Vitamin D in Health and Disease-Current Updates Dr. Saidunnisa Begum M.D Professor of Biochemistry

 All studies, in virtually all nations, irrespective of latitude, show that the majority of the world’s population has inadequate vitamin D status.  “Most people are not exposing themselves to the sun during the right hours which is from 11:00am to 2:00pm and this has resulted in a major Vitamin D epidemic and various health consequences related to it.  “The sun is the key source of vitamin D”. Studies suggest globally many suffer from Vitamin D deficiency

1.Sun exposure obtaining 10 to 15 minutes per day, with 40% of the skin exposed without sunscreen. 2.Consuming vitamin D rich foods such as oily fish example salmon, mackerel, sardines. 3.Vitamin D supplementation. Three Ways to Obtain Vitamin D

Vitamin D Metabolism (UVB nm)

 Vitamin D plays an important role in maintaining an adequate level of serum calcium and phosphorous.  Without Vitamin D, only 10-15% of dietary calcium and about 60% of phosphorous is absorbed.  It has great effect in forming and maintaining strong bones. Calcium homeostasis

Why does vitamin D affect so many biologic processes?

 Vitamin D controls (directly or indirectly) more than 3000 genes that 1.Regulate calcium and bone metabolism, 2.Modulate innate immunity, 3.Control cell growth and maturation, 4.Regulate the production of insulin and renin, 5.Inhibit angiogenesis 6.Induce apoptosis. WHY DOES VITAMIN D AFFECT SO MANY BIOLOGIC PROCESSES?

 The various tissues and cells of our bodies cannot make enough calcitriol to open up their DNA libraries adequately.  Their functioning is thus impaired When vitamin D is in short supply,

 Vitamin D receptors found in:  Gut, bone, brain, breast, prostate, lymphocytes, placenta, and other tissues, pancreatic islet cells, monocytes, transformed B cells, activated T cells, neurons, ovaries, pituitary, aortic endothelium, placenta, skeletal muscle cells.  Zittermann A. Br J Nutr. 2003;89(5):552.  Bischoff HA, et al. Histochem J 2001;33:19.  Cells containing enzyme 1,25 dihydroxycholecalciferiol are found in :  Breast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, brain, placenta  Holllick MF. Am J Clin Nutr (3):362.  Zehnder et al. J Clin Endocrin Metab. 2001;86(2) Vitamin D Receptors

 Universally accepted that the circulating level of 25-OH-Vitamin D should be used as an indicator of Vitamin D status due to its: 1. Ease of measurement, 2.Long half-life in circulation (approx 2- 3weeks) 3. Correlation of its level with clinical conditions. Laboratory Assessment

 Methodology: Vitamin D blood testing by HPLC or LC/MS-MS) (modified method)  Recommend serum as the sample of choice.  Express results in nmol/L or ng/ml  <20ng/ml (50nmol/L)= Vitamin D deficiency  21-29ng/ml(52-72nmol/L)= insufficiency  30ng/ml or>= sufficient Vitamin D Reference Ranges

1.UVB-related deficiency 2.Medical conditions-related deficiency Causes of Vitamin D deficiency

In elderly: 1.Elderly due to decreased presence of skin 7- dehydrocholesterol which is a precursor for vit-D synthesis. 2.Reduced mobility or institutionalization that discourages sun exposure. UVB-related deficiency

 Dark skin people have more melanin in epidermis which competes with 7-dehydrocholestrol for absorption of UVB photos.  Dark skin people are less efficient in producing vitamin D than whites.  It has been reported dark skin people require times more exposure to sunlight to produce the same amount of vitamin D as a person with white skin. Dark skin

Season, latitude, and the time of day  Zenith angle is dependent on factors such as:  Time of day  Season of the year  Latitude  These have great effects on Vitamin D production.  Example residents of 42 0 N (Boston), 52 O N (Canada) 61 0 N (Norway) cannot produce Vitamin D for 4,5,6 months respectively.

UV radiations  UV are EMR divided into 3 components according to wavelength:  UVA: nm  UVB: nm  UVC: nm

 Absorbed by the epidermal layer where highest concentration of 7-dehydrocholesterol exists.  Optimum wavelength range is nm (D-UV)  UVB exposure does not result in excessive production of vitamin D risking intoxication because previtamin D3 is converted to inactive product tachysterol and lumisterol. Advantages of UVB

 These efficiently absorb UVB radiation, dramatically prevents the interaction of UVB with 7-dehydrocholesterol, the process of previtamin D3 generation.  It has been shown that SPF of 8 reduces the production of pre vitamin D3 by 95% and 99% by SPF 15. Sunscreens

 Fat Malabsorption: vitamin D a fat soluble vitamin requires dietary fat in the gut for absorption.  Certain pathological conditions, such as fat malabsorption like CF, crohns, celiac disease etc. may lead to vitamin D deficiency. Medical conditions-related deficiency

 Anticonvulsants use: long term use can result in osteomalacia which is due to induction of the catabolism of 1,25-dihydroxyvitamin D.  Chronic renal disease: due to inadequate 1,25- dihydroxyvitamin D formation.  Obesity: have lower 25,hydroxyvitamin D levels. 7- dehydrocholestrol in the skin of obese and non- obese individuals is same, but the subcutaneous fat stores the vitamin D3 and results in less release in to circulation. Medical conditions-related deficiency

 IU/day for infants  IU/day for Children 1-10 years  IU/day for teenagers and adults  Michael F. Holick, Clinical Chemistry, 56: (2011) Recommendation:

Disease management and prevention  Disease management:  Osteoporosis  Muscle weakness  Hypertension  Multiple sclerosis  Malabsorption  Disease prevention:  Cancer  Rheumatoid Arthritis  Diabetes  Tuberculosis

 Link between vitamin D deficiency and osteoporosis is well established especially in elderly which is due to marked suppression of intestinal calcium absorption resulting in low mineral content and bone density thus increasing the risk of fractures. Osteoporosis

 Trials using IU/Day oral vitamin D with or without calcium supplementation found significant reduction by:  26% in risk of sustaining hip fractures. (are more prevalent world wide)  23% in non-vertebral fractures. Meta-analysis

 Non-specific muscle aches, weakness and pain are associated with vitamin D deficiency.  Vit D receptors in skeletal muscle require vitamin D for its function.  Bischoff HA, et al. Histochem J 2010;33:19.  Vit D deficiency reported to affect predominantly the weight-bearing antigravity muscles of the lower limb, which are necessary for postural balance and walking Glerup H et al. Calcif Tissue Int 2011;66:419.  Significant correlation between serum 25(OH)D3 concentration and the occurrence of falls in elderly reported in literature.  Mowé M et al. J Am Geriatr Soc 2005;47:220  Stein MS et al. J Am Geriatr Soc 2009;47:1195 Muscle weakness

1.5-Month randomized controlled trial in elderly people received 800IU of VitD2 plus calcium daily exhibited:  72% reduction in the risk of falls as compared with placebo group. 2. Long term intake of 700IU vit D plus 500mg calcium in 246 older women showed a:  Beneficial reduction in falls by: 46% as compared with placebo group. Meta-analysis

Hypertension  Millions of people are affected by hypertension worldwide.  Low 1,25-dihydroxyvitamin D levels activate renin- angiostensin -aldosterone system in which could predispose patients to blood pressure.

 BP higher in winter.  BP higher with increasing latitude.  BP higher with darker skin pigmentation.  HTN pts given UV light treatments 3 times per week for 6 weeks had Vit D level increases of 162% and saw decrease in BP  Krause et al. Lancet. 2011;352(9129):709. Hypertension

 "Vitamin D deficiency is an unrecognized, emerging cardiovascular risk factor,  Low vitamin D levels activate:  Renin-angiotensin-aldosterone system and, in doing so, predispose patients to hypertension and a stiffening and thickening of the heart and blood vessels.  Vitamin D deficiency also alters hormone levels and immune function, which can increase the risk of diabetes, a major contributor to CVD. Heart Disease

 Recent data suggest patients with vitamin D levels below 15 ng/ml were twice as likely to experience a heart attack, stroke or other CV event within the next five years compared to those with higher levels.  December, 9, 2011, issue of the Journal of the American College of Cardiology ( JACC ),  Deaths from CAD more common in winter  Scragg. Int J Epidemiol. 2010;10(4):337. Framingham Heart Study

 Diabetes  Cancer  Rheumatoid Arthritis  Tuberculosis Disease prevention

1.Plays a role in insulin secretion and resistance. 2.Vitamin D receptors are present on pancreatic β-cells and skeletal muscle and the active enzyme (1,25 dihyroxycholecalciferol) is expressed in pancreatic β- cells. 3.Vitamin D stimulates the expression of insulin receptor and enhances insulin responsiveness for glucose transport in cells. December, 9, 2011, issue of the Journal of the American College of Cardiology ( JACC ), Potential mechanisms for the effects of vitamin D on glucose homeostasis:

Mechanism same as glucose homeostasis  Vit D may directly induce insulin secretion by binding to the receptors on β-cells or it may indirectly affect β-cells function by regulating calcium level through β- cells.

 The prevalence of diabetes for all age groups would increase to 4.4% by  Vitamin D deficiency inhibits pancreatic secretion and turn over of insulin, resulting in impaired glucose tolerence.  Low Vit D levels associated with insulin resistance and β-cell dysfunction. Diabetes Type 2

 Highest Vit D levels associated with 60% improvement in insulin sensitivity  Chiu. Am J Clin Nutr. 2010;79:820.  Trial of 83,779 women with no history of DM over 2- 4years showed that a combined daily intake of >1200mg calcium and >800IU vitamin D are associated with 33% low risk of type-2 DM  Borrisova et al. Int J Clin Pract. 2011;57(4):258. Meta- Analysis

 TB is a major global problem.  Low vitamin D status is an independent risk factor for active TB in south Asians.  The relationship between vitamin D and tuberculosis may be mediated through two mechanisms:  Increased production of cathelicidin (defensins- antimicrobial peptides) resulting in TB destruction.  Enhancement of macrophage ability restricts intracellular growth of TB. Vitamin D insufficiency and tuberculosis

Autoimmune Disease, inflammation and cancer Decrease T-cell responsiveness through the inhibition of cellular proliferation and Reduction in lymphokine production so it is effective as immunosuppressant in Rhematoid Arthtritis and Graves Disease Cancer: Modulates the transcription of several oncogenes involved with cell differentiation and proliferation C-myc, c-fos, c-sis Vitamin D levels inversely correlated to colon cancer mortality The active form of vitamin D (1,25(OH)2D3) has been shown to inhibit growth of Mycobacterium tuberculosis (M. tuberculosis) through : Increased production of cathelicidin Enhancement of macrophage ability

 Vitamin D might help protect against cancer, some studies have shown it helps  Slows the proliferation of cancer cells.  It may also improve the immune system’s defense against some cancers and  May reduce the growth of blood vessels that nourish cancer cells. Vitamin D deficiency linked to cancer

 Multiple sclerosis is an autoimmune disease in which myelin sheath is attacked by autoantibodies.  Adequate vitamin D intake increases TGF-β-I which is an important anti-Inflammatory cytokines.  Thus inadequate vitamin D intake is suggested as a mechanism that could contribute to inflammation and, consequently, development of MS.  Zittermann A. Br J of Nutr. 2011;89: Vitamin D deficiency and inflammation and Multiple sclerosis

 Mood changes like anxiety and depression increase during winter months due to changing levels of vitamin D3 during winter.  Periodontal Disease: Common chronic inflammatory disease characterized by loss of periodontal attachment leading to tooth loss due to osteoporosis. Health maintenance and Vitamin D

 Excessive exposure to sunlight does not lead to overproduction of vitamin D.  Supplemental vitamin D in certain clinical settings may have toxicity.  Symptoms:  Hypercalcemia, High blood pressure, headache,  Fatigue, loss of appetite, excessive thrust and polyuria, severe itching, vomiting, diarrhea, constipation, kidney damage, joints and muscle pain. Is Vitamin D Toxic. ?..

 Studies showed that doses of more than 50,000 IU/day raises 25 hydroxy vitamin D to> than 150ng/ml.  Indicator of direct Vit D toxicity is :  Elevated serum calcium- and 25OHVitD > 90ng/ml  Berkow. Merck Manual. 2010:928.  Vieth R. Am J Clin Nutr. 2011;69 Toxicity

 With the recognition of widespread vitamin D deficiency/insufficiency in children and adults, there is no need to measure everybody's blood 25(OH)D.  It would be much more cost-effective to implement a vitamin D supplementation program for all children and adults until there is higher fortification of vitamin D in foods and drinks. The Dilemma: To Screen or Not to Screen for 25(OH)D Concentrations?

 Replacement  ,000IU per day for 5-9 months  Baseline supplementation  Infants 1000 IU/day  Children 2000 IU/day  Adults 2000 IU – 4000 IU/day  Pregnancy and Lactation 4000 IU/day Supplementing

 Future intervention studies which would aim at implementing awareness programs to educate people about the beneficial role of Vitamin D.  Vitamin D deficiency and insufficiency can be both corrected/treated and prevented safely through supplementation, fortification and UVB.  Encourage policy makers to implement a policy in the regarding the need for fortification of drinks and some food items with Vitamin D. Conclusions

Vitamin D deficiency 25 (OH)D <20ng/ml 50,000IU D2 every 2 wks IU D3 daily Sunlight exposure 50,000IU/wk D2 8weeks Treatment Recommendations For Vitamin D Deficiency

 Exposing to the sun during the right hours which is from 11:00am to 2:00pm to prevent various health consequences related to it. Recommendation