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


CHEST. 2011;139(2):353-360. 

In This Article

Abstract and Introduction


Background: Vitamin D is a steroid hormone with pleiotropic effects including immune system modulation, lung tissue remodeling, and bone health. Vitamin D deficiency has been implicated in the development of autoimmune diseases. We sought to evaluate the prevalence of vitamin D deficiency in a cohort of patients with interstitial lung disease (ILD) and hypothesized that vitamin D deficiency would be associated with an underlying connective tissue disease (CTD) and reduced lung function.
Methods: Patients in the University of Cincinnati ILD Center database were evaluated for serum 25-hydroxyvitamin D levels as part of a standardized protocol. Regression analysis evaluated associations between 25-hydroxyvitamin D levels and other variables.
Results: One hundred eighteen subjects were included (67 with CTD-ILD, 51 with other forms of ILD). The overall prevalence of vitamin D deficiency and insufficiency in the study population was 38% and 59%, respectively. Those with CTD-ILD were more likely to have vitamin D deficiency (52% vs 20%, P < .0001) and insufficiency (79% vs 31%, P < .0001) than other forms of ILD. Diminished FVC was associated with lower 25-hydroxyvitamin D 3 levels (P=.01). The association between vitamin D insufficiency and CTD-ILD persisted (OR, 11.8; P < 0001) after adjustment for potential confounders. Among subjects with CTD-ILD, reduced 25-hydroxyvitamin D 3 levels were strongly associated with reduced lung function (FVC, P =.015; diffusing capacity for carbon monoxide, P =.004).
Conclusions:There is a high prevalence of vitamin D deficiency in patients with ILD, particularly those with CTD-ILD, and it is associated with reduced lung function. Vitamin D may have a role in the pathogenesis of CTD-ILD


In addition to its essential role in calcium homeostasis, vitamin D has many nonskeletal effects that are important in health and disease.[1] In animal models, vitamin D has been studied as a modifiable environmental factor[2] in a wide array of autoimmune diseases, including connective tissue diseases (CTDs).[3–7] Epidemiologic evidence also supports an association between vitamin D and autoimmune disorder susceptibility and severity.[8–10] In systemic lupus erythematosus (SLE), for example, up to two-thirds of patients are vitamin D deficient, and one in five have critically low levels of 25-hydroxyvitamin D3, the form of vitamin D commonly measured in the serum.[10,11] Disease activity in SLE has been associated with vitamin D level,[12] and vitamin D supplementation has led to attenuation of some disease manifestations in experimental models.[3] Patients with undifferentiated connective tissue disease (UCTD),[13] rheumatoid arthritis (RA),[14] fibromyalgia,[9,15] and general rheumatologic populations[16] have also been shown to have lower serum 25-hydroxyvitamin D3 when compared with healthy control subjects, even after controlling for activity level and dietary intake. These epidemiologic and clinical associations suggest that vitamin D may be involved in the pathogenesis and end-organ dysfunction of these autoimmune disorders.

Lung involvement is common in CTD with prevalence estimates of up to 80%,[17] with diffuse interstitial lung disease (ILD) being the most common pulmonary manifestation. The impact of pulmonary involvement is underscored by the fact that it is now the leading cause of death in several CTDs.[17–20] Corticosteroids are a mainstay of treatment regimens in patients with CTD-ILD,[21,22] and the detrimental effects of long-term usage on bone health are well documented.[23] In SLE, vitamin D insufficiency was associated with cumulative corticosteroid exposure,[24] and the interplay of chronic inflammation and low vitamin D levels has been causally implicated in low bone mineral density in these patients.[25] In subjects with asthma, it has recently been reported that reduced vitamin D levels are associated with impaired steroid responsiveness.[26] Thus, the presence of hypo-vitaminosis D may be particularly relevant for patients with CTD-ILD, who are often treated with corticosteroids.

The pulmonary, bone, and autoimmune actions of vitamin D are of interest in the setting of CTD, given the significant role ILD can play in the lives of these patients. However, there is no available information in the literature regarding the prevalence of vitamin D deficiency among patients with diffuse parenchymal lung disease or whether reduced levels are associated with end-organ dysfunction. For this study, we examined the prevalence of vitamin D deficiency and insufficiency in a cohort of patients with ILD and hypothesized that 25-hydroxyvitamin D3 levels would be associated with the presence of an underlying CTD diagnosis. Further, we sought to determine if serum 25-hydroxyvitamin D3 levels were associated with impaired lung function as measured by pulmonary function tests and the 6-min walk test (6MWT).