Vitamin D Deficiency and Reduced Lung Function in Connective Tissue-associated Interstitial Lung Diseases

Jared T. Hagaman, MD; Ralph J. Panos MD, FCCP; Francis X. McCormack, MD, FCCP; Charuhas V. Thakar, MD; Kathryn A. Wikenheiser-Brokamp, MD, PhD; Ralph T. Shipley, MD; Brent W. Kinder, MD, FCCP

Disclosures

CHEST. 2011;139(2):353-360. 

In This Article

Discussion

We demonstrated that vitamin D deficiency and insufficiency are highly prevalent in a cohort of patients with ILD and are associated with the presence of an underlying CTD independent of other measurable confounders in this patient population. Furthermore, among those subjects with CTD-ILD, reduced 25-hydroxyvitamin D3 levels were strongly associated with reduced lung function. These findings have important implications for important ILD comorbidities, such as osteoporosis and opportunistic infections, and possibly the underlying fibrogenic process. Underscoring the potential impact on bone health is the observance that 55% of our cohort had taken corticosteroids prior to 25-hydroxyvitamin D3 measurement and thus were at high risk for bone demineralization. Beyond the impact on bone health, the strong association of vitamin D deficiency with the presence of CTD seen in this and other studies suggests a possible pathogenic role of vitamin D in autoimmune disorders, which frequently have life-threatening manifestations in the lung.

It has been suggested that corticosteroid usage re duces 25-hydroxyvitamin D3 levels through increased consumption.[33,34] As expected, those with CTD-ILD in our study were more likely to have received corticosteroids, which could potentially confound the relationship between 25-hydroxyvitamin D3 levels and CTD-ILD. However, we did not observe a statistically significant association between 25-hydroxyvitamin D3 levels and prednisone use, and any effect appeared to be modest (ie, those on prednisone had levels only 3 ng/mL less.) Indeed, the observed association of CTD-ILD with hypovitaminosis D was unchanged after adjusting for corticosteroid usage in multivariate models. This suggests the association of CTD-ILD and hypovitaminosis D cannot be explained by corticosteroid usage.

The immunoregulatory role of 1,25-(OH)2 D, the biologically active form of vitamin D, provides biologic plausibility for a pathogenic role of hypovitaminosis D in the development of autoimmune diseases and end-organ dysfunction, such as ILD. All cells of the adaptive immune system express vitamin D receptors and are sensitive to the action of 1,25-(OH)2 D.[35] High levels of 1,25-(OH)2 D are potent inhibitors of dendritic cell maturation with lower expression of major histocompatibility complex class 2 molecules, down-regulation of costimulatory molecules, and lower production of proinflammatory cytokines.[36,37] In several mouse models, 1,25-(OH)2 D drives the adaptive immune system from a T helper (Th) 1/Th17 response toward a Th2 and regulatory T-cell response, suggesting the potential for beneficial effects on the occurrence and progression of Th1-mediated autoimmune diseases in humans.[38] The immune system of vitamin D receptor-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases, such as inflammatory bowel disease or type 1 diabetes, after exposure to predisposing factors.[39] Furthermore, laboratory evidence suggests vitamin D might play a role in regulating autoantibody production by B cells, inhibiting the ongoing proliferation of activated B cells and inducing their apoptosis.[40] A common theme in the immunomodulatory functions of vitamin D is that higher levels are immunosuppressive, which is consistent with a potential role for hypovitaminosis D in the pathogenesis of autoimmune disorders.

Vitamin D has also recently been implicated in the development of lung disease. In patients with COPD, National Health and Nutrition Examination Survey III showed an association between FEV1 and 25-hydroxyvitamin D3, even when adjusted for activity level.[41] Despite this apparent relationship, a pathogenic relationship between low 25-hydroxyvitamin D3 levels and COPD has yet to be established.[35] In asthma, reduced 25-hydroxyvitamin D3 levels are also associated with impaired lung function, increased airway hyperresponsiveness, and reduced glucocorticoid response.[26] To our knowledge, our study is the first to document a high prevalence of hypovitaminosis D in patients with diffuse parenchymal lung disease. As in these recent studies of airway-centered diseases of the lung, we found a strong association between lung function and vitamin D level in subjects with ILD, particularly among those with CTD-ILD. In the laboratory, 25-hydroxyvitamin D3 levels are reduced in rats with bleomycin-induced lung fibrosis.[42] Further, vitamin D appears to inhibit the profibrotic effects of transforming growth factor β in lung fibroblasts and epithelial cells, and may blunt epithelial-to-mesenchymal tran sition.[43] The specific mechanisms for autoimmune parenchymal lung injury and how tissue vitamin D levels modulate its occurrence need to be further investigated.

Our study has limitations that merit discussion. First, although our study included a relatively large population by ILD cohort standards, it was only performed at a single tertiary center. Consistent with referral patterns to our center, we had a higher proportion of patients with CTD-ILD than may be seen in other institutions or in a population of patients with ILD in the general public. Given the potential influence of ambient sun exposure on serum vitamin D levels, it is possible that other centers from warmer climates may not observe such a high prevalence of hypovitaminosis D. We attempted to mitigate the influence of sun exposure during the analysis phase by adjusting for season of measurement. Next, as our study was cross-sectional in design, we did not evaluate whether vitamin D supplementation is associated with any improved clinical outcomes. Prospective controlled interventional studies are needed to determine if vitamin D supplementation can ameliorate symptoms and improve outcomes in patients with CTD-ILD.

Vitamin D is increasingly recognized as an important mediator of immune function and lung health.[26] We have shown that there is a high prevalence of vitamin D deficiency and insufficiency in patients with ILD, particularly those with CTD, and that lower 25-hydroxyvitamin D3 levels are associated with reduced lung function. Future study should investigate the underlying molecular mechanisms of this observed association and determine if supplementation with vitamin D is associated with improved clinical outcomes, including longitudinal changes in lung function as well as other systemic disease manifestations.

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