Review Article: Vitamin D and Inflammatory Bowel Disease

Established Concepts and Future Directions

M. Garg; J. S. Lubel; M. P. Sparrow; S. G. Holt; P. R. Gibson

Disclosures

Aliment Pharmacol Ther. 2012;36(4):324-344. 

In This Article

Clinical Considerations for Vitamin D Therapy

The optimal management of vitamin D status, along with its reported clinical effects, is perhaps one of the more vigorously debated and controversial areas in medicine today. To develop recommendations for therapeutic targets and means of optimisation, determinants of vitamin D status, evidence for current therapies and effectiveness of intervention, and toxicity need to be considered (Table 3), while allowing for evolutionary and physiological principles for the pleiotropic involvement of the vitamin D axis.

Determinants of Vitamin D Status: Genetic and Environmental

As outlined previously, 25(OH)D is considered the best measure of vitamin D status as it is the main storage and circulating form of vitamin D. 25(OH)D levels are determined by numerous variables (Table 2), both genetic and environmental, which have the potential to confound epidemiological observational studies. The total variation explained by genetic factors is less than that due to environmental factors.[202] Moreover, despite consideration of all of these factors, much of the variation in 25(OH)D levels in the general population remains unexplained.[5]

Vitamin D Deficiency, Insufficiency, Sufficiency, Toxicity and Supplementation

Current definitions of vitamin D deficiency, insufficiency and optimal levels are based largely on observations of PTH levels and bone health, but universal consensus remains elusive. The commonly quoted definition of vitamin D deficiency is a 25(OH)D level less than 25 nmol/L (10 ng/mL), the level that places an individual at highest risk for development of osteomalacia.[203] However, the Endocrine Society has recently published a less conservative level of less than 50 nmol/L (20 ng/mL) as vitamin D deficiency.[4] Vitamin D sufficiency is commonly quoted as 75 nmol/L or more, based on suppression of PTH and lack of pathological osteoid accumulation in bone.[66,68] However, many experts classify vitamin D sufficiency as 50 nmol/L or more.[203] The intermediate value, which variably becomes 25–50 nmol/L (or 25–75 nmol/L) in most cases, is referred to as vitamin D insufficiency.

Excess 25(OH)D levels may result in vitamin D toxicity, or hypervitaminosis D. The most easily recognisable manifestation of vitamin D toxicity is hypercalcaemia. However, there have been very few reports in the literature of hypercalcaemia from vitamin D ingestion only, with most occurring secondary to accidental overdose of very large quantities of vitamin D. The 25(OH)D level accounting for hypercalcaemia reported in these cases has varied from 320 to 1692 nmol/L, far in excess of levels noted in the population.[197] Such levels require the intake of oral supplementation of greater than 10 000–40 000 IU per day of vitamin D over prolonged periods.[197] There have been no reports of toxicity from UVB exposure alone.[197]

However, whether long-term exposure of lower doses of vitamin D may increase the risk of hypercalciuria and renal stones, nephrocalcinosis and potentially vascular calcification is uncertain and not adequately assessed in most short-term human trials to date.[197] Supporting these potential adverse effects is modelling from several observational and interventional trials demonstrating a 'reverse J' relationship between serum 25(OH)D levels and all-cause mortality.[197] An increase in mortality is seen with 25(OH)D levels below 50 nmol/L, a reduction between 50 and 75 nmol/L, and a slight upstroke in mortality at levels above 75–80 nmol/L.[197,204,205] For this reason, the Institute of Medicine of the National Academies recommend a relatively conservative dietary allowance of vitamin D for the general population of 600 IU/day and tolerable upper limit of 4000 IU/day in all adults and children aged above 8 years of age.[197] This upper limit, however, does not apply to patients already deficient in vitamin D or those with increased requirements due to malabsorption. In contrast, the Endocrine Society recommends a daily intake of 1500–2000 IU/day for adults with an upper limit of 10 000 IU/day.[4]

It is unknown what level of 25(OH)D is required for optimisation of potential immunomodulatory effects of vitamin D in vivo in humans. Some authorities believe that a 25(OH)D level of over 75 nmol/L is required, extrapolating from anti-TB studies,[206] but no solid evidence in autoimmune disease is present.

Just as variation in levels of 25(OH)D exist in the general population, so does the response to supplementation of vitamin D. Trials for fracture prevention noted a variable increase in mean 25(OH)D levels with 400 IU cholecalciferol administration; an increment from 47 to 64 nmol/L over 12 months in one trial of 1144 nursing home participants,[62] but only 37–47 nmol/L over 24 months in another trial of 7073 community dwelling participants.[207] Five-month administration of 0, 1000 IU, 5000 IU and 10 000 IU cholecalciferol in 67 healthy males with mean baseline 25(OH)D of about 70 nmol/L[208] demonstrated a dose response relationship, with significant increases obtained only by the higher two doses. Furthermore, the trajectory of rise in 25(OH)D plateaued in all groups, and no toxicity was noted in any patients. Mathematical calculation by this and other groups have noted an approximate increase in 25(OH)D level of 0.57–1.9 nmol/L/μg cholecalciferol administered daily.[208] Obesity, in increasing the pool of storage of 25(OH)D, limits the response to oral vitamin D, such that about twice the dose of vitamin D is required to obtain the same increase in serum 25(OH)D.[4] Furthermore, anticonvulsants increase catabolism of 25(OH)D, so patients on these therapies require additional dosing.[4]

Patients with CD may have an attenuated response to vitamin D therapy.[209] In a study of 37 patients with CD and 10 healthy controls, the increment in serum 25(OH)D2 (not total 25(OH)D) was 30% less in the CD patients 12 h after an oral dose of 50 000 IU ergocalciferol.

It is as yet unclear if daily dosing of vitamin D is equivalent to intermittent administration of high-dose vitamin D, with the latter formulation designed for rapid repletion. A comparison of 400 IU twice daily (800 IU/day) or 97 333 IU of cholecalciferol every 4 months (total dose 292 000 IU in both groups) in 40 elderly women found a higher proportion of the daily dosing group (47%) achieved a 25(OH)D level of 75 nmol/L compared with 28% in the intermittent high-dose group after 12 months.[210] In a separate trial, no difference in target levels were found between the administration of 50 000 IU daily for 10 days (total dose 500 000 IU) or 3000 IU daily for 30 days followed by 1000 IU daily for 60 days (total dose 150 000 IU) at 3 months in 26 vitamin D deficient patients.[211] Single large doses of oral and intramuscular cholecalciferol (300 000 to 600 000 IU) have been described as being safe and effective, but transient hypercalciuria needs to be monitored.[212,213] Intermittent large dosing may improve adherence outside the trial setting, so may be a reasonable alternative to daily dosing where this is a concern.

Some authors believe that cholecalciferol (VD3) supplementation, the naturally occurring form in humans, is more effective than ergocalciferol (VD2) for attainment of target 25(OH)D levels and skeletal protection.[11] Studies assessing this have been conflicting to date.[214–216] However, cholecalciferol has in recent years become more widely produced and available as commercial supplements worldwide, and supply of ergocalciferol has declined.

There is little evidence upon which a therapeutic plan can be based. However, a suggested approach to vitamin D supplementation in patients with IBD is illustrated in Figure 3.

Figure 3.

Suggested algorithm for vitamin D supplementation in IBD. There is a wide inter-individual variation in response to vitamin D supplementation and adjustment according to level achieved is often required. The target 25(OH) D level is based on current limited data and may evolve as more clinical evidence is obtained.

Activated vitamin D3 (1,25 (OH)2 D3) is not recommended for supplementation outside the chronic kidney disease setting, as this metabolite is not available for intracrine or paracrine actions, and may enhance vascular calcification and hypercalcaemia.

In an attempt to increase specificity for vitamin D therapy for the parathyroid gland and reduce PTH without inducing hypercalcaemia, and hence to reduce morbidity associated with vascular calcification in chronic kidney disease, vitamin D receptor agonists have been developed. To date, the oral compounds apart from calcitriol to have been licenced and studied include paricalcitol, maxacalcitol (22-oxacalcitriol), which directly activate VDR, and doxercalciferol, and alfacalcidol (1α(OH)D), which require 25-hyroxylation to become active.[81] Whether these agents are able to be applied outside chronic kidney disease, with sufficient tissue activity in immune cells for instance, is unknown. Given that many of these cells express 1α-hydroxylase, the supply of 25(OH)D may be just as important or potent as direct activation by VDR agonists. Interestingly, a topical agent, calcipotriol, alone and in combination with betamethasone, is under clinical use for psoriasis, another Th1-mediated disease.[217] A more detailed discussion of VDR agonists is beyond the scope of this review and is presented elsewhere.[81,218]

Vitamin D Assays

A complicating factor in the study of vitamin D and its effects has been variability in accuracy and precision of assays for 25(OH)D. Currently, liquid chromatography-mass spectrometry (LC-MS) and high performance liquid chromatography (HPLC) assays are considered the most accurate and are increasingly available in laboratories worldwide.[197,219] However, most literature in the past 20 years has quoted chemiluminescent assays or radioimmunoassays (still the most readily available), which are subject to more errors in observation and interpretation more than LC-MS and HPLC.[197,220] To optimise assays, a Vitamin D External Quality Assurance Scheme (DEQAS), which monitors the performance of 25(OH)D assays of more than 700 laboratories worldwide on a quarterly basis, has been established.[197] This scheme uses the 'all laboratory trimmed mean' as the gold standard for assessing these assays.

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