Prevalence of Vitamin D Deficiency in Patients with Inflammatory Bowel Disease

Abstract

Introduction

The relationship between hypovitaminosis D and the development of inflammatory bowel disease (IBD) is well established in countries with high prevalence and incidence of IBD and low exposure to solar ultraviolet radiation. However, only some studies included emerging countries, which have an increasing prevalence of IBD and diverse climate and social conditions.

Objective

This cross-sectional study's purpose is to evaluate the prevalence of hypovitaminosis D and its relationship with IBD activity in patients treated at a reference service in an emerging country.

Methods

This study analyzed the medical records of 113 patients from June 2022 to August 2023. We collected data about sex, age, IBD diagnosis, vitamin D serum levels, fecal calprotectin, and IBD medication. We presented the descriptive data as absolute and relative frequencies. We looked for possible links between calprotectin and vitamin D in people with Crohn's disease (CD) and ulcerative colitis (UC). We used the Chi-square test of independence (when expected cell counts were greater than 5) and Fisher's exact test (when expected cell counts were less than 5).

Results

We diagnosed 78 patients with UC and 35 with CD. Serum vitamin D levels were less than 30 ng/dl in 57.1% of patients with CD and 57,7% of those with UC. There was no association between low vitamin D serum levels and fecal calprotectin.

Conclusion

The present study indicates a prevalence of low vitamin D serum levels in patients with IBD, but this finding does not have a significant relationship with disease activity.

Keywords

inflammatory bowel disease - crohn's disease - ulcerative colitis - vitamin D - hypovitaminosis D

Introduction

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are long-lasting, multifactorial conditions of the digestive tract that cause inflammation that comes and goes. UC affects the rectum, confines to the mucosa, and persists continuously in the colon. The CD is characterized by transmural inflammation, a wide range of areas of involvement (i.e., segments of the bowel that appear normal but are diseased), and the potential to affect any part of the gastrointestinal tract. Both may present extra-intestinal involvement.[1]

Evidence suggests that vitamin D is an environmental factor associated with the risk of developing IBD. Vitamin D deficiency is prevalent in patients with IBD and may affect between 30% and 40% of patients. Low sun exposure, as demonstrated by a multicenter study in France, contributes to the development of CD. In this sense, this deficiency can be higher in CD, ranging from 35% to 100% of patients.[2]

Lower levels of vitamin D associated with reduced exposure to solar ultraviolet-B radiation may be responsible for the north-south incidence gradient. This gradient suggests that the incidence and prevalence rates of UC and CD are higher in northern countries. However, the prevalence of IBD has increased worldwide since the 1990s. In the 21st century, the incidence of IBD has rapidly increased in emerging countries.[3] Nevertheless, whether vitamin D deficiency is a cause or a consequence of IBD remains unclear.[2] [4]

The innate immune system, gut microbiota, environmental factors, and genetic predisposition interact to develop IBD. UC, a non-specific phenotype of IBD, arises from changes in various factors. +Genetic factors that impact the adaptive or innate immune systems and the function of intestinal epithelial cells may change how the digestive tract reacts to the gut microbiota, which can cause inflammation in the gut.[5]

Vitamin D has a well-established role in regulating calcium and phosphate metabolism. Recent studies have identified this vitamin as a modulator of immune responses, influencing T lymphocytes, dendritic cells (DCs), and macrophages, thereby preventing exacerbated immune responses. In addition, vitamin D has the function of repairing the intestinal mucosa.[3] [5] [6]

The main source of vitamin D is the interaction between the skin and solar ultraviolet-B radiation. Dietary sources, such as egg yolk, beef liver, fat-rich fish, fortified milk, and dairy products, may also provide vitamin D. In vertebrate skin, the precursor of cholesterol, dehydrocholesterol (pre-vitamin D), interacts with ultraviolet radiation to produce cholecalciferol (vitamin D3). The liver metabolizes this chemical compound to produce calcidiol (25-hydroxyvitamin D), which is the major circulating form of vitamin D in the body. The kidneys then convert calcidiol into the active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D). Lastly, the metabolization of vitamin D occurs in the liver.[7] [8]

The measurement of vitamin D is based on serum calcidiol levels. Values lower than 20 ng/dl indicate deficiency; values from 20 to 29 ng/dl indicate insufficiency; and normal values range from 30 to 100 ng/dl.[8]

Epidemiological studies suggest that patients with CD have a high prevalence of vitamin D deficiency. 7 Patients with less exposure to sunlight tend to have more active diseases, and sun exposure proved to be a protective factor in the development of CD.[8] [9]

There is a relationship between hypovitaminosis D and the development of IBD in countries with a high prevalence and incidence of the disease and low exposure to ultraviolet solar rays. However, emerging countries, where the incidence of IBD is increasing and the climatic and social conditions differ from other contexts, have conducted few studies.[7] [8] [9]

Objectives

The two objectives of this study were:

• I) To assess the prevalence of hypovitaminosis D in IBD patients from a region with significant UV solar ray exposure, making them immune to vitamin D deficiency;

• II) To evaluate fecal calprotectin to see if there is a correlation between vitamin D levels and disease activity.

Methods

This is a cross-sectional study conducted by the coloproctology outpatient clinic at Professor Alberto Antunes University Hospital of the Federal University of Alagoas, a reference center for IBD treatment.

The ethics committee received the study and approved it. CAAE 74680523.4.0000.0155.

Participants

We selected patients from the outpatient follow-up without oral replacement of vitamin D or other vitamins.

After reviewing medical records, 113 patients diagnosed with IBD who were being followed up at the outpatient clinic between June 2022 and August 2023 and who had records of serum vitamin D levels in this period were selected. Exclusion criteria were the presence of altered renal or hepatic function, the use of medications that interfere with vitamin D metabolism, and the use of oral replacements for vitamin D. The variables investigated were age, sex, main diagnosis (CD or UC), laboratory tests (serum levels of vitamin D and fecal calprotectin), and medication used to treat IBD.

The laboratory tests used the following reference values: [8] [9] [10] [11].

Serum vitamin D levels range from 20 ng/dl (deficiency), between 20 and 29 ng/dl (insufficiency), and from 30 to 100 ng/dl (normal);

Fecal calprotectin: < 150 mcg/g (normal).

We exported the data to Microsoft Excel software. Some variables were dichotomized, including calprotectin (≤ 150 mcg/g and > 150 mcg/g) and vitamin D (< 30 mg/dl and ≥ 30 mg/dl). We presented the descriptive data as absolute and relative frequencies. The Chi-square test of independence was used when cells presented expected counts greater than 5, and Fisher's exact test was applied when cells presented.

We used expected counts of less than 5 to assess potential associations between calprotectin and vitamin D in patients with UC and CD. The Phi coefficient quantified the effect size, ranging from weak (> 0.05), moderate (> 0.10), strong (> 0.15), or very strong (> 0.25). 12 The significance level adopted was p < 0.05, and the analyses were performed using SPSS® Statistics software (IBM®, Chicago, United States of America, version 26).

Results

Among the 113 patients selected, 78 patients (69%) received a UC diagnosis, while 35 patients (31%) received a CD diagnosis. ([Table 1]).

Table 1 Total patients with inflammatory bowel disease (Chron's disease and ulcerative colitis), serum vitamin D levels and Calprotectin levels in patients with vitamin D insufficiency and deficiency (< 30 ng/ml)

IBD		CD	RCU
Serum vitamin D levels (mg/dl)	<20: 19	4	15
	20–29: 46	16	30
	≥ 30: 48	15	33
	Total: 113	Total: 35	Total: 78
Fecal calprotectin (mcg/g)	≤ 150: 24	9	15
	> 150: 53	13	40
	Total: 77	Total: 22	Total: 55
VitD in Fecal calprotectin > 150mcg/g:	< 30mg/dl: 37	9	28
	≥ 30mg/dl: 16	4	12
	Total: 53	Total:13	Total:40

Among the 113 patients that had vitamin D levels measured, 19 (16.80%) presented deficiency, 46 (40.70%) presented insufficiency, and 48 showed normal values. ([Table 1])

A total of 35 patients with CD had serum vitamin D levels measured, of which 20 showed vitamin D deficiency or insufficiency. In turn, of the 78 patients with UC who had their serum vitamin D levels measured, 45 presented hypovitaminosis D ([Table 1]).

Among the 113 patients, 77 had calprotectin levels measured in the same period, of which 53 presented elevated values ([Table 1]).

Among these 53 patients with elevated calprotectin, 37 presented vitamin D levels < 30 ng/dl ([Table 1]).

Among patients with vitamin D deficiency or insufficiency, one was using corticosteroids and four were using no medication (two due to a recent diagnosis and two due to clinical remission). The immunobiological treatment most used for CD was infliximab, and for UC, mesalazine ([Fig. 1]).

Fig. 1 Medication is used for the treatment of inflammatory bowel disease.

In patients with CD and UC, the independent Chi-square test (χ2 = 2.800; 1 degree of freedom; p = 0.094; Phi = 0.190) revealed no link between vitamin D and calprotectin. ([Table 2])

Table 2 Association between vitamin D and calprotectin in patients with IBD

		Calprotectin		p-valor	Phi
		≤ 150mcg/g n (%)	> 150 mcg/g n (%)
Vitamin D n (%)	< 30 mg/dl ≥ 30 mg/dl	12 (15,58) 12 (15,58)	37 (48,05) 16 (20,79)	0,094	0,19

Abbreviations: mcg/g, micrograms/gram; n (%), absolute and relative frequency.

When assessing the different IBD conditions, Fisher's exact test revealed no association between vitamin D and calprotectin (for CD 2 = 0.430; 1 degree of freedom; p = 0.662; Phi = 0.140; and for UC 2 = 2.570; 1 degree of freedom; p = 0.128; Phi = 0.220). ([Tables 3] and [4])

Table 3 Association between vitamin D and calprotectin in patients with CD

		Calprotectin		p-value	Phi
		≤ 150 mg/dl n (%)	> 150 mg/dl n (%)
Vitamin D n (%)	< 30 mg/dl ≥ 30 mg/dl	5 (22.730) 4 (18.180)	9 (40.910) 4 (18.180)	0.662	0.140

Abbreviations: CD, Crohn's disease; mg/dl, milligrams per deciliter; n (%), absolute and relative frequency.

Table 4 Association between vitamin D and calprotectin in patients with UC

		Calprotectin		p-value	Phi
		≤ 150 mg/dl n (%)	> 150 mg/dl n (%)
Vitamin D n (%)	< 30 mg/dl ≥ 30 mg/dl	7 (12.730) 8 (14.540)	28 (50.910) 12 (21.820)	0.128	0.220

Abbreviations: mg/dl, milligrams per deciliter; n (%), absolute and relative frequency; UC, ulcerative colitis.

Discussion

The present study evidenced that hypovitaminosis D is prevalent in UC and CD. Clinical trials showed a relationship between vitamin D deficiency and the genetics involved in CD development. CDs may be associated with a deficiency of calcitriol-sensitive receptors in macrophages. Most studies report vitamin D deficiency or insufficiency in patients with IBD, which is associated with long-term disease, corticosteroid use, and other factors. 5 In a cohort of patients newly diagnosed with IBD from Manitoba, Canada, only 22% had sufficient levels of vitamin D.[9]

Only four patients, who had received a long-term diagnosis and were in clinical remission, did not use medication to treat IBD. One patient was using corticosteroids during the measurement of serum vitamin D levels due to her IBD activity and recent diagnosis. Vitamin D deficiency is a frequent occurrence in recent IBD-5 diagnoses. We found the prevalence of hypovitaminosis D in patients with IBD in the present sample, regardless of the time of diagnosis.

The north-south gradient in the incidence of IBD correlates to and accompanies the exposure to ultraviolet radiation and, consequently, vitamin D levels. Currently, people living in urban areas have lower levels of vitamin D than those living in rural areas due to pollution impairment of radiation absorption or high-rise buildings' physical obstruction of sunlight. Further, the amount of time spent indoors dramatically affects vitamin D status. If vitamin D deficiency causes IBD, industrialization, urbanization, and pollution may be linked. Emerging countries show an increase in the incidence of IBD that accompanies urbanization and industrialization. 6

Vitamin D plays well-described physiological roles in balancing the gut microbiota, regulating immunity, and safeguarding the intestinal mucosal barrier. These mechanisms may underlie the inverse relationship between serum levels and disease activity. Lower vitamin D concentrations are also associated with immune-mediated diseases, indicating that vitamin D plays a critical role in modulating the immune response.[7]

Currently, ileocolonoscopy with serial biopsies is the best method to assess the inflammatory activity in IBD. However, this invasive and expensive test requires anesthesia and imposes risks, posing barriers to access in countries such as Brazil. In this reality, the biomarkers calprotectin and C-reactive protein may monitor activity and guide condition management.[11] [12]

For CD and UC, the use of fecal calprotectin as a biomarker of disease activity is well established.[11] [13] Even though 69,8% of the patients with high calprotectin values had serum vitamin D levels below the reference value in the current study, there was no statistically significant correlation between these variables.

Although vitamin D replacement in patients with IBD increases serum levels, it is not yet associated with reduced disease activity. Studies have conflicting statistics regarding inflammatory markers and serum vitamin D levels.[14] [15] [16]

A meta-analysis of CD found a significant decrease in fecal calprotectin levels in patients who received supplementation of 50,000 IU/week of vitamin D for eight weeks. A study involving patients with UC found that fecal calprotectin was higher in patients with active disease and decreased after eight weeks of vitamin D at 40,000 IU/week. In another study, 10 participants with CD and UC used vitamin D over 12 weeks, with the dose adjusted four times a week between 1,000 and 10,000 IU/dia. Two patients with CD and two patients with UC experienced a reduction of over 50%, while fecal calprotectin showed no significant changes.[15] [16] [17]

Our study had limitations, including the challenges of performing colonoscopies and the need for patient sedation. As a result, we could not compare serum vitamin D levels with intestinal mucosa healing. This comparison effectively demonstrates the connection between hypovitaminosis and disease activity. In the service, there is still no vitamin D replacement protocol for patients with deficiency, and it was not possible to correlate clinical improvement or serum levels of calprotectin with supplementation.

We have yet to determine the relationship between disease activity and vitamin D replacement. Further studies should investigate the relationship between disease activity and vitamin D replacement.

Conclusion

The current findings demonstrated a high occurrence of vitamin D deficiency or insufficiency in the group of individuals with inflammatory bowel disease (IBD), despite the climatic conditions of the study region, which would be a protective factor for the development of hypovitaminosis D for the general population. It has reproducibility, strengthening its external validity by evaluating the generalizability of findings under different conditions, as there is a prevalence of hypovitaminosis D in individuals with inflammatory bowel disease, in the same way as there is in research performed in countries with low incidence of sunlight and high prevalence of hypovitaminosis D and IBD.

Genetic factors and lifestyle changes in the development of hypovitaminosis D and IBD may be involved in the genesis of these problems, despite the environmental factor.

This study did not find any correlation between elevated calprotectin levels and insufficient or deficient levels of vitamin D.

Conflict of Interest

None.

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Publication History

Received: 02 August 2024

Accepted: 21 January 2025

Article published online:
26 March 2025