Review Article

Vitamin D and Inflammatory Bowel Diseases

V. P. Mouli; A. N. Ananthakrishnan

Aliment Pharmacol Ther. 2014;39(2):125-136.

Abstract and Introduction

Abstract

Background Vitamin D is traditionally associated with bone metabolism. The immunological effects of vitamin D have increasingly come into focus.

Aim To review the evidence supporting a role of vitamin D in inflammatory bowel diseases.

Methods A comprehensive search was performed on PubMed using the terms 'crohn's disease' 'ulcerative colitis' and 'vitamin D'.

Results Vitamin D deficiency is common in patients with inflammatory bowel diseases (IBD) (16–95%) including those with recently diagnosed disease. Evidence supports immunological role of vitamin D in IBD. In animal models, deficiency of vitamin D increases susceptibility to dextran sodium sulphate colitis, while 1,25(OH)₂D₃ ameliorates such colitis. One prospective cohort study found low predicted vitamin D levels to be associated with an increased risk of Crohn's disease (CD). Limited data also suggest an association between low vitamin D levels and increased disease activity, particularly in CD. In a large cohort, vitamin D deficiency (<20 ng/mL) was associated with increased risk of surgery (OR 1.8, 95% CI 1.2–2.5) in CD and hospitalisations in both CD (OR 2.1, 95% CI 1.6–2.7) and UC (OR 2.3, 95% CI 1.7–3.1). A single randomised controlled trial demonstrated that vitamin D supplementation may be associated with reduced frequency of relapses in patients with CD compared with placebo (13% vs. 29%, P = 0.06).

Conclusions There is growing epidemiological evidence to suggest a role for vitamin D deficiency in the development of IBD and also its influence on disease severity. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation.

Introduction

Ulcerative colitis (UC) and Crohn's disease (CD) constitute chronic idiopathic inflammatory bowel diseases (IBD). The key underlying pathogenic mechanisms for both diseases is a dysregulated host immune response to commensal intestinal flora in genetically susceptible individuals.^[1,2] Known genetic variants incompletely explain the variance in disease incidence, suggesting a strong role for environmental factors, supported by epidemiological evidence.^[3,4]

Vitamin D has long been recognised as a major regulator of calcium and phosphorus metabolism and key in maintaining bone health.^[5–7] However, several recent studies have yielded new insights into the role of vitamin D in various other physiological processes. In particular, vitamin D appears to play important roles in immune regulation, particularly involving the innate immune system, cardiovascular and renal physiology, and development of cancer.^[6] Importantly, an increasing body of literature supports an important role of vitamin D in the pathogenesis as well as potential therapy of IBD.^[8–13] The current review examines the evidence linking vitamin D to IBD, both through its effect on bone health and association with pathogenesis and natural history of these diseases.

1 2 3 4

Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Prevalence of vitamin D deficiency in unselected cohorts of patients with inflammatory bowel diseases
Author	Year	Cohort size	Vitamin D status
Driscoll⁸⁴	1982	82 CD	65% of patients had low serum 25(OH)D 25% had levels below 10 ng/mL
Jahnsen⁴⁴	2002	60 CD 60 UC	27% of CD patients had 25(OH)D levels <30 nmol/L 15% of UC patients had 25(OH)D levels <30 nmol/L
Lamb⁸⁵	2002	23 UC 11 CD 18 IBS controls	Mean 25(OH)D was lower in IBD patients (18.7 mcg/L) compared with controls (28.5 mcg/L) (P < 0.05)
Sentongo²⁷	2002	112 CD*	16% of CD patients had vitamin D < 38 nmol/L
Siffledeen⁸⁶	2003	242 CD	22% had 25(OH)D levels <40 nmol/L 8% had 25(OH)D levels <25 nmol/L
Tajika²⁵	2004	33 CD 15 controls	27% of CD patients were deficient (25(OH)D < 10 ng/mL) compared to 7% of controls
McCarthy²²	2005	44 CD	During late-summer, 5% of controls and 18% of CD patients were deficient (<50 nmol/L) During late-winter, 25% of controls and 50% of CD patients were deficient
Gilman²¹	2006	58 CD	50% were vitamin D deficient during winter (<50 nmol/L) and 19% were deficient during summer
Pappa⁸⁷	2006	94 CD* 36 UC*	Prevalence of vitamin D deficiency (25(OH)D < 15 ng/mL) was 35%
Leslie²⁰	2008	56 CD 45 UC	88% had serum 25(OH)D levels below 75 nmol/L
Kuwabara⁸⁸	2009	29 CD 41 UC	Mean 25(OH) levels were lower in CD patients (11 ng/mL) compared with those with UC (20 ng/mL) (P < 0.001)
Joseph⁸⁹	2009	34 CD 34 controls	25(OH)D levels were lower in CD patients (16 ng/mL) compared with controls (23 ng/mL)
Ulitsky¹⁹	2011	403 CD101 UC	50% of patients had 25(OH)D < 30 ng/dL, 11% had levels below 10 ng/dL
Pappa⁹⁰	2011	288 CD* 143 UC* 17 IC*	Vitamin D insufficiency (<20 ng/mL) was seen in 31% of patients with CD and 28% of UC patients
Levin¹⁷	2011	70 CD 5 UC 3 IBDU	19% of patients were deficient in vitamin D (<51 nmol/L)
Atia⁹¹	2011	125 IBD	37% had vitamin D deficiency
Suibhne⁹²	2012	81 CD	63% of patients with CD were deficient (<50 nmol/L)
Fu⁹³	2012	60 UC 40 CD	39% of the entire cohort had low vitamin D (<50 nmol/L); this was more frequent in 43% of CD and 37% of UC patients
Laakso⁹⁴	2012	49 UC 28 CD	30% of patients with CD had levels below 37.5 nmol/L compared to 37% of controls
Hassan⁹⁵	2013	60 IBD	95% of patients had deficient vitamin D levels (25(OH)D < 30 ng/mL)
Ananthakrishnan¹³	2013	1763 CD 1454 UC	28% had insufficient (20–30 ng/mL) and 32% had deficient (<20 ng/mL) levels
Alkhouri¹⁸	2013	61 IBD*	62% of patients had low vitamin D levels compared to 75% of controls

IBD, inflammatory bowel diseases; CD, Crohn's disease; UC, ulcerative colitis, IC, indeterminate colitis.
*Paediatric cohorts.

Table 2. Observational studies of the association between vitamin D levels and outcomes in Crohn's disease and ulcerative colitis
Author	Year	Study design	Number of patients	Predictor variable	Outcome	Result
Joseph⁸⁹	2009	Cross-sectional	34 CD	Serum 25(OH)D	HBI	Serum 25(OH)D negatively correlated with disease activity (correlation co-efficient −0.484)
El-Matary⁷⁶	2011	Cross-sectional	60 IBD (39 CD, 21 UC)	Serum 25(OH)D	PCDAI or PUCAI	Vitamin D levels were not associated with disease activity
Ulitsky¹⁹	2011	Retrospective	504 IBD (403 CD, 101 UC)	Serum 25(OH)D	HBI or SCCAI Health-related quality of life	Vitamin D deficiency was associated with lower HRQoL (−2.2, 95% CI −4.1 to −0.3) and increased disease activity (1.1, 95% CI 0.4–1.7) in CD, but not in UC
Ananthakrishnan¹³	2013	Prospective	3217 IBD (1763 CD, 1454 UC)	Serum 25(OH)D	IBD-related surgery IBD-related hospitalisations	Vitamin D deficiency (<20 ng/mL) was associated with increased risk of surgery (OR 1.8, 95% CI 1.2–2.5) in CD and hospitalisations in both CD (OR 2.1, 95% CI 1.6–2.7) and UC (OR 2.3, 95% CI 1.7–3.1)
Zator⁷⁹	2013	Retrospective	101 IBD (74 CD, 27 UC) patients initiating anti-TNF therapy	Serum 25(OH)D within 3 months of anti-TNF initiation	Cessation of anti-TNF therapy	Patients with low vitamin D had an increased risk of early cessation of anti-TNF therapy (HR 2.1, 95% CI 1.0–4.4)

CD, Crohn's disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; HBI, Harvey Bradshaw index; PCDAI, Paediatric Crohn's disease activity index; PUCAI, paediatric ulcerative colitis activity index; SCCAI, simple clinical colitis activity index.

Table 3. Interventional studies examining the effect of vitamin D supplementation on disease activity in Crohn's disease and ulcerative colitis
Author	Year	Study design	Number of patients	Intervention	Outcome	Result
Miheller⁸⁰	2009	Open label	37 patients with inactive CD	Daily 0.5 mcg of alfacalcidiol or 1000 IU of cholecalciferol	CDAI	Mean CDAI decreased from 69 to 57 in patients treated with alfacalcidiol
Jorgensen¹²	2010	Randomised placebo-controlled trial	104 CD patients in clinical remission	Oral vitamin D3 1200 IU daily or placebo	Relapse	Relapse rate was lower in patients treated with vitamin D3 (13%) compared to placebo (29%) (P = 0.06)
Yang⁸¹	2013	Open label	18 patients with mild-to-moderate CD	Vitamin D3 at 1000 IU daily; dose increase after 2 weeks to achieved serum 25(OH)D of 40 ng/mL	CDAI Quality of life	Vitamin D supplementation reduced CDAI scores from 230 to 118 (P < 0.0001), and improved health-related quality of life

CD, Crohn's disease; CDAI, Crohn's disease activity index.

Table 4. Unanswered clinical questions regarding the role of vitamin D in inflammatory bowel diseases
1. Does low serum vitamin D cause Crohn's disease or ulcerative colitis, or is it a marker for other risk factors?
2. Can supplementation with vitamin D in high-risk individuals prevent or delay the onset of Crohn's disease or ulcerative colitis?
3. Does vitamin D deficiency cause a more severe phenotype or increased inflammatory activity in Crohn's disease, or is it merely a consequence of severity of disease? Is vitamin D status predictive of recurrence of Crohn's disease post-operatively?
4. What is the optimal role of vitamin D supplementation as a therapeutic modality in patients with IBD? Induction of remission? Maintenance of remission and prevention of relapse? Prevention of post-operative recurrence?
5. What is the optimal serum 25(OH)D level for its effect on inflammation in patients with IBD?
6. What is the optimal dose and modality for treatment of vitamin D deficiency in IBD patients?
7. Can vitamin D supplementation reduce risk of colorectal cancer in IBD?

processing....

Vitamin D and Inflammatory Bowel Diseases

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Email This

Feedback