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Vit D: synthesis, action, estimation, treatment

Vit D: synthesis, action, estimation, treatment

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  • 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!!