Vit D: synthesis, action, estimation, treatment

1. Vit D: Role in various
diseases
-Dr. Nilesh Chandra

2. Objectives:
 Introduction
 Synthesis
 Actions
 Diseases
 Supplementation

3. Introduction
 Not strictly a vitamin.
 Only when sunlight exposure is
inadequate is a dietary source
required.
 Main function is in the regulation of
calcium absorption and homeostasis.
 Most of its actions are mediated by
way of nuclear receptors that regulate
gene expression.

4. Introduction
 Also has a role in regulating cell
proliferation and differentiation.
 Intakes considerably higher than are
required to maintain calcium
homeostasis reduce the risk of:
◦ Insulin resistance
◦ Obesity
◦ The metabolic syndrome
◦ Various cancers.
 Deficiency, leading to rickets in
children and osteomalacia in adults.

5. Vitamin D Is Synthesized in the
Skin

6. Vitamin D Is Activated in Liver &
Kidney

7. Synthesis-summary

8. Regulation
 Calcitriol acts to reduce its own
synthesis by:
◦ inducing the 24-hydroxylase.
◦ repressing the 1-hydroxylase in the
kidney.
 Other regulators are serum levels of:
◦ Phosphorus
◦ Calcium
◦ fibroblast growth factor 23 (FGF-23)
◦ parathormone (PTH)

9. Vit. D Receptor (VDR)
 VDR: a transcription factor
 Regulates expression of upto 2000
genes, directly or indirectly.
 Membrane bound VDR postulated but
not yet proven.

10. Role in calcium homeostasis
 vitamin D maintains plasma calcium
concentration in three ways:
◦ it increases intestinal absorption of
calcium.
◦ it reduces excretion of calcium (by
stimulating resorption in the distal renal
tubules).
◦ it mobilizes bone mineral.

11. Other actions
 calcitriol is also involved in:
◦ insulin secretion.
◦ synthesis and secretion of parathyroid
and thyroid hormones.
◦ inhibition of production of interleukin by
activated T-lymphocytes and of
immunoglobulin by activated B-
lymphocytes.
◦ differentiation of monocyte precursor
cells.
◦ modulation of cell proliferation.

12. Normal levels
 Commonly, 25 (OH)D is measured.
Analyte Conventional
Unit
SI Unit
25(OH) D 10-65 ng/ml 25-162 nmol/L
1,25 (OH) D 15-60 pg/ml 36-144 pmol/L

13. Causes of Vit d deficiency
 Inadequate exposure to sunlight.
 Inadequate dietary vit D.
 Vit D malabosrption.
 Severe hepatocellular disease.
 Increased catabolism (e.g. drugs).
 Increased loss (nephrotic syndrome).

14. Vit D deficiency and bone morphology
 Vitamin D sufficiency leads to an
adequate calcium-phosphorus product
(Ca2+ × HPO42−) resulting in an
effective bone mineralization.
 Maternal vitamin D insufficiency during
pregnancy associated with a
significant reduction in bone mineral
acquisition in infants, persisting upto 9
years of age.

15.  In children, vitamin D deficiency with
25(OH)D levels <15 ng/mL causes:
◦ chondrocyte disorganization.
◦ hypertrophy at the mineralization front.
◦ skeletal mineralization defects.
This results in bone deformities and short
stature, the typical signs of vitamin D
deficiency rickets.
Vit D deficiency and bone morphology

16. Sister (right) and
brother (left)
ages 4 years and
6.5 years,
respectively,
demonstrating
classic knock-
knees and bow
legs, growth
retardation, and
other skeletal
deformities

17.  In adults low 25(OH)D and high PTH
also lead to a low serum calcium ×
phosphorus product.
 Results in osteomalacia, i.e., a
defective mineralization of the
collagen matrix .
 Causes a reduction of structural
support.
 Associated with an increased risk of
fracture.
Vit D deficiency and bone morphology

18.  A decrease in 25(OH)D leads to
secondary hyperparathyroidism.
 Associated with osteoclastogenesis,
which leads to:
◦ an increase in bone resorption exceeding
osteoblast-mediated bone formation.
 Can precipitate and exacerbate
osteopenia and osteoporosis in adults.
Vit D deficiency and bone morphology

19. Muscular health
 Vitamin D deficiency is associated with:
◦ diffuse muscle pain.
◦ muscle weakness predominantly in the
proximal muscle groups.
◦ a reduction in performance speed.
 Vitamin D supplementation lowered the
adjusted-incidence rate ratio of falls by
72% compared to those taking placebo
over 5 months.

20. Protective role in
carcinogenesis
 1,25(OH)2D inhibits carcinogenesis by
several mechanisms:
◦ promotes cyclin-dependent kinase (CDK)
inhibitor synthesis.
◦ influences several growth factors and their
signaling pathways including:
 insulin-like growth factor 1 (IGF-1)
 transforming growth factor β (TGFβ)
 Wnt/β-catenin
 MAP kinase 5 (MAPK5)
 nuclear factor κB (NF-kB)

21. Beneficial effects on cardiovascular
risk factors and cardiovascular health
 The vitamin D receptor is present in
endothelium, vascular smooth muscle, and
cardiomyocytes.
 May protect against atherosclerosis
through:
◦ The inhibition of macrophage cholesterol uptake
and foam cell formation.
◦ reduced vascular smooth muscle cell
proliferation.
◦ reduced expression of adhesion molecules in
endothelial cells.
◦ inhibition of cytokine release from lymphocytes.

22. Protective role in Type II DM
 vitamin D exerts various antidiabetic
effects.
 The VDR is expressed in pancreatic beta
cells and 1,25(OH)2D stimulates insulin
secretion.
 Improvement in vitamin D status also
leads to a improvement of insulin
sensitivity, mediated by upregulation of
insulin receptors.
 Vit D modulates inflammation, which is
also thought to play a role in type 2

23. Additional benefits
 Protective role has been found in:
◦ Autoimmune Disease:
 Multiple Sclerosis
 Type I DM
 Rheumatoid Arthritis
◦ Infections, especially:
 Tuberculosis
 Influenza
 Viral URTI
◦ Respiratory Diseases

24. A Schematic representation of the major causes for
vitamin D deficiency and potential health

25. A Schematic representation of the major causes for
vitamin D deficiency and potential health

26. Vit D supplementation
 According to the Endocrine Society
Practice Guidelines:
Age Daily
supplementation
Safety limit
Upto 1 year 400–1000 IU up to 2000 IU
1-18 years 600–1000 IU up to 4000 IU
>18 years 1500–2000 IU up to 10,000 IU

27. Treatment of deficiency
 According to the Endocrine Society Practice
Guidelines:
Age Initial therapy
for 6 weeks
Maintenance
Upto 1 year 2000 IU/day or 400–1000 IU/day
50,000 IU/wk
1-18 years 2000 IU/day or 600–1000 IU/day
50,000 IU/wk
>18 years ~6000 IU/day or 1500–2000
IU/day
50,000 IU/wk
(both for 8 wks)
In obese patients, patients with malabsorption syndromes,
and patients on medications affecting vitamin D
metabolism, two to three times higher doses are

28. Summary
 Vit D synthesis.
 Actions and systems affected.
 Effects of deficiency.
 Treatment of deficiency.

29. References
 Tietz Textbook of Clinical Chemistry
and Molecular Diagnosis, Fifth Edition.
 Harper’s Illustrated Biochemistry, 29th
Edition.
 Wacker,M and Holick, M.F . Vitamin
D—Effects on Skeletal and
Extraskeletal Health and the Need for
Supplementation. Nutrients. 2013
January; 5(1): 111–148.

30. THANK YOU!!