2. Objectives
• Tounderstand the mechanism of Vitamin D
metabolism
• Todiscuss the neurologic correlation of
disease and Vitamin D
• Todiscuss treatment and its ramifications of
Vitamin D
3. Introduction
• Only vitamin that can be synthesized from
human body
• Vitamin D is a fat soluble vitamin present in
several molecular forms
– Exists in 2 forms
4. Upto 90% indians are deficient due to
I. Dark skin
II. veg diet
III. poor sun exposure
IV. not in food fortification program
API text book of Medicine, 9th edition
5. Vit D2 – Ergocalciferol (yeast)----- dietary
Vit D3 – Cholecalciferol (skin, fish in diet) -----skin
Main indicator of Vit D levels, storage and circulating form –
25(OH) Vit D3(calcidiol)(2-3wks)
Main active form – 1,25(OH) Vit D3(calcitriol)(15hrs)
6. Natural – Cod, Shark & other fish liver oils,
Salmon, Sardines, Mushroom,
Egg yolk, Sunlight exposure.
Fortified food - Milk, butter, Cheese margarine,
Vegetable oils , Infant formula.
Drug suppliments - Vit D2, Vit D3
RDA-15 mcg to 20 mcg(600-800 U/d).
8. METABOLISM OF VITAMIN-D
Solar UV B rays penetrates skin & converts
7- dehydrocholesterol to previtamin D3
which is converted to Vit D3.
Vit D2 & D3 from Diet travels in
in chylomicrons ,stored in fat cells
From skin & diet, vit-D is metabolized to
25-OH Vit D in liver.
This is metabolized by
1alfa hydroxylase to 1,25 –(OH)
Vit-D (active form) in kidney
25-OH Vit D is used to determine Vit D
status
9. Integrated metabolism of Vit D,
Calcium & Parathormone
Calcium , FGF-23 and E’s product 1,25-OH
Vit D decreases the enzyme and major inducers
PTH and hypophosphatemia.
1,25-OH Vit D decreases own synthesis by
negative feedback & decreases synthesis and
secretion of PTH
1,25-OH Vit D increases 24 -OHase to form
24,25 (OH)2 vit D (metabolically inactive )
1,25 OH-Vit D enhances calcium absorption
from small intestine.
1,25-OHVit D recognized by osteoblast to
increase expression of RANKL , which act on
osteoclasts to maintain calcium & phosphate
level in blood
10. no recommendations are issued for the amount of sun
exposure required to meet vitamin D requirements.
Sun exposure between 10 am-3 pm .
prolonged exposure to the sun does not cause vitamin D
toxicity - further degraded to the inactive tachysterol and
lumisterol.
11. CNS
VDR are widely distributed throughout the embryonic
brain (Stumpf et al., 1982) , adult brain in temporal,
orbital, cingulate cortex, thalamus, amygdala ,
hippocampus and the olfactory system.
Local synthesis of 1,25-(OH)2D is performed by 1a-
hydroxylase-expressing neurons and microglia.
12. CNS
Vitamin D may also affect processes such as axogenesis.
Vitamin D has also been reported to inhibit the synthesis of
inducible nitric oxide synthase , an enzyme induced in neurons
and non-neuronal cells during ischemia or in the
neurodegenerative conditions.
Vitamin D simultaneously targets several factors leading to
neurodegeneration
• Immunoregulatory, antioxidant, anti-ischemic factors
• Clearance of amyloid beta peptide
13. Ageing, Obesity, High Latitude
Skin - Sunscreen use, Skin pigmentation
Malabsorption syndrome –
Drugs - Anticonvulsants, Glucocorticoids, HAART,
Immunosupressants
CLD and CKD
14. Heritable causes- Rickets
Vit D D rickets- Type 1- 1alfa hydroxylase defect
Type 2- VDR defect
Vit D resistant rickets
Hypophosphatemic rickets (autosomal & X linked)
17. VITAMIN D DEFICIENCY
Increase Insulin resistance
Decrease Insulin production
Assoc. with Metabolic syndrome
Assoc. with Congestive Heart Failure
Increased inflammatory factors
Increased incidence of Schizophrenia & Depression
18. •SCREENING : only high risk for vitamin D deficiency,
osteoporosis
• malabsorption syndrome,
• black and Hispanic individuals,
• obese persons (BMI >30 kg/m2),
with several other medical conditions
19. How Vitamin D and Its Receptor Affect
Immune Regulation
• Vitamin D can increase expression of:
– Anti inflammatory cytokines
• Vitamin D can decrease expression of:
– Pro inflammatory cytokines
21. Multiple Sclerosis
• “Vitamin D has been shown to regulate the
expression of the MS associated HLA-DRB1.”
Loken-Amsrud KI, Holmey T,Bakke SJ et al. Vitamin D and disease activity in multiple sclerosis before and during
interferon-β treatment. Neurology 2012;79:267-273.
22. Multiple Sclerosis
• However,
– “in untreated patients with MS, increasing levels
of Vit D 25 (OH) are inversely associated with
radiologic disease activity irrespective of their
HLA-DRB1*15 status”
Loken-Amsrud KI, Holmey T,Bakke SJ et al. Vitamin D and disease activity in multiple sclerosis before and during
interferon-β treatment. Neurology 2012;79:267-273.
23. Multiple Sclerosis• Each 10 nmol/L increase in 25 (OH) Vit D was
associated with
– 12.7% reduced odds of new T1 gad enhancing
lesions
– 11.7% for new T2 lesions
– 14.1% for combined activity
Loken-Amsrud KI, Holmey T,Bakke SJ et al. Vitamin D and disease activity in multiple sclerosis before and during
interferon-β treatment. Neurology 2012;79:267-273.
24. Multiple Sclerosis
• IFN-β associated with greater production of
Vit D from sun exposure, suggesting that part
of the therapeutic effects on MS relapses may
be through modulation of Vit D metabolism!
Stewart N, Simpson S, van der Mei I, et al. Interferon-β and serum 25-hydroxyvitamin D interact to modulate
relapse risk in MS. Neurology 2012;79:254-260.
25. • So patients on IFN-β should have Vit D levels
maintained in the sufficiency range by
monitoring
Stewart N, Simpson S, van der Mei I, et al. Interferon-β and serum 25-hydroxyvitamin D interact to
modulate relapse risk in MS. Neurology 2012;79:254-260.
26. Multiple Sclerosis
• Why this association with the IFN-β and
Vitamin D?
– How they work unknown but thought to
• Increase IL-10 expression
• Reduce antigen presentation
• Restore the blood-brain barrier
Stewart N, Simpson S, van der Mei I, et al. Interferon-β and serum 25-hydroxyvitamin D interact to modulate relapse
risk in MS. Neurology 2012;79:254-260.
27. Multiple Sclerosis
– Higher Vitamin D levels are associated with
decreased exacerbation risk in RRMS
– “For each doubling of the serum Vit D 25 (OH)
concentration, the relapse risk in MS decreases by 27%”
Runia TF, Hop WCJ, Buljevac D, Hintzen RQ. Lower serum vitamin D levels are associated
with a higher relapse risk in multiple sclerosis. Neurology 2012;79:261-266.
28. Pregnancy
Pregnant with higher levels of vitamin D - lower risk of
developing multiple sclerosis (MS) than women with
lower levels, while their babies may not see the same
protective effect,
Salzer, medical journal of the American Academy of Neurology: 2012, 20 Nov
29. Multiple Sclerosis:The Bottom Line
on Vit D 25(OH)
• Appears to influence MS risk and course of
disease
• It is cheap, safe and easy to administer and
could be a valuable addition to treatment
30. Parkinson's disease (PD)
chronically deficient levels of vitamin D may play a
role in the development of PD.
Not known how or even if vitamin D levels affect
Parkinson's risk, but the findings are generating interest
in more research.
Archives of Neurology July 2010
31. Parkinson's disease (PD)
• The substantia nigra -VDR is most highly expressed (Eyles
et al., 2005).
• vitamin D positively regulates the expression tyrosine
hydroxylase (Puchacz et al., 1996).
• a higher prevalence of hypovitaminosis D was observed in
patients with Parkinson’s disease, when compared to both
healthy controls and patients with Alzheimer’s disease
(Evatt et al., 2008).
• Finally the vitamin D binding protein (VDBP) has been
recently shown to a cerebrospinal fluid biomarker in
Parkinson’s disease (Zhang et al., 2008).
32. EPILEPSY
The threshold for provoked seizures is reduced
(Siegeletal.,1984).
ONLYANIMAL BUT NO HUMAN STUDIES
AVAILABLE
33. DEMENTIA
those who were deficient in vitamin D had double the
risk of developing dementia.
Studies suggest that vitamin D protects against
dementia by helping to break down and sweep out
Alzheimer's disease-related proteins and by enhancing
blood flow to the brain
Llewellyn Neurology in 2014
34. DEMENTIA
a moderate deficiency (10 to 20 ng/mL) was associated
with a 53 percent increased risk of developing dementia
and a 69 percent increased risk of developing
Alzheimer's disease compared to those who had
adequate levels (more than 20 ng/mL).
Llewellyn Neurology in 2014
35. Peripheral neuropathy
– Has been associated with type I and II diabetes as
well as both the microvascular and macrovascular
complications of diabetes
– Has been shown to be common in diabetic
patients who have symptoms of distal symmetrical
polyneuropathy
– Often diagnosed in those with established
diabetes and replacement may prevent or delay
the onset of diabetic complications
36. Myopathy
– Vitamin D is important to maintain healthy
muscles
– Vitamin D deficiency doesn’t normally cause a
significant myopathy, but can cause muscle
weakness
37. • Secondary compression of spinal cord, plexus,
or peripheral nerves from rickets or
osteomalacia
38. Other Effects of Vit D
• Cutaneous hyperalgesia
– Resistant to antidepressants and opiates
– Responds to Vit D correction
39. Depression
Vitamin D Responsive Elements have been identified in
the promoter regions of serotonin receptors and
tryptophan hydroxylase, two genes associated with
depression.
In study involving more than 1000 older adults, mean
levels of 25-hydroxyvitamin D were found lower in those
with minor and major depression when compared to
controls.
Hoogendijk et al., 2008
40. Schizophrenia
those born in winter and spring have a significantly
increased risk of developing schizophrenia (Torrey and
Miller, 1997).
The incidence and prevalence of schizophrenia is also
greater from sites at higher latitudes (Saha et al., 2006).
The incidence of schizophrenia is also significantly higher
in dark-skinned migrants to cold countries compared to
the native born (Cantor-Graae and Selten, 2005).
41. Inadequate Sun Exposure/ supplementation
60000 IU cholecalciferol every week X 8 weeks then mnthly
for 3-6 months
Chronic Kidney Disease
Stage 2 & 3 : 50000 IU Vit D2 every week X 8 weeks
Stage 4 & 5 : 0.25 – 1.0 mcg calcitriol p.o. a day
Malabsorption- 2.4 lakh IU/ 6mnths i.m.
API text book of Medicine, 9th edition
42. If level is low despite several attempts at correction with oral
vitamin D, a trial of UVB light therapy (ie, by tanning lamps) may
be considered to improve vitamin D status.
Sensible sun exposure, especially between the hours of 10:00 am
and 3:00 pm produces vitamin D in the skin that may last twice as
long in the blood compared with ingested vitamin D.
If sun exposure produces slight pinkness, the amount of vitamin D
produced in response to exposure of the full body is equivalent to
ingesting 10,000-25,000 IU
API text book of Medicine, 9th edition
44. Recommendations and
Conclusions
• Alternative Supplementation
– 15 minutes of noon day sunlight or
– Artificial UVB radiation ( in some tanning bed
biweekly in the buff)
• Gives us 10, 000 IU of 25 (OH) Vit D in fair skinned
people
45. Recommendations and
Conclusions
– UV treated mushrooms
• Potent source up to 75% of daily requirement in a
single 3.5 ounce serving
UV Treated Mushrooms Pop with Vitamin D. Environmental Nutrition. The Newsletter of Food, Nutrition, and
Health. 2013;36(9); pg 2.
46. Conclusions• Interpreting the findings of Vit D studies still
warrants more investigation
– In MS, there is a complex interplay among diverse
multiple environmental factors, including viral
infections, hygiene, UV sunlight exposure, smoking,
and nutrition on genetic vulnerability being implicated
as potential risk for the development of MS
– Vitamin D and VDR especially may affect gene
expression and risk of developing MS! as well as other
diseases