Vitamin D and Calcium
Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.48,49
Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D3 and then thermally isomerizes into vitamin D3. This vitamin D3 is then transported to the liver on vitamin D–binding protein.50 The second mechanism is through oral vitamin D3 that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)2D for redistribution throughout the body.50 This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.51 Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.52
Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.52 A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.53
Vitamin D and calcium are further implicated in maintaining skeletal health,47 while vitamin D specifically helps maintain intestinal homeostasis54 and immune system modulation in the skin.55
Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.56 Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.60 Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.61
Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.62 Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.63-65
An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.66
Evaluation of calcium can be done through serum levels in patients with IBD.67 Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,68 which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.69
Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.62 Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.65
Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.70 In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.71
These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.