EDITORIAL
Clin. Invest. (2011) 1(5), 615–618
“In future, public health policy aimed
at the prevention of TB should stress
the need for adequate dietary intake of
vitamin D in all vulnerable groups
including immigrants...”
1
Specialist Registrar, Liverpool Heart & Chest
Hospital NHS Foundation Trust, Liverpool, UK
2
Regional Tuberculosis Centre, Liverpool Heart
& Chest Hospital NHS Foundation Trust,
Thomas Drive, Liverpool L14 3PE, UK
†
Author for correspondence:
Tel.: +44 151 228 1616
E-mail: p.d.o.davies@liv.ac.uk
ISSN 2041-6792
Vitamin D as an adjuvant
therapy for tuberculosis:
pharmacogenomic implications
Dilip Nazareth1 & Peter Davies†2
It is estimated that in the UK alone, tuberculosis (TB) or phthisis (Greek) affects
approximately 9000 people every year and the WHO reports that worldwide, there
were 9.4 million incidents of TB in 2008. Over the last 10 years, there have been
new threats from MDR-TB and XDR-TB and there has been a renewed interest in
vitamin D, its deficiency and its association with TB.
Tuberculosis was the biggest killer during the Victorian era with at least one in
every four deaths being attributed to ‘consumption’. Poor living conditions, harsh
weather and the lack of sunlight, in addition to industrialization, contributed to the
spread of TB. Prior to the introduction of chemotherapy, milk, meat and eggs were
recommended for the treatment of TB. Subsequently the administration of cod liver
oil, rich in vitamin D, was used [1] , as the fatty acids in cod liver oil were found to
inhibit the growth of the tubercle bacilli. At the beginning of the 20th century TB
was the biggest health problem in the UK. Sir Robert Philip (b.1857), set up two
small rooms in Edinburgh, probably the first TB clinic and concentrated his efforts on
contact tracing, educating people about containing the spread of disease and ­making
TB a notifiable disease.
In the late 1800’s, sanatoriums were developed to ensure containment of disease,
with plenty of fresh air and nutrition, as were the introduction of solariums, to provide
light. The sanatorium method of treatment became popular in continental Europe and
America, as it provided isolation of infected individuals, thereby making it ­possible
to control the spread of disease and provided patients with regulated hospital care.
Vitamin D is synthesized in the skin through a photosynthetic reaction triggered by
exposure to UV radiation. This photosynthesis produces vitamin D3, which undergoes
further transformations, with the production of 25-hydroxyvitamin D (25[OH D),
the major form of vitamin D circulating in the bloodstream, which is measured to
determine a person’s vitamin D levels. By the late 1800s, approximately 90% of all
children living in Europe and North America had some manifestation of rickets
secondary to vitamin D deficiency. The medical fraternity throughout Europe and
America began promoting whole-body sunbathing to help prevent rickets. Around
this same time, TB was also found to respond to sunlight and in 1903, the Danish
physician, Niels Finsen was awarded the Nobel Prize in Medicine and Physiology for
his successful treatment of lupus vulgaris with phototherapy.
Epidemiological link between TB & vitamin D deficiency
Vitamin D in high doses was used to treat TB prior to the availability of anti­
biotics and subsequently moved to the back burner. In 1961, it was observed that
Pakistani immigrants in Glasgow had widespread rickets and osteomalacia secondary
Keywords: genetic subgroups • immigrants • screening • supplementation • vitamin D
10.4155/CLI.11.35 © 2011 Future Science Ltd 615
EDITORIAL   Nazareth & Davies
to vitamin D deficiency that was not related to dietary
deficiency and it was suggested that advice on the proph-
ylaxis of vitamin D deficiency should be given to all
Pakistanis and Indians in the UK [2] . There is growing
evidence that vitamin D and mycobacterial infection
are closely linked and that patients with TB have lower
levels of vitamin D than those without [3] .
Immigrants in London, from the Indian subconti-
nent, on a purely vegetarian diet were found to have
an 8.5-fold increased risk of TB, compared with those
who ate meat and fish daily. This increased risk is pos-
tulated to have been caused by deficiencies in possibly
iron, ­vitamin B12 or vitamin D [4] .
There is evidence of an inverse relationship between
serum vitamin D levels and the likelihood of both hav-
ing any mycobacterial TB infection and the likelihood of
having TB/past TB rather than latent TB infection [5] , a
concept first suggested by the corresponding author, over
25 years ago, by demonstrating lower levels of vitamin D
in patients with TB when compared with matched con-
trols [6] . A case–control study by Wilkinson in Gujurati
Indians residing in northwest London, demonstrated that
vitamin D deficiency was significantly associated with
active TB disease and those with undetectable serum
vitamin D levels, carried the greatest risk of TB [7] . Racial
differences in the pathogenesis of TB have been suggested
to be due to a decline in vitamin D levels, that may cor-
relate with a decline in cell-mediated immunity, in a
person infected with the tuberculosis bacillus, resulting
in marked differences in rates of TB infection between
black and white patients, one study reporting rates among
racial/ethnic minorities were five- to ten-times higher
than those in white patients [8] . It is postulated, that a
decrease in the exposure to sunlight when a person moves
from a country with plentiful sunlight to one with less
sunlight with a decline in vitamin D [9] , may have an
important role to play and is supported by the pattern of
increased rates of TB during the winter season [10] .
Disappointing trials of therapy
There have been no randomized control trials looking
at the supplementation of vitamin D in the prevention
of TB. Martineau et al. demonstrated that a single dose
of vitamin  D enhanced the ability of an individual
who had contact with TB to restrict mycobacterial bio­
luminescence at 24 h post-inoculation ex vivo [11] . In a
randomized study of 365 adults in Guinea-Bissau after
the administration of three doses (at initiation of treat-
ment, months 5 and 8) no effect was seen on the primary
outcome (a specially developed TB score) [12] .
Another trial has shown that adding vitamin D to the
treatment of TB makes no difference to the outcome [13] .
Moreover, a recent multicenter randomized controlled
trial has shown that the administration of four doses of
616 www.future-science.com
2.5 mg vitamin D3 in patients receiving intensive-phase
treatment for smear positive pulmonary TB, did not sig-
nificantly affect time to sputum culture conversion in the
study population [14] .
These differences in outcomes could be due to a vari-
ety of factors, explained well by Awumey and colleagues,
that the intrinsic hydroxylase activity in some Asians
may be higher compared with non-Asian controls and
the possible effect of rifampicin and isoniazid on vita-
min D metabolism, exacerbating the above effect [15] . In
addition, there is the possibility of a paradoxical reaction,
in which more severe disease leads to the paradoxical
depletion of vitamin D metabolism during treatment.
“...with an increasing incidence of MDR-
and XDR-TB, its associated mortality and the
decreased effectiveness of routine anti-TB drugs,
where does treatment with vitamin D
find a place?”
The current drugs in TB treatment are so powerful,
that vitamin D supplementation can add very little.
That brings us to resistance patterns in TB. MDR-TB
is caused by resistance to the two most powerful first-
line anti-TB drugs – isoniazid and rifampicin. XDR-TB
is caused by resistance to isoniazid and rifampicin, in
addition to any fluoroquinolone and at least one of three
injectable second-line drugs. The exact scale of the prob-
lem of MDR- and XDR-TB is not known and there
has been limited reduction in drug-resistance patterns
making it increasingly difficult to contain the disease.
However, with an increasing incidence of MDR- and
XDR-TB, its associated mortality and the decreased
effectiveness of routine anti-TB drugs, where does treat-
ment with vitamin  D find a place? There is limited
knowledge of the factors influencing the development
of these resistance patterns and there may be a place for
a trial of vitamin D in MDR- or XDR-TB to determine
if augmentation of current treatment will be effective.
Prevention with vitamin D supplementation may
be more valuable
Could the dose of vitamin D have an effect on the out-
come? The treatment of severe vitamin D deficiency
could be ample to reduce the risk of TB. Vitamin D
deficiency, brought about by immigration from tropi-
cal to temperate climates and from an area of abundant
sunlight to that of less, appears to be a risk factor for
TB. The mean serum vitamin  D concentration has
been shown to drop fourfold or more, on emigration
from Asia to Britain [16] . The implication for vitamin D
therapy is that it should be given to individuals, prob-
ably lifelong, as they move from a tropical to a tem-
perate climate, to prevent the development of TB in
future science group
 Vitamin D as an adjuvant therapy for tuberculosis  EDITORIAL

susceptible individuals. As vitamin D supplementation Future perspective

did not improve the clinical outcome among patients
with TB  [14] , vitamin  D as a prophylactic treatment
would be more effective as a treatment for latent rather
than active TB infection.
To determine if vitamin D would actually benefit
in preventing the development of TB would mean
undertaking a large-scale population study with large
numbers. The obvious difficulties in doing such studies
would be ensuring that supplementation was taken and
that the sunlight exposure was controlled, that is, the
trial subjects were not exposed to sunlight more than
those without supplementation. Such a study would be
very difficult to undertake at present.
Genetic subgroups & TB
The genetic susceptibility of a host has been suggested as
an important factor for the differences in the risk of TB
in individuals and several host genes have been attrib-
uted to contribute to the development of the disease.
This was first demonstrated in the Gambian popula-
tion with active TB where an association with the car-
riage of the T allele of the TaqI VDR polymorphism
was found [17] . Gujurati Asians, found to be vitamin D
deficient, were also found to carry the T allele of the
TaqI VDR polymorphism and the ff genotype of the
FokI VDR polymorphism [7] . It has been shown that
in a subgroup of patients with a particular genotype
(tt genotype of the TaqI vitamin D receptor polymor-
phism) vitamin D supplementation decreased the time
to ­sputum culture conversion [14] .
Vitamin D binding protein is a glycoprotein encoded
on chromosome 4. It has been previously shown that
there is no association between this genotype and the
susceptibility to TB [18] ; however, a recent study has
demonstrated an association between this genotype
and susceptibility to TB [19] . Although the results are
varied, the studies determining the factors of genetic
host susceptibility increasing our understanding of the
pathogenesis of TB and forms a base for further ­studies
with a view of developing new t­ reatment strategies.
Evidence, so far, suggests an association between low
serum vitamin D and TB in certain population groups.
Despite advances in the knowledge of the potent
immuno­modulatory activity of vitamin D, it is not
known whether the lower level of vitamin D contrib-
utes to people developing TB or if having TB alters the
metabolism of vitamin D.
Vitamin D supplementation is more effective than the
recommended sunlight exposure for treating vitamin D
deficiency in non-western immigrants and vitamin D
supplementation may augment current treatment regi-
mens to enable a more rapid conversion to a sputum
negative status [20] .
In addition, there are genetic factors that play a role.
In genetically susceptible individuals, there is an inher-
ent inefficiency to control bacterial numbers, leading
to the development of drug-resistant TB. However, the
vitamin D receptor gene tt is thought to offer protection
against disease and this area needs exploring further.
The interaction of TB infection on cellular vitamin D
metabolism needs to be further examined in addition
to definitively prove a relationship between vitamin D
and TB.
In future, public health policy aimed at the prevention
of TB should stress the need for adequate dietary intake of
vitamin D in all vulnerable groups including immigrants
from the Indian subcontinent. Ultimately, there could
be a role for administering vitamin D to all immigrants
and those with drug-resistant TB, in order to modify the
treatment duration and efficacy in treating TB.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement
with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the
manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert t­estimony, grants or patents
received or pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

4 Strachan DP, Powell KJ, Thaker A, defence to Mycobacterium tuberculosis.

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