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Expert Critique
FROM THE ASCO Reading Room
The impact of having low vitamin D levels remains unknown. However, recent studies show that vitamin D plays an important role in maintaining a state of health, while low vitamin D levels are associated with many diseases, including diabetes, heart disease, and cancer.
The role of vitamin D and the impact of low vitamin D levels in the inflammatory bowel disease population, including those with Crohn’s disease and ulcerative colitis, also remains under investigation. A recently published study correlated low vitamin D levels with an increased risk of developing Crohn’s disease. Another study found an increased risk for surgery and hospitalization in patients with Crohn’s disease who had low vitamin D levels compared with the Crohn’s disease patients with normal vitamin D levels. The authors noted an even higher risk for these adverse outcomes in those patients with vitamin D deficiency compared with those with insufficiency. Importantly, the study showed a reduced risk following normalization of vitamin D levels for Crohn’s patients; this risk reduction, however, was not seen in patients with ulcerative colitis.
The exact mechanism by which vitamin D influences active inflammation in the intestinal tract is likely multifactorial, yet remains poorly defined. However, the evidence of an interaction or at least an association between vitamin D and intestinal inflammation is clear.
Vitamin D appears to play a prominent role in the intestinal inflammation characteristic of inflammatory bowel disease (IBD), with epidemiologic and clinical evidence supporting a potentially bidirectional association.
Normal levels of vitamin D generally are considered to be at least 30 ng/mL, while insufficient levels are 20 to 30 ng/mL, and levels below 20 ng/mL are considered deficient. Some studies have suggested that individuals with Crohn's disease or ulcerative colitis have low levels of vitamin D, with up to 60% to 70% of patients possibly having insufficiency and half of those being deficient. Those numbers are influenced by other factors, however, such as the location and the season of the year when the vitamin D levels are measured.
Several studies have shown geographic variation in the incidence of IBD. For instance, in the prospective Nurses' Health Studies I and II, 175,912 women reported their area of residence in 1992. During more than three million person-years of follow-up, the incidence of both Crohn's disease and ulcerative colitis increased with and less ultraviolet exposure. Compared with women living in northern areas of the U.S., those residing in the south had an adjusted hazard ratio of 0.48 (95% CI 0.30-0.77) for Crohn's disease and 0.62 (95% CI 0.42-0.90) for ulcerative colitis (P<0.01).
What remains unclear is whether vitamin D deficiency is a cause or an effect of IBD, according to Ashwin N. Ananthakrishnan, MBBS, of Harvard ľֱ School and the Crohn's & Colitis Center of Massachusetts General Hospital in Boston.
"It should be noted that as people have more active disease and have a longer duration of IBD, several factors -- including reduction in physical activity, alteration in diet, and changes in the intestinal absorption of vitamin D -- can contribute to making patients more susceptible to vitamin D deficiency as a consequence of IBD," he wrote in .
"However, there are data from prospective cohort studies where we have looked at predicted plasma vitamin D levels in a large cohort of nearly 80,000 women who were followed for 26 years," he told ľֱ. "We showed that people who were low in vitamin D at baseline had a much higher risk of developing Crohn's disease in the future."
In that study, the low levels of vitamin D did not result from individuals being symptomatic and staying indoors, he pointed out.
Another question is whether vitamin D correlates with disease severity and complications in patients with IBD. To examine this, Ananthakrishnan and his colleagues conducted that included 3,217 patients with Crohn's disease or ulcerative colitis who had at least one measurement of plasma 25(OH)D level as part of routine care. Outcomes included the need for IBD-related surgery or hospitalization, which are common and costly events associated with IBD.
Patients' mean age was 49, most were white women, and 55% had Crohn's disease while the remainder had ulcerative colitis. A total of 28% had insufficient vitamin D and 32% were deficient.
Logistic regression analysis showed that only 10% of patients with Crohn's disease who had never been deficient in vitamin D required surgery compared with 13% of those who were insufficient (OR 1.70, 95% CI 1.24-2.34) and 17% of those considered deficient (OR 2.05, 95% CI 1.53-2.75). In addition, odds ratios for hospitalizations were 1.65 (95% CI 1.30-2.10) for those considered insufficient and 2.49 (95% CI 1.98-3.12) for those who were deficient.
The authors of that study also considered whether subsequent normalization of 25(OH)D levels among those with low levels influenced the need for surgery and hospitalization. Among patients with Crohn's, the likelihood of IBD-related surgery was significantly reduced if previously low levels normalized (OR 0.56, 95% CI 0.32-0.98), although a similar result was not seen for ulcerative colitis.
"Though one cannot exclude the possibility that improvement in vitamin D status was consequent to increasing physical activity and outdoor sun exposure as better control of disease is achieved, considerable evidence both from our study and prior work suggests this is unlikely to be the explanation for our findings," the authors commented.
provided some prospective interventional data, randomizing 108 patients with Crohn's disease who were all in remission to 1,200 IU oral vitamin D3 daily or placebo for 12 months. At the conclusion of the study the rate of relapse was 13% among those given vitamin D compared with 29% among those receiving placebo (P=0.06).
"So there are lots of data that strongly support causality, that vitamin D plays a role in intestinal inflammation," Ananthakrishnan said.
Nonetheless, "I believe that there is likely a bidirectional relationship in which IBD and its consequences can cause a patient to have low levels of vitamin D, and in which having a low vitamin D level itself can affect a patient's immune response and predispose the patient to having IBD or having a relapse of his or her IBD."
But more interventional studies are needed. The optimal dose for supplementation has not been established, and the precise threshold for sufficiency is uncertain, as the 30 ng/mL threshold was intended for assessing bone health. "We don't know the threshold from an intestinal/inflammation standpoint," he said.