More than meets the eye - Vitamin D

1. Vitamin D
What, when, where, how and why?

2. Objectives of discussion
• Current status
– Dosage 60,000 units
– Indications Limited
– Need to expand perception
– Need to expand usage & market How?
• Suggestions
– Dosage
– Non standard Indications, Perception
– How to expand usage & market?

3. Vitamin D
Pandemic?
Pleotropic?
Paracrine?

4. What?
• Producing more than one effect, the enabler
• Paracrine
– Chemical signals that diffuse into the area
and interact with receptors on nearby cells
– New insights due to the discovery of
1. Key activating and inactivating enzymes of
vitamin D.
2. Its intracellular receptor, VDR - present in nearly
every tissue and cell in the body
3. And hence adequate vitamin D status is essential
for optimal functioning of all tissues and cells

5. Why?
Dr. Robert P.
Henry
Creighton
University
Close
this gap

6. When?
• Serum 25(OH)D concentrations of 10 ng/ml
(25 nmol/l) considered the cut-off for defining
the lower limit of adequacy (in terms of
preventing rickets).
– But, serum concentration of > 30 ng/l (> 75
nmol / l) considered more appropriate to define
physiologically optimal concentrations,
associated with many other health benefits
– Epidemiological studies have revealed a dose-
dependent association between serum 25-OHD
levels and immunity, pulmonary function, etc.

7. Where?
• Serum total 25(OH)D is the:
– Functional indicator of vitamin D status
– Major storage form of vitamin D
• Serum total 25(OH)D2 is of no value unless
measured following vitamin D therapy;
• Serum total calcitriol does not measure
Risk assessment for vitamin
vitamin D status; D -- Hathcock et al. 85 (1): No toxicity
below 30,000
6-18, AJCN, 2007 iu/ day
Tolerable
upper level =
10,000 iu/

8. Where?

9. How?
Vitamin D deficiency Vitamin D insufficiency
Indexed mechanism Malabsorption Non-indexed mechanisms Genomic
of Ca & P signaling
Short latency Long latency Short latency Long latency
effects effects effects effects
Rickets, Osteoporosis The Falls • Cancer,
Osteomalacia amount • Immune
enough disorders,
for the • Infections
left side
However, current intake is based is not
on recommendations of 1997 for enough Hence, what is the more
the left side, totally overlooking for the useful endpoint?
the needs for the right side right

10. Vitamin D
A closer focus

11. Vitamin D and homeostasis
1. Regulates more than 200 genes including
genes for cellular proliferation,
differentiation and apoptosis.
2. Regulates extracellular matrix homeostasis
in tissues, either indirectly or directly.
3. Potent immune modulator of the adaptive
immune system
4. Stimulates the innate immune response
upon infection.

12. Vitamin D and homeostasis
Regulation of immune function by 1,25(OH)2D. 1,25(OH)2D suppresses adaptive immunity (A) by inhibiting the maturation
of dendritic cells, reducing their capacity to present antigen to CD4 cells. 1,25(OH)2D further inhibits the proliferation and
differentiation of CD4 cells into Th1 and Th17 cells and promotes the production of Th2 and Treg cells. On the other hand
1,25(OH)2D promotes innate immunity (B) in that when the macrophage is activated by TLRs, VDR and CYP27B1 are
induced enabling the macrophage to produce 1,25(OH)2D, which then induces cathelicidin, a potent antimicrobial peptide.

13. Vitamin D and immunomodulation
• Immunomodulation is the therapeutic
approach in which interventions can be
achieved in auto regulating processes of
the defense system.

14. Vitamin D and immunomodulation
• All cells of the adaptive immune system (dendritic
cells, monocytes, T cells and B cells, NK cells)
express VDR either constitutively or after
appropriate immune stimulation and are sensitive
to calcitriol action.
• High level of vitamin D causes:
1. Potent inhibition of dendritic cell maturation +
2. Lower expression of major histocompatibility complex
(MHC) class II molecules,
3. Down-regulation of costimulatory molecules and
4. Lower production of proinflammatory cytokines such as
IL-2, IL-12, IFN-y and IL-23

15. Vitamin D and immunomodulation

16. Vitamin D and immunomodulation

17. Vitamin D and immunomodulation

18. Vitamin D and immunomodulation
• Dendritic cells (DCs) are immune cells that
function as antigen-presenting cells. They
act as messengers between the innate and
adaptive immunity.
• Vitamin D-induced inhibition of IL-12
release by dendritic cells has a profound
effect on T lymphocyte differentiation by
downregulating Th1 & upregulating Th2.
• As a result, the following are achieved:

19. Vitamin D and immunomodulation
1. Promotes differentiation
2. Antiproliferative - Potent antiproliferative effects on
T cells, principally T helper cells, and suppresses
B cell antibody production both directly and
indirectly
3. Immunosuppressive – one of the most important
modulatory actions is its effect on regulatory T
cells (Tregs) which prevent the activation of
peripheral autoreactive T cells.
4. Promotes infection control - can enhance the
phagocytic activity of macrophages and increase
the activity of natural killer cells.

20. Vitamin D and infection
• In cell types such as epithelial cells and WBCs, the
genes encoding for antimicrobial polypeptides such
as cathelicidin are driven by VDRE-containing
promoters
– As cathelicidin is also diffusely expressed in the surface
epithelia of human airways, in the submucosal glands,
and in secretory granules of macrophages and
neutrophils, vitamin D insufficiency may contribute to
chronic respiratory infections and airway colonization
– In monocytes, a local increase of the 1,25-(OH)2D-VDR
complex (via TLR-2) stimulates the production of
cathelicidin, resulting in an improved intracellular
eradication of MBT.

21. Vitamin D and Tuberculosis
• Higher sputum conversion and radiological
improvement (100%) compared to a placebo
group (76·7%) in TB patients administered
vitamin D or placebo following the 6th week of
standard TB treatment.
• Addition of calcitriol to primary human
macrophages infected with virulent M.
tuberculosis reduced the number of viable
bacilli.

22. Vitamin D and Tuberculosis
• The immune system is able to detect M.
tuberculosis via pathogen-associated
molecular patterns (PAMPs); VDR activation
and induction of cathelicidin.
• The cathelicidin gene encodes an anti-
microbial peptide, LL-37, and this gene, in
humans (but not in mice), contains a vitamin
D response element.
• Therefore binding of vitamin D leads to LL-
37-mediated killing of M. tuberculosis.

23. Vitamin D and Tuberculosis
• Cathelicidins and defensins
are small peptides with
amphipathic structures that
allow them to disrupt the
integrity of the pathogen cell
membrane, resulting in its
death.
• These proteins are expressed
by most immune cells or
those epithelial cells that are
in contact with the
environment.
• Deficiency in these peptides
results in increased
susceptibility to infection.

24. Vitamin D and HIV
• Use of certain ARTs, especially efavirenz, is
associated with alterations in cholecalciferol
levels.
• Studies have also shown that vitamin D
insufficiency/deficiency at baseline was
associated with increased risks of HIV
disease progression, anemia, and all-cause
mortality, as well as mother-to-child
transmission of HIV.

25. Vitamin D and HIV

26. Vitamin D and COPD
• Although still defined using pulmonary criteria,
COPD is a chronic disease state that is not
confined to the lungs but is typically associated with
systemic inflammation and different comorbidities.
• The importance of such broader context has been
indirectly confirmed by the Toward a Revolution in
COPD Health (TORCH) study.
– In the 3-year follow-up of a large cohort of patients with
COPD, only one-third of deaths could be attributed to
respiratory failure, whereas the majority died from lung
cancer or cardiovascular events
Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009

27. Vitamin D and COPD
• A strong relationship exists between serum
levels of 25-OHD and pulmonary function, as
assessed by FEV1 and FVC.
• The observation that smoking African
Americans develop severe airflow
obstruction more rapidly than Caucasians is
in agreement with the idea that a presumed
lower vitamin D status in African Americans
correlates with an increased susceptibility to
COPD. bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009
Vitamin D beyond

28. Vitamin D and COPD
• Appropriate antimicrobial therapy is considered the
mainstay for treating acute exacerbations of COPD.
• In case of colonization, repetitive and long-term
antibiotic therapy are still avoided as they
contribute to multiresistance of colonizing strains.
• A potent alternative approach would be the up-
regulation of the innate immune defense system,
especially with regard to native antimicrobial
polypeptides (AMP).
• the ability of vitamin D to enhance cathelicidin
expression, might reduce pathogen load and the
frequency of these exacerbations.
Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009

29. Vitamin D and COPD
• Muscle weakness is a prominent feature in rickets
and chronic renal failure,
• Skeletal muscle weakness common observation in
moderate to severe COPD and is an independent
predictor of respiratory failure and death.
• Main causes of COPD deterioration include a
combination of:
– Disuse because of respiratory limitation,
– Elevated oxidative stress,
– Systemic inflammation,
– Hypoxia, and
– Frequent steroid intake.
Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009

30. Vitamin D and COPD
• Whether sufficient vitamin D
supplementation will finally reduce
cardiovascular or lung cancer mortality in
patients with COPD is currently unknown,
but, given the potential beneficial effects of
other anti-inflammatory agents like statins in
the treatment of COPD, it is worthwhile to
further explore such hypothesis.
Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009

31. Vitamin D and fractures
• A +ve association between 25-OHD and
muscle strength or lower extremity function
in elderly people has been noted.
• A meta-analysis of 5 randomized clinical
trials revealed that vitamin D
supplementation reduces the risk of falls by
22% compared with placebo.

32. Vitamin D and cancer
• Studies in males have shown an increment
of 10 ng/ml in estimated 25-OH D was
associated with:
– a 17% reduction in total cancer incidence,
– a 28%reduction in total cancer mortality, and
– a 45% reduction in digestive cancer mortality

33. Summmary

34. Summmary

35. Summmary

36. Summmary

37. A rule of thumb
• To raise Serum 25-
(OH)D by 1 ng./ml.
[2.5 nmol / L] one
needs 100 additional
i.u. / day of vitamin D3
– Hence, to raise a
patient’s Vitamin D
level from 15 to 30
ng. / ml.; there will be
an additional
requirement of 1500
i.u./ day.
– Great inter-patient
variability in Cmax