More CD patients were female and smoked compared to UC patients, although this did not reach statistically significance (Table 1). Median 25(OH)D (P = .002) and albumin (P = .008) levels of the CD cohort were significantly lower compared to the UC cohort (Table 1). Only 23% of CD patients were in DR compared to 36% of UC patients (P = .03).
Significantly more CD patients had 25(OH)D levels below 20 ng/mL compared to UC patients (60% versus 30%, P<.001), respectively. Around 7% of CD and 6% of UC patients had zinc levels below 7 μmol/L, respectively (P = .86).
Neither the IFX- nor the ADA-TC of CD patients compared to UC patients differed [IFX: 1.6 (IQR: 0.6–3.4] versus 1.2 (IQR: 0.9–2.5) μg/mL, P = .77; ADA: 4.9 (IQR: 0.6–8.8) versus 8.6 (IQR: 0.4–12.0) μg/mL, P = .24).
3.1 Association of variables of CD patients with regard to CR and DR
Around 49% (n = 76) of CD patients were in CR (Table 1). CD patients had significantly higher levels of 25(OH)D (P<.001) compared to those without CR (Fig. 1C). Zinc levels were not associated with CR in CD patients (Fig. 2C).
Univariate analysis revealed that disease duration (P = .01), anti-TNF-α-TC (P = .001), 25(OH)D (P<.001), albumin (P = .001) and CRP levels (P = .001) were associated with CR. Fecal calprotectin level (P = .09) and smoking status tended to be associated (P = .07) with CR. In multivariable analysis, anti-TNF-α-TC (P = .02), 25(OH)D (P = .008) and CRP (P = .02) levels were associated independently with CR (Table 2). The odds ratio (OR) of CD patients for CR was 1.4 (95%-confidence interval (CI): 1.1–1.8) for anti-TNF-α-TC, 1.2 (95%-CI: 1.1–1.3) for 25(OH)D and 0.8 (95%-CI: 0.7–0.9) for CRP levels, respectively. We further analyzed for 25(OH)D and CRP levels the optimal cutoff levels and their diagnostic accuracy utilizing ROC curves. For 25(OH)D and CRP levels, the threshold values to discriminate patients with CR or active disease were 19 ng/mL and 4.9 mg/L with an AUROC of 0.77 (95%-CI: 0.68–0.85) and 0.81 (95%-CI: 0.74–0.87), respectively (Fig. 3A). The sensitivity, specificity, positive and negative predictive values for 25(OH)D cutoff value were 68%, 71%, 69% and 70%, respectively (Table 3).
23% (n = 35) of CD patients were in DR (Table 1). CD patients in DR had higher levels of 25(OH)D (P = .009) compared to those without (Fig. 1D). Zinc levels (P = .10) did not differ in CD patients with or without DR (Fig. 2D).
DR was defined as having CR with CRP and calprotectin normalization and/or endoscopic remission. Therefore, we did not include CRP and calprotectin levels in the logistic regression analysis. Univariate analysis revealed that therapy regime (P = .04), smoking status (P = .03), age (P = .05), disease duration (P = .03), anti-TNF-α-TC (P = .009), 25(OH)D (P = .009) and albumin levels (P = .001) were associated with DR. In multivariable analysis, anti-TNF-α-TC (P = .04) and 25(OH)D (P = .04) level were associated independently with DR (Table 2). The OR for anti-TNF-α-TC and 25(OH)D levels were 1.3 (95%-CI: 1.1–1.8) and 1.1 (95%-CI: 1.0–1.3), respectively. For 25(OH)D the threshold value to discriminate patients with DR or active disease were 26 ng/mL with an AUROC of 0.75 (95%-CI: 0.68–0.83) (Fig. 3B). The sensitivity, specificity, positive, and negative predictive values for 25(OH)D cutoff values were 94%, 34%, 46% and 91%, respectively (Table 3).
3.2 Association of variables of UC patients with regard to CR and DR
Around 60% (n = 46) of UC patients were in CR (Table 1). UC patients had significantly higher levels of 25(OH)D (P<.001) compared to those without CR (Fig. 1E). Zinc levels were not associated with CR in UC patients (Fig. 2E).
Univariate analysis revealed that disease duration (P = .02), anti-TNF-α-TC (P = .009), 25(OH)D (P = .001) and calprotectin levels (P<.001) were associated with CR. In multivariable analysis, 25(OH)D (P = .04) and calprotectin (P = .04) levels were associated independently with CR (Table 4). The OR of UC patients were 1.2 (95%-CI: 1.1–1.4) for 25(OH)D and 1.1 (95%-CI: 1.0–1.2) for calprotectin levels, respectively. For 25(OH)D and calprotectin levels, the threshold values to discriminate patients with CR or active disease were 32 ng/mL and 223 mg/L with an AUROC of 0.83 (95%-CI: 0.71–0.95) and 0.96 (95%-CI: 0.92–0.99), respectively (Fig. 3C). Calprotectin showed the best diagnostic accuracy for diagnosing UC patients with CR (Table 3).
About 36% (n = 28) of UC patients were in DR (Table 1). UC patients in DR had a higher levels of 25(OH)D (P = .002) compared to those without (Fig. 2F). Zinc levels (P = .69) did not differ in UC patients with or without DR (Fig. 2F).
Univariate analysis revealed that anti-TNF-α-TC (P = .04) and 25(OH)D (P = .002) levels were associated with DR. No variable was associated with DR in UC cohort in multivariable analysis (Table 4).
Currently, there is little evidence for routine evaluation of micronutrients in IBD patients. Only few data address the importance of micronutrient in IBD patients. Micronutrient deficiencies in IBD patients, especially 25(OH)D deficiency, was found to be prevalent in patients with IBD[23,24] as well as in the general population. To date, there is little information available regarding zinc deficiency in patients with IBD. Some studies reported prevalence rates of 15% to 40% for zinc deficiency in young and adolescent IBD patients.[6,26]
In this single-center study, we found for the first time an independent association between 25(OH)D level and CR as well as DR in CD patients. In UC patients, a significant association was found only between 25(OH)D levels and CR but not regarding DR. Specifically, CD and UC patients who had high 25(OH)D levels had an increased probability of being in remission. This observation is supported by previously published studies suggesting associations between 25(OH)D levels and disease severity as well as complications of IBD.[27–29] Furthermore, animal models of colitis showed that 25(OH)D supplementation ameliorate intestinal inflammation. Human studies with 25(OH)D supplementation showed decreased risk of relapse, decreased risk of IBD-related surgery, and decrease of peripheral inflammatory markers and Crohn's disease activity index. However, it is still a matter of debate which 25(OH)D dose is appropriate to substitute IBD patients. A study of Garg et al could show that a close control of 25(OH)D levels and careful dose adaptation thereafter, could improve symptom-based activity scores in IBD patients. One prospective randomized study could surprisingly show that patients with CD, who received IFX as induction therapy and had low levels of 25(OH)D, reached higher CR rates than those with normal 25(OH)D levels. The results of this study further support the hypothesis that 25(OH)D status may contribute to disease activity in IBD patients, suggesting that the 25(OH)D deficiency is not only a consequence of the IBD activity, but the exact molecular pathways still need to be elucidated.
Serum zinc levels are maintained by a balance of intake in the proximal gastrointestinal tract, fecal losses, and slow release from tissue stores. Animal and human studies have demonstrated that serum zinc is as useful and accurate as tissue concentrations of zinc accumulation in solid organs. Moreover, serum zinc levels may reflect zinc status better during states of acute zinc depletion due to the slow equilibration of total zinc pools. Zinc also has an important function in wound healing, and one study showed that fistulizing CD patients had lower levels compared to those without fistulas. Zinc deficiency was also associated with acrodermatitis enteropatica, an extraintestinal skin manifestation of CD.
Regarding zinc status, 7% of the CD and 6% of the UC cohort showed zinc deficiency. Zinc level neither differed between CD and UC cohort of patients nor was associated with CR or DR in both cohorts either. First, these results are in contrast to the known prevalence rates of 15% to 40% of zinc deficiency mentioned above. Nevertheless, this is the first study that shows zinc deficiency rates in adult IBD patients. Second, to date only one study is published so far and showed that serum zinc deficiency in IBD patients is more likely associated with adverse disease-specific outcomes such as increased risk of subsequent hospitalizations, surgeries, and disease-related complications. Nevertheless, this study did not analyze an association between serum zinc level and disease activity status at the time of measurement. Therefore, the results of the present study do not further support the hypothesis that zinc deficiency may contribute to the disease status of IBD patients.
In our opinion, it is important to obtain new markers to evaluate IBD disease activity status because its pathophysiology is still not completely understood. Moreover, new markers are bringing new insights into the perspectives of IBD therapy. The 2 investigated parameters serum 25(OH)D and zinc are micronutrients with important metabolic implications. Their deficiency could lead to severe forms of extraintestinal manifestations like osteoporosis and fractures. In case of deficiency both micronutrients can be easily substituted, preventing important complications. Possibly, after supplementation of 25(OH)D better remission rates could be achieved, giving a clinical importance.
Further variables associated with disease status were anti-TNF-α-TC, CRP, and calprotectin levels. Anti-TNF-α-TC were independently associated with CR and DR in CD patients and CR in UC patients treated with an TNF-α-inhibitors as known in previously published studies.[39–41] Both, CRP and calprotectin are well known biochemical markers associated with different disease status of patients with CD and UC.
Our study has certain limitations, including a mixture of patients with CD and UC and different therapy regimens. Furthermore, the study is a single-center study and was conducted at a tertiary care center, which could have caused bias, especially for more severe disease manifestations. We could not measure disease activity for some patients directly by endoscopy or radiological examinations because of the study design. Instead, we tried to assess disease severity by measuring serum CRP and fecal calprotectin levels. Furthermore, the lack of dietary intake monitoring could affect the micronutrient status of the IBD patients included. Nonetheless, we do believe that our “real world” assessment of these measures and outcomes have clinical value.
In conclusion, 25(OH)D deficiency but not zinc deficiency is common in IBD patients. Serum 25 (OH)D levels were independently associated with CR and DR in CD patients and with CR in UC patients but not serum zinc level. Therefore, beside CRP and fecal calprotectin serum 25(OH)D levels may be a further useful noninvasive marker for characterizing different disease activities status in IBD patients. Measurement of serum 25(OH)D levels in IBD patients may thus be warranted. 25(OH)D supplementation in deficient IBD patients is recommended.
Conceptualization: Nicolae-Catalin Mechie, Albrecht Neesse, Ahmad Amanzada.
Data curation: Nicolae-Catalin Mechie, Eirini Mavropoulou.
Formal analysis: Golo Petzold, Ahmad Amanzada.
Funding acquisition: Ahmad Amanzada.
Investigation: Nicolae-Catalin Mechie, Albrecht Neesse, Ahmad Amanzada.
Methodology: Steffen Kunsch, Ahmad Amanzada.
Project administration: Ahmad Amanzada.
Software: Ahmad Amanzada.
Supervision: Volker Ellenrieder.
Validation: Nicolae-Catalin Mechie, Ahmad Amanzada.
Visualization: Ahmad Amanzada.
Writing – original draft: Nicolae-Catalin Mechie, Ahmad Amanzada.
Writing – review & editing: Eirini Mavropoulou, Volker Ellenrieder, Golo Petzold, Steffen Kunsch, Albrecht Neesse, Ahmad Amanzada.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
25(OH)D; clinical remission; Crohn's disease; deep remission; ulcerative colitis; vitamin D; zinc