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Vitamin d perspectives
- 1. Vitamin D perspectives …… Dr K Sanyal 28 Feb 2017
- 2. Objectives : 1. Role and metabolism 2. Receptor regulation 3. Clinical assessment of 25OHD and 1,25 OHD 4. Hypovitaminosis D 5. Vit D defects – Maternal status / Osteomalacia 6. Fractures 7. Relevance of – Immune system /Extra-skeletal /Cancer/DM/CKD 8. In CTD
- 3. Vit D is a steroid hormone ( Brincat 2015) VitD3Cholecalciferol Fortified diary product Fish oil Skin 80 % 7 dehydrocholesterol
- 5. 7 Dehydrocholesterol (skin) UV Vit D3 Cholecalciferol (Liver) 25 OH lase 25 OHD3 To ( in kidney) 24,25 OH D3 FGF 23 1,25 OH D3 (Target tissue) FGF 23 1,24,25 (OH)D3 Calcitriol Acid (Excretion) 25 OH lase 1 OH lase Vit D resistant rickets
- 6. • Stable to measure Vit D status - 25 OHD3 > 1,25 OH2D3 • Low Vit D and Calcium cause - High 1 alpha OH lase • 1,25 OH2 D3 – tight regulates the system • FGF23 - Cause phosphate excretion ( decreased absorption in PCT ) Found in – Kidney / Parathyroid Gland /Choroid Plexus AD Hypophosphatemic Rickets XL Hypophosphatemic Rickets
- 7. • Estrogen + androgen / Estrogen +Progesterone Stimulate 1,25 OHD3 • Estrogen by itself - Decrease 24,25 OH2D3 • 1 OH lase – Kidney / Maternal decidua / Fetal trophoblast Zehnder 2002 • 1,25 OH D3 – activates innate immunity Liu 2009 cathelecidin , antimicrobial peptide • 1 alpha hydroxylase and 1,25 OH2D3 – Monocyte and macrophages expresses them as well
- 8. Chronic kidney disease : Decrease in 1 alpha hydroxylase • Loss in functional renal mass Cheng 2007 • Metabolic Acidosis Lee 1977 • High phosphate level Portale 1984 • High FGF 23 ( High FGF leads to 1 alpha OH lase ) Gutierez 2005
- 9. Receptor Regulation VDR – Vit. D receptor ( Cause diverse biologic reaction) Haussler 1998 Receptor - Zinc finger also found in : Estrogen / Androgen /Glucocorticoids/Thyroid / Retinoic Acid N-Terminal ( Zinc finger ) C – Terminal Unstructured region
- 10. Vit D is a 9 , 10 seco steroids It exist in 2 forms D2 28 carbon molecule – from plant - Ergosterol D3 27 carbon molecule – from cholesterol
- 11. 25 OH D and 1 , 25 di OH D 25 OH D CALCIFEDOL • Half Life 21- 30 days • Liver • More amount is found • Estimation level better 1,25 di OH D3 CALCITRIOL Half Life 4 – 15 hour s • Kidney Less amount in found • Eventually provides no information with respect to nutritional status
- 12. • Vitamin D deficiency cause- Muscle weakness/Falls/Non-skeletal morbidities • Bone effected – Osteomalacia / rickets • Muscle function – Vitamin D fall by 20 % Bischoff- Ferrai 2004 • Vitamin D is anti-proliferative and pro differentiating effect to stop from cancer • Vitamin D also got immunomodulatory effect
- 14. • Vitamin D enhance monocytic mycobacterial activity • Vitamin D helps in decreasing cardiovascular abnormality • Low Vitamin D – exaggerates Connective tissue disease – Vasculitis SLE Abou-raya 2013 Primary scleroderma Erten 2015 Inclusion myositis Azali 2013
- 15. • Vit D is broad immunomodulatory in innate and adaptive system • In lupus – low Vit D related to aortic stiffness Reynolds 2012 • In lupus – low Vit D leads ti increased carotid plaque Ravenell 2012 • In lupus – low Vit D leads to increased fatigue Lima 2016 • DsDNA decreases after 4 weeks of Cholecalciferol • In scleroderma High VitD leads to lower –peripheral neuropathy /lymphoma Also lowers the skin fibrosis in scleroderma
- 16. Difference of Osteoporosis and Osteomalacia Osteoporosis Osteomalacia • Decrease bone volume • Decrease bone volume • No mineralisation defect • Excess osteoid accumulation
- 18. Difference between Rickets and Osteomalacia Rickets Osteomalacia • Child and Adolescent • Child and Adult • Impaired mineralisation of cartilage • Excess accumulation of unmineralised bone matrix
- 19. Rickets Whistler 1645 Glisson 1650 Age : 6M – 2 ½ years Dunn 1998
- 20. Osteomalacia Pommer German Pathologist Late 19th century Severe Vit D or Phosphate depletion Bone pain Muscle weakness
- 21. In UK • Face exposure /week – 2hours • Limbs exposure /week – 30 min • Dark skin needs more sunlight to absorb • Birth weight is associated with Vitamin D status ( superior neuro-cognitive outcome associated with heavier birth weight)
- 22. Cause of Vitamin D deficiency Extrinsic Intrinsic • Low sunlight • Sun screen use • Dark pigmentation of skin MALABSORTPTION : • Gastrectomy • Small Bowel disease • Gluten • Pancreatic Insufficiency OTHER CAUSES : • Calcium deficiency with sec. hyper PTH • Primary hyper PTH • Pagets
- 23. Clinical manifestation of Osteomalacia : Osteomalcic symptoms • Bone pain and tenderness • Muscle weakness • Difficulty in walking • Skeletal pseudofractures Biochemical classic triad : • Low Ca • Low PO4 • High Alk Po4 In presence of : • Low vitamin D • High PTH
- 24. Genetic • VDDR-type 1 Vit D dependant rickets ( 1 alpha hydroxylase deficiency ) • HVDDR VDR ( Vitamin D receptor ) is defective
- 25. Vitamin D ( RCT ) Reduces the risk of fall by 19 % Reduces the risk of hip fracture by 18 % Reduces the risk of non vertebral fracture by 20 % Anti fall efficacy of Vit D > 60 Anti fracture efficacy of Vit D > 75
- 27. Vitamin D TB innate response to TLR activation of Myc TB Increases efficiency of macropahges MS Autoimmune encephalomylitis Type I DM Vit D protects against DM type I Crohns Important role in crohns
- 29. Source : • Vit D is the oldest homone Holic 1989 • A phytoplankton in the Sargasso sea ( Atlantic Ocean ) 500 million years old – have 1 % of dry weight of Vit D2 ( ergosterol) • Cod liver oil • Non-oily fish • Yeast • Mushrooms • Fortification – milk / Orange juice
- 30. • Finsen received a Noble prize in 1903 Exposure to sunlight was effective in treating several skin disorders like Lupus Vulgaris ( cause of TB infection in the skin ). • Low level of Vit D leads to 50 % high risk of Colorectal ,prostate, breast ,pancreatic, oesophageal cancer Gorham 2007 • Topical 1 , 25 OH2 D3 is used in treatment of the psoriasis Perez 1996 • High level of Vit D3 leads to low risk of MS Munger 2006
- 31. Vit D helps in • Otitis media Linday 2008 • URTI Ginde 2009 • Influenza infection Cannell 2006 • Downregulates renin productions helps in BP Li 2002 • Stimulates insulin production Mohr 2008 • Inhibit CRP and IL-10 Lee 2008
- 33. Vitamin D toxicity Hypercalcemia Hypercalciuria Renal stones Cancer Vit D toxicity is > 40 , 000 IU /day or 200 nmol /day
- 34. National Osteoporosis Society Guidelines on Vitamin D No universal consensus in Vit D Excluded Vit D in childhood / pregnancy / ESRD ( CKD 4-5 ) Conversion factor – 10 mu g Vit D = 400 IU Vit D Institute of Medicine ( IOM ) vitamin D threshold 25 OH D < 30 nmol is deficient 25 OH D 30 – 50 nmol /L is inadequate 25 OH D > 50 nmol /L for almost in whole population
- 35. Vit D Calciferol ( D2 or D3 ) D2 Ergocalciferol D3 Cholecalciferol 25 OHD Calcidiol / Calcifediol 1,25 di OH D Calcitriol
- 36. Treatment : • 25OHD - used in measurement Prentice 2008 • 25 OH D has a inverse relationship with PTH ( but also depends on – age /calcium intake /ethnicity /renal function/magnesium ) • Vit D3 - is the treatment of choice Rapid treatment - If too low - To start bisphosphonates No rapid treatment - No loading dose LOAD ING 300 000 IU for 6 weeks - MAINTENANCE 2000 IU daily MAINTENANCE 800 – 2000 IU daily
- 37. 2 Major systematic reviews Dietary intake of Calcium and vitamin D with relationship to vitamin D and bone health • Agency of healthcare research and Quality ( AHRQ) , University of Ottawa Chung 2009 • TUFTs evidence based practice Centre Cranney ,2007
- 38. DOH guidance : Not to test routinely in • Pregnant /breast feeding /teenage /young woman • > 65 years of age • Cultural reason of non exposure to sun • Darker skin
- 39. Future : Participation of 25 (OH) D and 1,25 (OH)2 D3 in various • anti-inflammatory • and immunoregulatory pathway
- 40. Thanks for listening ……..