Effect of Vitamin D on Tuberculosis and HIV ... - ATS Journals

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External validation is necessary in predic- tion research: a clinical example. J Clin Epidemiol 2003;56:826–832. Effect of Vitamin D on Tuberculosis and HIV.
Correspondence 3. Bleeker SE, Moll HA, Steyerberg EW, Donders AR, Derksen-Lubsen G, Grobbee DE, Moons KG. External validation is necessary in prediction research: a clinical example. J Clin Epidemiol 2003;56:826–832.

Effect of Vitamin D on Tuberculosis and HIV Replication Depends on Conversion to Calcitriol and Concentration

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To the Editor:

Dr. Wejse and colleagues reported results of a randomized controlled trial of cholecalciferol supplementation in patients on treatment for tuberculosis and found no effect on clinical outcome or mortality (1). The authors used 25 hydroxy cholecalciferol for supplementary treatment and did not report on its effect on levels of the active form of vitamin D, which is 1,25 dihydroxy cholecalciferol. The distinction between 25 hydroxy cholecalciferol and its active form 1,25 dihydroxy cholecalciferol (calcitriol) is important because inflammatory stimuli associated with increased tumor necrosis factor (TNF) concentrations can block the stimulatory effect of parathyroid hormone (PTH) on the renal 1-a-hydroxylase generating calcitriol (2). TNF appears to down-regulate PTH receptors. TNF is a key mediator in the immune response to Mycobacterium tuberculosis, and in HIV infection there was a strong negative correlation of TNF and calcitriol levels (3). It may therefore be important to give 1,25 dihydroxy cholecalciferol and not 25 hydroxy cholecalciferol to achieve an effect on immunity against tuberculosis. The authors speculated that the dose of vitamin D used may not have been sufficient to generate a clinical effect but did not discuss the potential implications of the choice of a high dose of vitamin D for the immune response in patients with tuberculosis and on viral replication in HIV infection. The calcitriol effect is concentration dependent. In supraphysiological concentrations calcitriol acts as an immune suppressant. It inhibits the production of a wide range of cytokines including IFN-g. IFN-g is a key cytokine involved in antimycobacterial immunity, and calcitriol concentrations above 10 nmol/L have been shown to reduce IFN-g production in vitro in peripheral blood mononuclear cells (4). Subsequent investigations found that calcitriol suppressed IFN-g production in response to live M. tuberculosis in human peripheral blood mononuclear cells (PBMC) with a maximum suppression at a concentration of 100 nmol/L (5). Wejse and coworkers observed a trend for increased mortality in HIV positive vitamin D supplemented patients (1). Recent experiments in HeLa, U937 and Cos-1 cells revealed that the vitamin D receptor is able to stimulate HIV-1 long terminal repeat transactivation increasing HIV gene expression (6). Future trials need to use calcitriol to avoid potential problems with lack of activation of the applied vitamin D preparation due to systemic inflammation. Dose regimes need to avoid high doses leading to immune suppression associated with plasma levels greater than 10 nmol/L to optimize its effect against M. tuberculosis infection.

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for tuberculosis: a double-blind randomized placebo-controlled trial. Am J Respir Crit Care Med 2009;179:843–850. Ebert R, Jovanovic M, Ulmer M, Schneider D, Meissner-Weigl J, Adamski J, Jakob F. Downregulation by nuclear factor kappa-B of human 25 hydroxyvitamin D3 1-hydroxylase promoter-1. Mol Endocrinol 2004;18:2440–2450. Haug CJ, Aukrust P, Haug E, Morkrid L, Mueller F, Froland SS. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 1998;83:3832–3838. Manolagas SC, Provvedini DM, Tsoukas CD. Interactions of 1, 25dihydroxyvitamin D3 and the immune system. Mol Cell Endocrinol 1985;43:113–122. Vidyarani M, Selvaraj P, Jawahar MS, Narayanan PR. 1,25 dihydroxyvitamin D3 modulated cytokine response in pulmonary tuberculosis. Cytokine 2007;40:128–134. Nevado J, Tenbaum SP, Castillo AJ, Sanchez-Pacheco A, Aranda A. Activation of the human immunodeficiency virus type 1 long terminal repeat by 1a 25-dihydroxy vitamin D3. J Mol Endocrinol 2007;38:587– 601.

From the Authors:

Dr. Eisenhut in his letter points out that 1,25-dihydroxycholecalciferol (calcitriol) is the active form of vitamin D and suggests that we should have used calcitriol instead of 25-OH-cholecalciferol (25-OH-D3) in our study (1). 25-OH-D3 is the storage form of vitamin D (half life 2–3 wk), and consequently we determined s-25OH-D3 levels to be a measure of the vitamin D status. Measurement of s-calcitriol often gives very confusing results due to the short half life (12–24 h), and in severe vitamin D deficiency, low to normal and even raised levels of s-calcitriol have been reported. Dr. Eisenhut ignores the important local autocrine 1-ahydroxylase activity in the monocytes and macrophages (2). Holick and Chen recently reviewed the calcemic and noncalcemic effects of vitamin D (3). The PTH-stimulated renal 1-ahydroxylase activity appears to be important for the calcemic actions of vitamin D, and maintains stable serum levels of calcium. The noncalcemic actions of vitamin D seem primarily to be mediated through autocrine 1-a-hydroxylase activity. Local calcitriol synthesis is not dependent on PTH stimulation, but is dependent on the substrate 25-OH-D3, and seems to be maximal with serum concentrations of 25-OH-D3 greater than 75 nmol/L. The use of calcitriol as suggested by Dr. Eisenhut would demand a close monitoring of serum levels of calcitriol to avoid supraphysiological concentrations, which could result in immunosuppression or even hypercalcemia. We believe in the use of vitamin D3, as it is safer and easier to use. Correction of vitamin D deficiency ensures a sufficient intracellular level of calcitriol due to local autocrine 1-a-hydroxylase activity. Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

CHRISTIAN WEJSE Aarhus University Hospital Skejby, Denmark HENNING GLERUP Aarhus University Hospital Silkeborg, Denmark

Conflict of Interest Statement: The author has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.

MICHAEL EISENHUT Luton & Dunstable Hospital NHS Foundation Trust Luton, United Kingdom References 1. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen PL. Glerup H, Sodemann M. Vitamin D as supplementary treatment

References 1. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen PL, Glerup H, Sodemann M. Vitamin D as supplementary treatment for tuberculosis: a double-blind randomized placebo-controlled trial. Am J Respir Crit Care Med 2009;179:843–850. 2. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, et al. Toll-like receptor triggering of a