Vitamin D

Dr. Manjeeta
Gupta08-07-2016
Department of Pharmacology
MIMER Medical College Talegaon Dhabade
1

Sun (UVB) on skin turns
cholesterol into vitamin D
We can also get Vitamin D
from food & supplements
Synthesis
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Vitamin D Receptor(VDR)
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Protein
Ribosome
Messenger RNA makes
a copy of DNA
Goes out of nucleus
to ‘production’
factory (ribosomes)
mRNA runs through
ribosome like a tape,
giving instructions on
protein to make
DNA is blue
print
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Transcription

Genes don’t want to be making proteins
continuously – they need to be turned on & off
– Regulators
Vitamin D  major regulator in humans
Over 230 VDRs in nucleus of most tissues
found
Vitamin D affects gene expression  It turns genes on & off
What does Vitamin D do to make such
a difference in health?
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VDR is present in:
Kidneys; Parathyroid glands;
Osteoclasts & osteoblasts
Intestines; Macrophages
Nuclei of islets of pancreas;
Brain  Neurons, Substantia nigra,
Limbic system, Cortex, Cerebellum
May stimulate Neurotrophins
(regulate neuronal development)….

Adams & Hewison (2008). Nature Clinical Practice
Endocrinology & Metabolism, Volume 4, 80-90.
TLR = Toll-like receptor
allows immune system to
recognize microbes by
looking at molecular
patterns
CYP27B1: a gene
that encodes an
enzyme to convert
inactive vitamin D
to active vitamin D
Active vitamin D
VDR = Vitamin D Receptor
Active vitamin D binds to VDR
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Vitamin D Signaling Pathway
Pathogen invades cell
Toll-like receptor signaling activated
↑ Expression of VDR & CYP27B1 genes
Active vitamin D binds to VDR
Production of cAMP ↑ (fight microbes)
Vitamin D & VDR go to nucleus, binds
to vitamin D response element (VDRE)
Innate
Adaptive
VDRE

The literature on Vitamin D
has exploded in recent years
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No Dodging Prostate Cancer With Vitamin D
Vitamin D May Help Curb Breast
Cancer, Study Finds
Vitamin D Deficiency Worsens Breast
Cancer?
Study backs Vitamin D in cancer fight
‘Sunshine vitamin’ may ward off
breast cancer
Vitamin D in preventive
medicine: are we ignoring
evidence?
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What does vitamin D do?
This is one vitamin
we ALL need to
understand & take
from an early age!
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Does sun exposure matter?
Further from equator  Less UVB throughout year  Higher incidence of various diseases
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Cancer
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Recent publicity on melanoma - has reduced our sun
exposure – so we are getting less vitamin D
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Vitamin D and Bones
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Osteoporotic BoneNormal Bone
Osteoporosis disease
in which bones lose
minerals & bone density
Bones become thin, fragile
& easily broken
Source: The 2004 Surgeon General’s Report on Bone Health and Osteoporosis
http://www.surgeongeneral.gov/library/bonehealth
Myth  Osteoporosis is only a
problem for older women
Osteoporosis can occur at any
age & in anyone
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Parathyroid hormone (PTH)
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Calcium sensing organ

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Vitamin D  inhibits parathyroid gene  supresses proliferation of glands &
stimulates cellular differentiation of promyelocytes
Renal osteodystrophy (prevent hypertrophy of gland & inhibit secretion of PTH)
Calbindin

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Vitamin D in pregnancy

Osteopenia of Prematurity
Staging:
1. Hypodensity of bones
2. Abnormalities of metaphyses
Fraying and cupping
Dense line (healing)
3. Fractures
Courtesy of Steve Abrams MD

Vitamin D: Essential for our immune system
When ‘Foreign’ protein enters body
Helper T cells  turn into Killer T cells
An army of specific killer cells attack & kill
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Research from Copenhagen – May 2011
“Without vitamin D the white cells lie dormant!”
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Researchers at Queen Mary at University of London
decided to test out old treatment with modern day
antibiotics. What they discovered was that when
coupled together, antibiotics & high doses of vitamin
D - which is created in body when it is exposed sun -
helped people recover faster from tuberculosis."
"Before antibiotics were readily available, doctors
would to send their patients to receive heliotherapy -
basically prescribed sunbathing. Practice was
stopped since more effective antibiotics were
invented, but physicians have often wondered why
sunshine treatment seemed to somewhat work.”
'Sunshine Vitamin' Helps Treat Respiratory infections
“272 adults attending emergency department with
community-acquired pneumonia were examined for disease
severity & outcomes. Over half (53 %) of patients were
vitamin D deficient, of which 24 % had severe deficiency.
http://www.erscongress2012.org/
http://www.gponline.com/News/article/1148164/vitamin-d-testing-could-slash-
pneumonia-deaths/
It has long been thought that by inducing muscle
weakness (especially of diaphragm & intercostal
muscles), vitamin D deficiency gives rise to
difficulties in eliminating respiratory secretions,
facilitating development of infections
Several epidemiological studies have suggested that
vitamin D deficiency is associated with an increased
incidence of asthma & allergy symptoms.

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Vitamin D has been shown to influence microarray gene expression
in bronchial smooth muscle cells, with consequent effects on
remodeling, cell growth & survival
Functions of vitamin D also depend on individual VDR variability
Lower vitamin D levels are associated with ↑ airway
responsiveness, higher eosinophil counts & IgE levels, while higher
vitamin D levels associated with a lower likelihood of hospitalization
for asthma exacerbations

Whenever there is a risk of infection, make sure
Vitamin D levels are optimal
Is it a coincidence that flu & infections
are higher in winter months?
Vitamin D switches on production of over 200
antimicrobial peptides – Most important CATHELICIDIN
(naturally occurring broad-spectrum antibiotic)
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A study demonstrated that vitamin D supplementation improved muscular power in
healthy overweight & obese individuals within 4 weeks.
Elevated vitamin D status was associated with greater losses in waist circumference, with
no additional benefits in lean mass accumulation, muscular strength, or glucose tolerance
during participation in a 12-week resistance exercise training program.
Another study, supports previous findings that indicate a relationship between vitamin D
status & waist circumference rather than fat mass.
Inverse relationship with waist circumference is particularly important as abdominal fat
has been implicated as an important factor in development of Type 2 diabetes.
Waist circumference is also an independent risk factor for cardiovascular disease.
Therefore, greater decrease in waist circumference associated with higher vitamin D
intake represents a potential reduction in risk for metabolic disease & cardiovascular risk.
http://www.clinicalnutritionjournal.com/article/S0261-5614(12)00181-1/abstract
Vitamin D and waist circumference
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Diabetes in Children under 14 in Finland 1965 -2009
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Vitamin D seems to do all the right things for the heart
VDR  Present in artery walls, heart muscle
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Vitamin D in cancer
Switches apoptosis back on – programmed cell death
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Vitamin D tells cells when to divide,
stop dividing & also when to die
(apoptosis)
With low vitamin D levels:
Cells continue to divide out of
control!
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Major vitamin D catabolizing
enzyme, CYP24A1 (24-
hydroxylase), is often amplified &
over expressed in tumor cells

Slows down multiplication & spread of cancer cells
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Reduces growth of new blood vessels to feed cancer cells & ↓ spread
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"Vitamin D3 plays a key role in immune regulation & may protect against aging process.
Age-related changes  In outer retina, there is high metabolic demand resulting in a
gradual ↑ in extracellular deposition, inflammation, & cell loss  rise to visual decline.
Vitamin D3 administration for only 6 weeks in aged mice has a significant impact on this
aging process...
Recently, vitamin D3 has been linked epidemiologically to protect against age-related
macular degeneration."
In a study, supplemention with vitamin D3  helps rejuvenate aging eyes by
reducing inflammation & amyloid beta (risk factor for age-related macular
degeneration  leading cause of blindness)
Vitamin D in Eye
http://www.neurobiologyofaging.org/article/S0197-4580(11)00519-7/abstract
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“A cohort study included women over age of 75 years to study risk factors for
hip fractures over 4 years. Dietary factors & midday sun exposure habits were
examined. Presence of Alzheimer’s disease & other dementias was assessed
7 years after enrolment.”
Vitamin D and Alzheimer’s
http://www.ncbi.nlm.nih.gov/pubmed/22503994
http://blog.vitamindcouncil.org/2012/04/23/dietary-vitamin-d-intake-and-sun-
exposure-linked-to-lower-risk-of-alzheimers-in-france/
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Those in highest 5th of vitamin D intake had ¼ incidence rate of Alzheimer's
disease...
In addition, those in highest 5th of sun exposure had 50 % less incidence
of Alzheimer's..."

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A link between lack of exposure to sunlight, consequent lack of
vitamin D production & development of MS
Whether low levels of vitamin D affect number of relapses &
disease course?
There is some evidence that lower levels of vitamin D are
associated with higher relapse rates & greater disability
One study also found that people with progressive forms of MS
had lower levels than those with relapsing remitting MS
Whether lack of vitamin D contributes to risk
of developing Multiple Sclerosis?
http://www.mstrust.org.uk/news/article.jsp?id=5503

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Vitamin D Improves Seizure Control in Epilepsy
Pilot study included 13 subjects between ages of 19 - 60, who had had epilepsy anywhere
between 10-42 years.
All subjects were given a one-time mega-dose of vitamin D3, ranging from 40,000 IU to 200,000
IU, followed by a daily dose of 2,000-2,600 IU for 3 months, in an effort to correct each
individual's vitamin D status & bring them up to at least 30 ng/ml.
At 90-day follow-up, median vitamin D level for group was 38 ng/ml (23.3 to 45 ng/ml).
They then tallied number of seizures experienced during 3-month long treatment period, compared to 3
months prior to treatment.
10 out of 13 had a decrease in number of seizures; 5 of which experienced more than 50 % reduction.
2 participants had more seizures, while 1 experienced no change at all. Overall, group had 40 % reduction
in number of seizures.
http://www.ncbi.nlm.nih.gov/pubmed?term=Correction%20of%20vitamin%20D%20deficiency%20improves%20seizure%20control%20in%20epilepsy%3A%20A%20pilot%20study

Vitamin D and Depression: Where is all the
Sunshine?
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Role of Vitamin D in skin
VDR present on keratinocytes
Vitamin D induce differentiation of keratinocytes
& inhibit their proliferation
Effective in psoriasis vulgaris
(hyperproliferative disease), actinic keratitis

Role of vitamin D in hair growth
Researchers at Cairo University found - women with hair loss problems
also had lower levels of iron & vitamin D
Hair loss only got worse as levels dropped
“It might regulate expression of genes that promote normal hair follicle
growth”
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Some studies have shown that vitamin D when applied topically to
scalp can ↓ chance of cancer patients developing hair loss after
being given certain types of chemotherapy

Arctic Circle EquatorGeographic Location
SeasideElevation Mountains
Sun-seeking Behaviors Always outsideNever outside
DeepSkin Pigmentation Light
Mostly uncoveredCultural Dress Mostly covered
Never Owned AnySunscreen Use Applies to any exposed skin
SUNLIGHT EXPOSURE FACTORS
Assessment of Vitamin D Stores
Diet No milk, No fish Vit D fortified Milk, Salmon 3 X a week
Present
Diseases assoc. with Vit D
Deficiency
Not present
Supplements No supplements 400 IU Vit D per day
DIETARY FACTORS

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Need more vitamin D with age
Age
Daily
vitamin D
(IU)
600 IU
200 IU
400 IU
0
100
200
300
400
500
600
up to 50 51-70 over 70
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How much vitamin D should we take?
**Some cancers can raise blood calcium level, so in cancer patients ask for calcium
levels to be checked before starting & after being on high dose of vitamin D
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UVA
UVB
Middle hours of day (between
10 am & 2 pm)
With low sun, good UVB rays are
filtered out & UVA gets through

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Vitamin D2 (Ergocalciferol) or Vitamin D3 (Calcitriol)
Calcitriol analouges – Calcipotriol (topical), Doxercalciferol (1α hydroxy D2) & paricalcitol
Adults treated with vitamin D2 showed ↑ total blood levels of 25(OH)D & maintained total
blood levels of 1,25(OH)2D same as adults who received same dose of vitamin D3
Recent meta-analysis indicated that vitamin D3 is more efficacious at ↑ serum 25(OH)D
concentrations than vitamin D2
11-week course of treatment with 1000 IU vitamin D2, 1000 IU vitamin D3, or combination of
500 IU vitamin D2 & 500 IU of vitamin D3 daily  equivalent ↑ in serum total 25(OH)D levels
Type of Vitamin D Supplementation
Mayo Clinic Proceedings Volume 88, Issue 7, Pages 720 - 755, July 2013
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Skepticism grows regarding widespread vitamin
D supplementation
• Serious questions about safety & efficacy of popular practices of high-dose vitamin D supplementation
across population
• One of these concerns is that not all of extra calcium absorption promoted by boosting vitamin D goes into
bone to prevent fractures
• Serum 25-hydroxyvitamin D levels were positively associated with increased calcified atherosclerotic
plaque in aorta & carotid arteries
• A large prospective randomized trial assessed effects of using calcium supplements on vascular event
rates:
NNT for 5 years of supplemental calcium in order to cause one additional MI than with placebo was 44.
NNT for one stroke was 56
NNT to cause one additional cardiovascular event was 29
In contrast, NNT to prevent one symptomatic fracture was 50
“The question we have to ask is: What does that low serum vitamin D level mean?
Is it the thing that predisposes, or is it somehow a byproduct of illness?”
(J.Clin.Endo.Metab. Jan. 8, 2010; Epub ahead of print PMID:20061416)
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Too much Vitamin D – Is it toxic?
Vitamin D intoxication  hypercalcemia, hypercalciuria, &
hyperphosphatemia  responsible for soft-tissue, vascular
calcifications & nephrolithiasis (long term use)
Serum 25(OH)D levels markedly elevated (>150 ng/mL)
Daily doses of vitamin D3 up to 10,000 IU (safe in healthy
males) with no evidence of hypercalcemia / hypercalciuria for
5 months
Tolerable upper level – 4000 IU (IOM guidelines)08-07-2016
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Drug interactions
1. Drugs that impair vitamin D absorption –
 Obesity medication – Orlistat
 Bile acid sequestrants – Cholestyramine & Colestipol
2. Drugs that may ↑ vitamin D catabolism –
 Anticonvulsants, cimetidine, thiazides
3. Drugs that may ↓ vitamin D absorption –
 Olestra (Fat substitutes)
 Liquid paraffin
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Putting it all together…
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Low Vitamin D levels associated with:
Archives of Neurology, March 2011
American Heart Association's (AHA) Annual Scientific Sessions, Chicago, IL
November 15,
2010
Journal of Allergy and Clinical Immunology June 8, 2010
Diabetes Care. 2011 March08-07-2016
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Leg artery disease  80% more (NHANES2001-2004)
Heart attacks  62% more (Framingham study,Circulation Jan 2008)
High BP  300% more (In15 year study of women in Michigan School of
public health, AHA BP Conference 2009)
Diabetes  57% more (Australian Institute of medicine 2011)
Cancer  72% more colorectal cancer (NHANES 2010)*
Low Vitamin D levels
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In people taking Vitamin D supplements:
Pancreatic cancer 45% reduction in
120,000 in 2006
All cancers reduced by 77% in 1,200
Cancer Epidemiology Biomarkers & Prevention 15 (9): 1688–95. 2006
The American Journal of Clinical Nutrition 85 (6): 1586–91 2007
American Journal of Clinical Nutrition 91 (5): 1324–35. 2010
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Once the diseases have developed, Vitamin D levels still make a difference:
Doubles survival in people with colon cancer
Hospitalisation due to heart failure & mortality is reduced
Lowered heart deaths by 33% in women
Vitamin D supplements reduced cancer by up to 60% women
British Journal of Cancer September 15, 2009; 101(6):916-23
European Society of Cardiology (ESC) Congress 2010 August 28-September
1, 2010, Stockholm, Sweden
2nd annual conference on Cardiovascular Disease and Epidemiology
Prevention in Honolulu, Hawaii. April 23, 200208-07-2016
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Cancer Hypertension Heart disease
Autism Obesity Rheumatoid arthritis
Diabetes 1 and 2 Multiple Sclerosis Crohn"s disease
Flu Colds Tuberculosis
Septicemia Aging Psoriasis
Eczema Insomnia Hearing loss
Muscle pain Cavities Periodontal disease
Athletic performance Macular degeneration Myopia
Pre-eclampsia Seizures Fertility
Asthma Cystic fibrosis Migraines
Depression Alzheimer’s disease Schizophrenia
The list of illnesses benefitting from vitamin D grows by the day
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1. Goodman Gillman
2. Martindale
3. KD Tripathi
4. KK Sharma
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References

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• Determine whether vitamin D inadequacy ↑ cancer risk
• Whether greater exposure to nutrient is protective
• Need to consider metabolism, catabolism, & VDR polymorphisms
• Address methodology to measure serum vitamin D level (biomarkers)
• Need surrogate markers of vitamin D activity
• Determine molecular targets for vitamin D
• Explore vitamin D/sun exposure dilemma
Further research is needed:

Vitamin D

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