Download Turnbull and Drobniewski 2015 Vitamin D- A

Vitamin D Supplementation: A Comprehensive Review On Supplementation For
Tuberculosis Prophylaxis
Turnbull ER, Drobniewski FA
Abstract
Vitamin D plays a large role in the inmate immune response against Mycobacterium
tuberculosis (MTB) infection, activation and progression. Likewise, vitamin D deficiency
is shown by evidence presented here, to be a known risk factor for developing both MTB
infection and active tuberculosis (TB). This comprehensive review discusses the
evidence and remaining questions regarding vitamin D supplementation as a
prophylactic measure in those who are at high risk of MTB infection and active TB.
Vitamin D supplementation is routinely prescribed for osteoporosis prevention yet
guidelines are lacking for its prescription for TB prevention. Concerns have been raised
over a recommended dosage yet adverse effects appear to be rare even at high loading
doses. Policy makers are urged here to review the literature and provide urgent
guidelines on vitamin D as a prophylaxis for tuberculosis.
Acquisition, Synthesis and Role of Vitamin D
Humans acquire Vitamin D in two different forms: Vitamin D2 (ergocalciferol), through
the diet; and Vitamin D3 (cholecalciferol) which is synthesized in the body by the
cleaving and isomerization of 7-dehydrocholesterol, following epidermal exposure to
ultraviolet B rays or alternatively obtained from the diet. These two inactive vitamins
are hydroxylated, first in the liver via 25-hydroxylase to 25-hydroxyvitamin D
(25(OH)D), then secondly in the kidneys via 1α hydroxylase to the active form:
1,25(OH2)D (Calcitriol). Vitamin D metabolites are largely taken up and transported by
Vitamin D binding proteins (DBPs), yet in its free form, Calcitriol, (classified as a steroid
hormone) acts on intracellular vitamin D receptors (VDRs) to initiate intracellular
signalling and influence gene transcription [1]. Importantly, VDRs are expressed on
helper T (Th) immune cells: Th1 and Th2. Th1 cells are generally thought to be involved
in cell-mediated immunity and autoimmune reactions but these cells also enhance
innate immune responses; cytokines, such as interferon ϒ (IFN- ϒ) and interleukin-2 (IL2), are secreted by Th1 cells in response to pathogens and can induce bacterial killing
through various mechanisms [2, 3]. Th2 cells respond to extracellular pathogens, such
as bacteria, by initiating an antibody-mediated response via IL-4 and IL-5 [2, 4]. A
sufficient physiological level of vitamin D, through VDR activation, thus enhances innate
immunity through both Th1 and Th2 responses[5], as described further in the following
section.
Calcitriol also functions non-genomically, to regulate phosphate and calcium
concentrations and maintain bone health. Hydroxylation of vitamin D into its active
form is dependent on 1α hydroxylase, which is self regulated by a negative feedback
loop involving phosphate and parathyroid hormones, initiating its own metabolism [1].
The Role of Vitamin D in Tuberculosis
Vitamin D plays a large role in the inmate immune response against Mycobacterium
tuberculosis (MTB) infection, activation and progression [2, 5, 6]. MTB entry to the body
is mediated by macrophage Toll like receptors which upregulate VDRs and increase 1α
hydroxylase (CYP27B1), a mediator of Vitamin D activation to calcitriol [7]. Calcitriol
activation of VDRs induces cathelicidin antimicrobial peptide (CAMP) gene expression
and subsequently production of cathelicidin[8]. This important antimicrobial peptide,
cathelicidin, disrupts the bacterial cell membrane [9] and induces autophagy in
monocytes creating an antimicrobial effect [10-12]. Acquired immune activity also relies
on Vitamin D; in response to MTB infection, T cells will secrete IFN- ϒ, which when in
conjunction with Vitamin D sufficiency, provokes antimicrobial peptide expression [13],
autophagy, phagosomal maturation and antimicrobial action. However studies have
shown that these actions do not occur when patients are vitamin D deficient [3].
Studies have shown that vitamin D deficiency is a risk factor for developing both MTB
infection and active tuberculosis (TB), for delaying bacterial clearance and for poorer
treatment outcomes, showing its role in both prevention and treatment of MTB [14-16].
This paper will focus specifically on the evidence surrounding vitamin D
supplementation as prophylaxis for developing active TB in those who are considered to
be high risk, namely considered to be those with HIV infection or contacts of those with
active TB.
Evidence Suggesting Benefits Of Vitamin D Supplementation
Multiple studies have looked at the effect of vitamin D supplementation as an adjunct to
anti tuberculosis treatment [17-22]. Few however have examined the benefits of
supplementation for prophylaxis purposes, though consistent evidence shows that low
vitamin D levels are a risk factor for developing active TB. In Pakistan, vitamin D
deficiency (defined as <20ng/ml) in household contacts of tuberculosis (TB) patients led
to five times the adjusted risk for progression to active TB [23]. In a retrospective
London study, 46% of paediatric patients with active TB were vitamin D deficient
(<20ng/ml)[24]. A case-control study in Greenland, with 72 matched pairs, found that
those with low vitamin D concentrations (<30ng/ml) had significantly higher risks of
active TB [25]. A systemic review and meta-analysis of 531 participants from 7 studies,
where vitamin D levels were taken in those presenting with untreated active TB, found
that compared to matched controls TB patients had significantly lower vitamin D levels
[26]. Most importantly, from the perspective of supplementation, an Australian study
found that higher serum vitamin D levels were significantly associated with a lower
probability of both MTB infection and of active TB [27], favouring the idea of
supplementation in deficient patients.
To our knowledge no prospective randomised controlled trial (RCT) has been
completed to assess whether supplementation would decrease the risk of developing
active TB in those who are at high risk [28], perhaps due to a lack of funding
opportunities for this research area [29]. One RCT has however proposed to give at-risk
Mongolian school children 28000 IU vitamin D3 bi-weekly as a prophylactic measure to
reduce both MTB infection and active TB disease, though this has not yet started
recruitment [30].
The same research group recently published results regarding supplementation to
prevent MTB infection. 120 Mongolian schoolchildren considered to be at high risk of
MTB infection received 800 IU of vitamin D/day for 6 months. Although not statistically
significant due to the small sample size, those receiving supplementation had 59%
greater reduction in tuberculin skin test (TST) conversion, a marker of MTB infection.
Interestingly, 60% of the children’s vitamin D levels remained <20 ng/mL after 6
months, and only one TST conversion (out of 16) occurred in a child with a level > 20
ng/mL [28], indicating a protective effect of higher vitamin D levels. This is
substantiated by a Spanish study where sufficient serum levels of vitamin D (>30ng/ml)
were thought to be protective again tuberculin skin test (TST) conversion in TB
contacts, since mean vitamin D levels was significantly lower in those with TST
conversion compared to controls [31].
An in vitro study has shown that in healthy TB contacts, 2.5mg supplementation of
vitamin D enhanced the immunity, largely innate immunity, against MTB infection[32].
In keeping with this a Canadian study that showed increased macrophage response to
MTB infection post vitamin D supplementation [33].
Remaining Questions Regarding Vitamin D Supplementation
Vitamin D levels in the body are generally determined by proxy by measuring serum 25hydroxyvitamin D (25(OH)D), a prehormone which requires activation by 1α
hydroxylase to form the active metabolite, calcitriol. Classification of vitamin D
deficiency or insufficiency varies widely. The Institute of Medicine states that a 25(OH)D
level of 20ng/ml is sufficient for 97.5% of the population [34], whilst some studies
define those with 25(OH)D <30ng/ml as having mild deficiency or as being vitamin D
insufficient [6, 25], and others report <25ng/ml as being a moderate to severe
deficiency[27]. Having no internationally agreed and standardised definitions for
immunodeficiency complicates studies on implementation of supplementation.
Vitamin D3 is generally the first choice for supplementation [35], though Vitamin D2
has also been used [32]. Vitamin D binding protein (DBP) uptake of Vitamin D3 is
superior to that of Vitamin D2, meaning clearance is slower, and higher concentrations
can be achieved over longer periods of time [18]. However these are both inactive
supplements that require renal and hepatic hydroxylation, and sufficient enzymatic
capacity (e.g. such as 1α hydroxylase,) before an active metabolite is produced.
Supplements may therefore have lower efficacy in those with impaired renal or hepatic
functioning. Over active negative feedback loops, regulating vitamin D availability, may
also be triggered by a high dose of vitamin D, increasing parathyroid hormone, limiting
1α hydroxylase and thus reducing activation of the vitamin D supplement. In these
situations calcitriol, the active metabolite could perhaps be prescribed as a supplement
instead, since it is currently used as an oral preparation to treat deficiency in dialysis
patients [36].
Various genetic polymorphs associated with different populations may mean that
different levels of supplementation are required. For example, the extent of vitamin D
uptake by DBPs, and ultimately its activity, has been shown to differ amongst different
DBP genotypes, with low levels of circulating DBPs increasing Vitamin D activity [1].
Patients with various polymorphisms in the vitamin D receptor (VDR) gene, particularly
TaqI and FokI polymorphisms, have an increased risk of developing TB [37, 38] and
benefit from vitamin D supplementation as an adjunct to their TB treatment [17],
indicating that these patients may also benefit from prophylactic supplementation.
Side Effects Of Supplementation
The potential side effects of vitamin D supplementation include hypercalcemia,
hypercalciuria and potential for nephrocalcinosis in patients with renal failure [39],
indeed one case report details a patient who developed severe hypercalcemia following
daily supplementation with 5500 IU of cholecalciferol (giving rise to 25(OH)D levels of
103ng/ml) alongside 2020 mg of calcium, which likely provided an additive detrimental
effect [40]. A systematic review of supplementation RCTs however found very few
serious adverse effects [35]. One RCT with 365 adult TB patients reported no serious
adverse events after supplementation with 100,000 IU of cholecalciferol at baseline, 5
and 8 months [18]. A further double-blinded RCT with 192 healthy adults found no
hypercalcemia following administration of 2.5 mg of vitamin D in a single dose [32].
Lastly an evidence review advised that 800 IU (20 μg) daily was a safe dosage, without
side effects, for elderly people and others at risk [41]; this same dosage has also been
used in children over a six month period with no reported serious adverse events [28].
Who Would Benefit Most From Supplementation? A Public Health Perspective
From a public health perspective vitamin D assessment and supplementation for active
TB prophylaxis where necessary should be given to those most at risk of developing
active TB, primarily those with known HIV infection and those who are TB contacts. The
questions raised above however highlight that individual patients may require differing
doses of vitamin D supplementation in order to reach sufficient prophylactic levels.
Current best practice would suggest the need for baseline testing for a patient’s vitamin
D levels and then regular monitoring to assess supplementation response. Patients
might also need investigation for the underlying cause of deficiency and/or regular
vitamin D monitoring post supplementation to ensure deficiency has not reoccurred.
This is potentially time and cost intensive. Daily-recommended intakes for vitamin D
supplementation are required that could on balance ensure major deficiencies were
corrected for within a more normal range. Data from supplementation trials can be
used in an iterative process to answer questions of dose/frequency of supplementation
in different environmental areas (high/low sun), the most appropriate supplements and
the real importance of different patient phenotypes.
Conclusions
In summary, there is extensive evidence to suggest that low vitamin D levels are
associated with a higher risk of developing both MTB infection and active tuberculosis.
It is however less clear whether those with marginally low levels are at any
meaningfully greater risk. It seems apparent that raising vitamin D levels in the
population would reduce tuberculosis incidence in those at high risk. Vitamin D
supplementation has long been used for prevention of osteoporosis, but policy
development for TB prevention seems to have fallen be the wayside. Concerns have
been raised over a recommended dosage yet adverse effects appear to be rare even at
high loading doses. Policy makers are urged to review the literature and provide urgent
guidelines on vitamin D as a prophylaxis for tuberculosis.
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