Objectives of discussion• Current status – Dosage 60,000 units – Indications Limited – Need to expand perception – Need to expand usage & market How?• Suggestions – Dosage – Non standard Indications, Perception – How to expand usage & market?
What?• Producing more than one effect, the enabler• Paracrine – Chemical signals that diffuse into the area and interact with receptors on nearby cells – New insights due to the discovery of 1. Key activating and inactivating enzymes of vitamin D. 2. Its intracellular receptor, VDR - present in nearly every tissue and cell in the body 3. And hence adequate vitamin D status is essential for optimal functioning of all tissues and cells
Why? Dr. Robert P. Henry Creighton University Close this gap
When?• Serum 25(OH)D concentrations of 10 ng/ml (25 nmol/l) considered the cut-off for defining the lower limit of adequacy (in terms of preventing rickets). – But, serum concentration of > 30 ng/l (> 75 nmol / l) considered more appropriate to define physiologically optimal concentrations, associated with many other health benefits – Epidemiological studies have revealed a dose- dependent association between serum 25-OHD levels and immunity, pulmonary function, etc.
Where?• Serum total 25(OH)D is the: – Functional indicator of vitamin D status – Major storage form of vitamin D• Serum total 25(OH)D2 is of no value unless measured following vitamin D therapy;• Serum total calcitriol does not measure Risk assessment for vitamin vitamin D status; D -- Hathcock et al. 85 (1): No toxicity below 30,000 6-18, AJCN, 2007 iu/ day Tolerable upper level = 10,000 iu/
How? Vitamin D deficiency Vitamin D insufficiency Indexed mechanism Malabsorption Non-indexed mechanisms Genomic of Ca & P signalingShort latency Long latency Short latency Long latency effects effects effects effects Rickets, Osteoporosis The Falls • Cancer,Osteomalacia amount • Immune enough disorders, for the • Infections left sideHowever, current intake is based is noton recommendations of 1997 for enough Hence, what is the more the left side, totally overlooking for the useful endpoint? the needs for the right side right
Vitamin D and homeostasis1. Regulates more than 200 genes including genes for cellular proliferation, differentiation and apoptosis.2. Regulates extracellular matrix homeostasis in tissues, either indirectly or directly.3. Potent immune modulator of the adaptive immune system4. Stimulates the innate immune response upon infection.
Vitamin D and homeostasis Regulation of immune function by 1,25(OH)2D. 1,25(OH)2D suppresses adaptive immunity (A) by inhibiting the maturation of dendritic cells, reducing their capacity to present antigen to CD4 cells. 1,25(OH)2D further inhibits the proliferation and differentiation of CD4 cells into Th1 and Th17 cells and promotes the production of Th2 and Treg cells. On the other hand 1,25(OH)2D promotes innate immunity (B) in that when the macrophage is activated by TLRs, VDR and CYP27B1 areinduced enabling the macrophage to produce 1,25(OH)2D, which then induces cathelicidin, a potent antimicrobial peptide.
Vitamin D and immunomodulation• Immunomodulation is the therapeutic approach in which interventions can be achieved in auto regulating processes of the defense system.
Vitamin D and immunomodulation• All cells of the adaptive immune system (dendritic cells, monocytes, T cells and B cells, NK cells) express VDR either constitutively or after appropriate immune stimulation and are sensitive to calcitriol action.• High level of vitamin D causes: 1. Potent inhibition of dendritic cell maturation + 2. Lower expression of major histocompatibility complex (MHC) class II molecules, 3. Down-regulation of costimulatory molecules and 4. Lower production of proinflammatory cytokines such as IL-2, IL-12, IFN-y and IL-23
Vitamin D and immunomodulation• Dendritic cells (DCs) are immune cells that function as antigen-presenting cells. They act as messengers between the innate and adaptive immunity.• Vitamin D-induced inhibition of IL-12 release by dendritic cells has a profound effect on T lymphocyte differentiation by downregulating Th1 & upregulating Th2.• As a result, the following are achieved:
Vitamin D and immunomodulation1. Promotes differentiation2. Antiproliferative - Potent antiproliferative effects on T cells, principally T helper cells, and suppresses B cell antibody production both directly and indirectly3. Immunosuppressive – one of the most important modulatory actions is its effect on regulatory T cells (Tregs) which prevent the activation of peripheral autoreactive T cells.4. Promotes infection control - can enhance the phagocytic activity of macrophages and increase the activity of natural killer cells.
Vitamin D and infection• In cell types such as epithelial cells and WBCs, the genes encoding for antimicrobial polypeptides such as cathelicidin are driven by VDRE-containing promoters – As cathelicidin is also diffusely expressed in the surface epithelia of human airways, in the submucosal glands, and in secretory granules of macrophages and neutrophils, vitamin D insufficiency may contribute to chronic respiratory infections and airway colonization – In monocytes, a local increase of the 1,25-(OH)2D-VDR complex (via TLR-2) stimulates the production of cathelicidin, resulting in an improved intracellular eradication of MBT.
Vitamin D and Tuberculosis• Higher sputum conversion and radiological improvement (100%) compared to a placebo group (76·7%) in TB patients administered vitamin D or placebo following the 6th week of standard TB treatment.• Addition of calcitriol to primary human macrophages infected with virulent M. tuberculosis reduced the number of viable bacilli.
Vitamin D and Tuberculosis• The immune system is able to detect M. tuberculosis via pathogen-associated molecular patterns (PAMPs); VDR activation and induction of cathelicidin.• The cathelicidin gene encodes an anti- microbial peptide, LL-37, and this gene, in humans (but not in mice), contains a vitamin D response element.• Therefore binding of vitamin D leads to LL- 37-mediated killing of M. tuberculosis.
Vitamin D and Tuberculosis• Cathelicidins and defensins are small peptides with amphipathic structures that allow them to disrupt the integrity of the pathogen cell membrane, resulting in its death.• These proteins are expressed by most immune cells or those epithelial cells that are in contact with the environment.• Deficiency in these peptides results in increased susceptibility to infection.
Vitamin D and HIV• Use of certain ARTs, especially efavirenz, is associated with alterations in cholecalciferol levels.• Studies have also shown that vitamin D insufficiency/deficiency at baseline was associated with increased risks of HIV disease progression, anemia, and all-cause mortality, as well as mother-to-child transmission of HIV.
Vitamin D and COPD• Although still defined using pulmonary criteria, COPD is a chronic disease state that is not confined to the lungs but is typically associated with systemic inflammation and different comorbidities.• The importance of such broader context has been indirectly confirmed by the Toward a Revolution in COPD Health (TORCH) study. – In the 3-year follow-up of a large cohort of patients with COPD, only one-third of deaths could be attributed to respiratory failure, whereas the majority died from lung cancer or cardiovascular eventsVitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009
Vitamin D and COPD• A strong relationship exists between serum levels of 25-OHD and pulmonary function, as assessed by FEV1 and FVC.• The observation that smoking African Americans develop severe airflow obstruction more rapidly than Caucasians is in agreement with the idea that a presumed lower vitamin D status in African Americans correlates with an increased susceptibility to COPD. bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009Vitamin D beyond
Vitamin D and COPD• Appropriate antimicrobial therapy is considered the mainstay for treating acute exacerbations of COPD.• In case of colonization, repetitive and long-term antibiotic therapy are still avoided as they contribute to multiresistance of colonizing strains.• A potent alternative approach would be the up- regulation of the innate immune defense system, especially with regard to native antimicrobial polypeptides (AMP).• the ability of vitamin D to enhance cathelicidin expression, might reduce pathogen load and the frequency of these exacerbations.Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009
Vitamin D and COPD• Muscle weakness is a prominent feature in rickets and chronic renal failure,• Skeletal muscle weakness common observation in moderate to severe COPD and is an independent predictor of respiratory failure and death.• Main causes of COPD deterioration include a combination of: – Disuse because of respiratory limitation, – Elevated oxidative stress, – Systemic inflammation, – Hypoxia, and – Frequent steroid intake.Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009
Vitamin D and COPD• Whether sufficient vitamin D supplementation will finally reduce cardiovascular or lung cancer mortality in patients with COPD is currently unknown, but, given the potential beneficial effects of other anti-inflammatory agents like statins in the treatment of COPD, it is worthwhile to further explore such hypothesis.Vitamin D beyond bones in COPD; Am J Respir Crit Care Med Vol 179. pp 630–636, 2009
Vitamin D and fractures• A +ve association between 25-OHD and muscle strength or lower extremity function in elderly people has been noted.• A meta-analysis of 5 randomized clinical trials revealed that vitamin D supplementation reduces the risk of falls by 22% compared with placebo.
Vitamin D and cancer• Studies in males have shown an increment of 10 ng/ml in estimated 25-OH D was associated with: – a 17% reduction in total cancer incidence, – a 28%reduction in total cancer mortality, and – a 45% reduction in digestive cancer mortality
A rule of thumb• To raise Serum 25- (OH)D by 1 ng./ml. [2.5 nmol / L] one needs 100 additional i.u. / day of vitamin D3 – Hence, to raise a patient’s Vitamin D level from 15 to 30 ng. / ml.; there will be an additional requirement of 1500 i.u./ day. – Great inter-patient variability in Cmax