involvement of the small bowel. Furthermore, newly diagnosed patients tended to have a lower vitamin D level than patients with established cases in the CD group (18 ± 6 ng/mL vs 27 ± 11 ng/mL) and the UC group (22 ± 9 ng/mL vs 26 ± 12 ng/mL). Although the severity of the flare in UC patients did not affect serum vitamin D levels, CD patients with moderate to severe disease activity had significantly lower vitamin D levels than patients in remission or with mild disease activity (16 ± 6 ng/mL vs 26 ± 7; 16 ± 6 ng/mL vs 31 ± 9 ng/mL, respectively, P < 0.05). Finally, there were no statistically significant associations between vitamin D levels and smoking or medication status, or with serum levels of C-reactive protein or fibrinogen, or with erythrocyte sedimentation rate.

The incidence and prevalence of IBD is higher in Northern Europe, North America, North Australia and New Zealand than in Asia[2,3]. Although the incidence of IBD in the Indian subcontinent is low, individuals migrating to developed countries in northern latitudes have an increased risk for developing the disease[12]. The association between vitamin D levels and sunlight exposure and IBD incidence is confounded by numerous factors, and therefore a causal relationship cannot be confirmed. The available reports on vitamin D levels in adults with IBD show a range of prevalence of vitamin D deficiency of 22% to 70% in CD cases and between 15% and 45% in those with UC[13-15]. This study found that only 24% of UC patients, 21% of CD patients, and 50% of healthy subjects were vitamin D sufficient. These results were somewhat unexpected, given that Romania is considered by some to be a sunny country, and therefore an adequate source of vitamin D.

Although low vitamin D concentrations have been reported in IBD[16,17], there are contradictory data regarding the correlation between 25-hydroxyvitamin D levels and IBD activity[18-20]. However, despite some reports showing no association[21], we anticipated that patients with small bowel CD would have lower vitamin D levels, as a study by Tajika et al[22] showed that 25-hydroxyvitamin D levels correlated with CD duration and activity. The current study indicates that, despite the high prevalence of vitamin D deficiency in IBD patients, serum vitamin D levels were only associated with IBD activity in CD patients, in contrast to a previous finding[19]. However, our results are in agreement with a similar study published by Lamb et al[23] showing that overall, vitamin D levels did not differ between patients with CD and patients with UC. Interestingly, our study indicated that newly diagnosed IBD patients tended to have lower vitamin D levels, though the small number of patients prohibited this difference from reaching statistical significance. It has been suggested that vitamin D deficiency in IBD patients is related to inadequate absorption[24]. Although this study demonstrated an increased incidence of vitamin D deficiency in IBD patients, it is unclear whether the low vitamin D level is due to the IBD and associated inflammation of the gut, or if the IBD is a consequence of the immune disorders induced by the vitamin D deficiency.

A large population study found that high sunlight exposure was associated with a significantly decreased risk of CD[25]. Furthermore, patients with reduced sun exposure have lower serum 25-hydroxyvitamin D levels and increased disease activity[26]. While the onset and exacerbation of IBD is thought to show seasonal variation, suboptimal vitamin D levels have been observed even during the summer[27]. This study similarly failed to demonstrate a seasonality effect, though a trend for reduced deficiency rates in summer was observed in UC patients. In addition to sunlight exposure, steroid treatment for IBD may contribute to vitamin deficiency, as vitamin D-deficient patients are statistically more likely to be treated with steroids, but not other immunosuppressants such as infliximab, methotrexate, azathioprine, adalimumab or mercaptopurine[28], however, the sample size in this study was insufficient to allow for proper analysis of the impact of different treatments on vitamin D levels.

This is the first report of an assessment of vitamin D levels in IBD patients from northeastern Romania. Although the small number of patients was a limitation of the study, there are some advantages to the research design. Patients included in the study were excluded based on specific criteria, and disease activity was based on laboratory, clinical and endoscopic assessments. Furthermore, patients were compared with geographically similar control subjects, with all blood sampling performed in the same laboratory. The study highlights the low prevalence of sufficient vitamin D levels in IBD patients, and an association between vitamin D deficiency and moderate to severe CD. Future prospective cohort studies with larger patient samples are needed to determine the causal relationship between the vitamin D deficiency and the incidence of IBD. Moreover, the effect of vitamin D supplementation on IBD outcome should be investigated, which may provide insight to possible therapeutic or preventative measures for the treatment of IBD.