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

doi:10.1378/chest.10-0968

Chest

Volume 139, Issue 2, February 2011, Pages 353-360

https://doi.org/10.1378/chest.10-0968 Get rights and content

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 D₃ 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 D₃ 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.

Section snippets

Study Subjects, Clinical Evaluation, and Radiographic Evaluation

Consecutive patients seen in the University of Cincinnati Interstitial Lung Disease Clinic were enrolled in a longitudinal database and evaluated for serum 25-hydroxyvitamin D₃ levels as part of a standardized evaluation protocol between October 2008 and January 2010. Subjects enrolled in the database underwent a detailed questionnaire evaluating symptom and exposure history, past and current medication usage, functional status, family history, and comorbidities. Medical records of all patients

Subjects

One hundred eighteen patients were included in the study (67 with CTD-ILD and 51 with other forms of ILD). Clinical characteristics of the cohort and comparisons between patients with CTD-ILD and other forms of ILD are shown in Table 1. The distribution of patients with ILDs not associated with CTD was the following: idiopathic interstitial pneumonias (n = 22), granulomatous diseases (n = 16), unclassifiable ILD (n = 8), and miscellaneous forms of ILD (n = 5). The CTD-ILD subjects were more

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

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Cited by (27)

Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis
2019, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Administration of VitD has been shown to attenuate several types of experimental fibrosis including renal, hepatic and lung fibrosis through mechanisms that involve both epithelial protective effects and negative regulation of fibroblast homeostasis [26–28,31,41]. With regards to lung fibrosis both clinical and mechanistic data are still scarce [32,42–44]. Early epidemiologic evidence suggested a link between low VitD levels and functional indicators of disease severity in a small and heterogeneous cohort of patients with ILDs-associated with connective tissue disorders [42].
Vitamin D (VitD) is a steroid hormone with cytoprotective and anti-inflammatory properties. Epidemiological studies have suggested a link between VitD deficiency and risk of development of chronic lung diseases. Its role in lung fibrosis is largely unknown. The aim of our study was to investigate the role of VitD in experimental and human lung fibrosis.
VitD (25-OH-D3, 2 μg/kg) was orally administered from day 3-day 13 following bleomycin-challenge, in 8–10 weeks-old C57/BL6 mice. Mouse Lung Fibroblasts (MLFs) were pre-treated with VitD (2 μM for 24 h) and then stimulated with TGFB1 (10 ng/ml). Serum samples from 93 patients with IPF and other forms of interstitial lung diseases (ILDs) were prospectively collected for VitD measurement.
VitD administration prevented bleomycin-induced lung fibrosis, as assessed by reductions in hydroxyproline levels, mRNA levels of col1a1, col3a1 and a-SMA (1.4-, 3.1-, 2.25-, 2.5-fold, respectively) and Masson Trichrome staining compared to the untreated group and these changes were associated with restoration of the bleomycin-induced downregulation of vitamin D-receptor (Vdr) mRNA levels. Pre-treatment with VitD reduced the responsiveness of MLFs to pro-fibrotic stimuli, as indicated by significant decreases of col1a1, col3a1 and a-SMA (3.6-, 4.1- and 2.7-fold, respectively).These changes were associated with restoration of the TGFB1-induced downregulation of vitamin D-receptor (VDR) mRNA levels. VitD treatment deactivated TGFB1-induced Smad3 phosphorylation. Patients with IPF and other forms of ILDs displayed deficient VitD serum concentrations (mean VitD = 18.76 ± 8.36 vs. 18.54 ± 8.39 ng/ml, respectively, p = 0.9). VitD deficiency was correlated with baseline FVC%predicted (r = 0.47, p < 0.0001), DLCO%predicted (r = 0.6, p < 0.0001), GAP score (r = −0.4, p < 0.0001) and all-cause mortality in patients with IPF (HR: 3.7, p = 0.001).
VitD could serve as a prognosticator and potential therapeutic target in patients with IPF. Further studies are sorely needed.
Serum 25-Hydroxyvitamin D Concentrations Are Associated with Computed Tomography Markers of Subclinical Interstitial Lung Disease among Community-Dwelling Adults in the Multi-Ethnic Study of Atherosclerosis (MESA)
2018, Journal of Nutrition
Activated vitamin D has anti-inflammatory properties. 25-Hydroxyvitamin D [25(OH)D] deficiency might contribute to subclinical interstitial lung disease (ILD).
We examined associations between serum 25(OH)D concentrations and subclinical ILD among middle-aged to older adults who were free of cardiovascular disease at baseline.
We studied 6302 Multi-Ethnic Study of Atherosclerosis (MESA) participants who had baseline serum 25(OH)D concentrations and computed tomography (CT) imaging spanning ≤ 10 y. Baseline cardiac CT scans (2000–2002) included partial lung fields. Some participants had follow-up cardiac CT scans at exams 2–5 and a full-lung CT scan at exam 5 (2010–2012), with a mean ± SD of 2.1 ± 1.0 scans. Subclinical ILD was defined quantitatively as high-attenuation areas (HAAs) between –600 and –250 Hounsfield units. We assessed associations of 25(OH)D with adjusted HAA volumes and HAA progression. We also examined associations between baseline 25(OH)D and the presence of interstitial lung abnormalities (ILAs) assessed qualitatively (yes or no) from full-lung CT scans at exam 5. Models were adjusted for sociodemographic characteristics, lifestyle factors (including smoking), and lung volumes.
The cohort's mean ± SD characteristics were 62.2 ± 10 y for age, 25.8 ± 10.9 ng/mL for 25(OH)D concentrations, and 28.3 ± 5.4 for body mass index (kg/m²); 53% were women, with 39% white, 27% black, 22% Hispanic, and 12% Chinese race/ethnicities. Thirty-three percent had replete (≥30 ng/mL), 35% intermediate (20 to <30 ng/mL), and 32% deficient (<20 ng/mL) 25(OH)D concentrations. Compared with those with replete concentrations, participants with 25(OH)D deficiency had greater adjusted HAA volume at baseline (2.7 cm³; 95% CI: 0.9, 4.5 cm³) and increased progression over a median of 4.3 y of follow-up (2.7 cm³; 95% CI: 0.9, 4.4 cm³) (P < 0.05). 25(OH)D deficiency was also associated with increased prevalence of ILAs 10 y later (OR: 1.5; 95% CI: 1.1, 2.2).
Vitamin D deficiency is independently associated with subclinical ILD and its progression, based on both increased HAAs and ILAs, in a community-based population. Further studies are needed to examine whether vitamin D repletion can prevent ILD or slow its progression. The MESA cohort design is registered at www.clinicaltrials.gov as NCT00005487.
High dose Vitamin D administration in ventilated intensive care unit patients: A pilot double blind randomized controlled trial
2016, Journal of Clinical and Translational Endocrinology
Citation Excerpt :
Despite a rapidly growing body of scientific literature, the mechanisms underlying the potential benefit of high-dose vitamin D therapy remain uncertain. Several epidemiologic studies have shown an association between vitamin D deficiency and increased risk of respiratory infections [32,33] as well as an direct relationship between vitamin D and decreased lung function in patients with chronic obstructive pulmonary disease and interstitial lung disease [34–37]. Therapeutically, administration of 25(OH)D was associated with an increase in lung function for adult patients with asthma [38] and with improved one year survival in patients with cystic fibrosis [39].
There is a high prevalence of vitamin D deficiency in the critically ill patient population. Several intensive care unit studies have demonstrated an association between vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) < 20 ng/mL] and increased hospital length of stay (LOS), readmission rate, sepsis and mortality.
Pilot, double blind randomized control trial conducted on mechanically ventilated adult ICU patients. Subjects were administered either placebo, 50,000 IU vitamin D₃ or 100,000 IU vitamin D₃ daily for 5 consecutive days enterally (total vitamin D₃ dose = 250,000 IU or 500,000 IU, respectively). The primary outcome was plasma 25(OH)D concentration 7 days after oral administration of study drug. Secondary outcomes were plasma levels of the antimicrobial peptide cathelicidin (LL37), hospital LOS, SOFA score, duration of mechanical ventilation, hospital mortality, mortality at 12 weeks, and hospital acquired infection.
A total of 31 subjects were enrolled with 13 (43%) being vitamin D deficient at entry (25(OH)D levels < 20 ng/mL). The 250,000 IU and 500,000 IU vitamin D₃ regimens each resulted in a significant increase in mean plasma 25(OH)D concentrations from baseline to day 7; values rose to 45.7 ± 19.6 ng/mL and 55.2 ± 14.4 ng/mL, respectively, compared to essentially no change in the placebo group (21 ± 11.2 ng/mL), p < 0.001. There was a significant decrease in hospital length of stay over time in the 250,000 IU and the 500,000 IU vitamin D₃ group, compared to the placebo group (25 ± 14 and 18 ± 11 days compared to 36 ± 19 days, respectively; p = 0.03). There was no statically significant change in plasma LL-37 concentrations or other clinical outcomes by group over time.
In this pilot study, high-dose vitamin D3 safely increased plasma 25(OH)D concentrations into the sufficient range and was associated with decreased hospital length of stay without altering other clinical outcomes.
Sarcoidosis in childhood. A rare systemic disease
2016, Boletin Medico del Hospital Infantil de Mexico
La sarcoidosis es una enfermedad sistémica de etiología desconocida que raramente se presenta en la infancia. Generalmente afecta los pulmones; sin embargo, puede involucrar diversos órganos. Ocasionalmente afecta el estado general, y origina fiebre, hepatomegalia y esplenomegalia.
Se presenta el caso de un adolescente de doce años de edad con sarcoidosis infantil de inicio tardío, cuyo diagnóstico fue confirmado con un estudio histopatológico de ganglio linfático. El paciente cursó con afección general, hipercalcemia, eritema nodoso, alteraciones pulmonares graves, adenopatías, hepatomegalia y masa testicular. Recibió tratamiento con esteroides, con excelente respuesta clínica.
Se resalta la importancia de considerar el diagnóstico de sarcoidosis en los pacientes con hepatomegalia, adenopatías, daño pulmonar difuso, eritema nodoso, masa testicular e hipercalcemia, así como la necesidad del abordaje multidisciplinario para valorar el compromiso orgánico múltiple y el inicio oportuno de la terapia con esteroides, con el fin de evitar la progresión de la enfermedad.
Sarcoidosis is a systemic disease of unknown etiology that rarely occurs in children. It usually affects the lungs, however, it may involve various organs. It occasionally affects the general condition, and causes fever, hepatomegaly and splenomegaly.
We report the case of a twelve-year-old adolescent with late-onset childhood sarcoidosis which diagnosis was confirmed by lymph node histopathological study. The patient presented general condition, hypercalcemia, erythema nodosum, severe lung disorders, lymphadenopathy, hepatomegaly and testicular mass. He received treatment with steroids, with excellent clinical response.
We highlight the importance of considering the diagnosis of sarcoidosis in patients with hepatomegaly, lymphadenopathy, diffuse lung damage, erythema nodosum, testicular mass and hypercalcemia, as well as the need for a multidisciplinary approach to assess multiple organ involvement and the early beginning of steroid treatment in order to prevent the progression of the disease.
The Role of Vitamin D in Chronic Obstructive Pulmonary Disease, Asthma and Other Respiratory Diseases
2014, Archivos de Bronconeumologia
En los últimos años existe un creciente interés por las acciones extraóseas de la vitamina D.
En este artículo revisamos la fisiología de la vitamina D, los aspectos fisiopatológicos asociados a su déficit y la evidencia existente sobre su papel etiopatogénico en enfermedades respiratorias. Teniendo en cuenta las acciones pleiotrópicas de la vitamina D, existe plausibilidad biológica sobre un potencial papel patogénico del déficit de esta vitamina en el desarrollo de diversas enfermedades respiratorias. Sin embargo, los numerosos estudios epidemiológicos que han encontrado asociación entre niveles bajos de vitamina D y mayor riesgo de desarrollar diversas enfermedades respiratorias o de conllevar un peor pronóstico no permiten demostrar causalidad. Los análisis post hoc de algunos ensayos clínicos, especialmente en enfermedad pulmonar obstructiva crónica (EPOC) y asma, parecen demostrar que ciertos subtipos de pacientes podrían beneficiarse de la corrección del déficit de vitamina D. En este sentido, resultará interesante averiguar si las variantes genéticas implicadas en el metabolismo de la vitamina D pueden explicar las diferencias interindividuales encontradas en cuanto al efecto del déficit de vitamina D y la respuesta a su corrección. En último término, solo los ensayos clínicos adecuadamente diseñados permitirán determinar si los suplementos de 25-OH D pueden tener un efecto preventivo o mejorar la evolución de las distintas enfermedades respiratorias en las que se ha descrito asociación epidemiológica entre su pronóstico y el déficit de esta vitamina.
There has been growing interest in recent years in the extraosseous effects of vitamin D.
In this article, we review the physiology of vitamin D, the physiopathological effects associated with vitamin D deficit and the available evidence on its etiopathogenic role in respiratory diseases. Given the pleiotropic actions of vitamin D, it is biologically plausible that the deficit of this vitamin could play a pathogenic role of in the development of various respiratory diseases. However, the many epidemiological studies that have shown an association between low vitamin D levels and a higher risk of developing various respiratory diseases or a poorer prognosis if they do appear, were unable to show causality. Post-hoc analyses of some clinical trials, particularly in chronic obstructive pulmonary disease (COPD) and asthma, appear to suggest that some patient subtypes may benefit from correction of a vitamin D deficit. In this respect, it would be interesting to determine if the interindividual differences found in the effect of vitamin D deficit and responses to correcting this deficit could be explained by the genetic variants involved in vitamin D metabolism. Ultimately, only appropriately designed clinical trials will determine whether 25-OH D supplements can prevent or improve the course of the various respiratory diseases in which an epidemiological association between prognosis and vitamin D deficit has been described.
Diagnosis and prognostic value of restrictive ventilatory disorders in the elderly: A systematic review of the literature
2012, Experimental Gerontology
Citation Excerpt :
These observations have been reinforced by Zosky et al. (2011), who clearly demonstrated in an animal model that vitamin D deficiency results in significant reduction of lung volumes. Hagaman et al. (2011) recently reported a strong association between low levels of vitamin D and interstitial lung diseases (ILDs), especially connective tissue-associated ILD, after adjustment for potential confounders (Odds Ratio [OR], 11.8; 95% CI: 3.46–40.6). Despite this evidence, molecular mechanisms explaining this association are obscure and data are available only for in vitro and animal models (Koli and Keski-Oja, 2000; Dobak et al., 1994; Boyan et al., 2007; Sundar et al., 2011).
Although less extensively studied compared to pulmonary obstructive diseases, restrictive lung disease (RLD) is highly prevalent and frequently disabling in the adult and, more, the elderly population. The underlying conditions may be either primarily pulmonary diseases, such as idiopathic pulmonary fibrosis, or non respiratory conditions secondarily affecting the lung, e. g. congestive heart failure, or else conditions affecting the lung expansion, e. g. obesity or rib cage deformity. The diagnosis is frequently based on the measurement of surrogate indexes such as the forced vital capacity (FVC) used as a proxy for total lung capacity (TLC). As a consequence, diagnosis of RLD is often characterized by poor specificity. In the elderly, worsening in the quality of life and poor prognosis are variably, but significantly, associated to RLD, being the underlying condition an important source of variability. Several causes of RLD are preventable and treatable conditions. A prompt identification of these conditions may allow to slow the decline of respiratory reserve and, thus, to preserve both personal independence and resistance to acute respiratory infections.
This review gives an update on the latest evidence available on the prevalence and the prognosis of RLD in the elderly. Studies were identified through systematic searches of the electronic database MEDLINE. Reference list of eligible papers were also manually searched.

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These data were presented at the American Thoracic Society International Conference in New Orleans, Louisiana, on May 16, 2010.

Funding/Support: This study was supported by the National Heart, Lung, And Blood Institute [award number K23HL094532] and a National Institutes of Health Clinical Research Loan Repayment Grant (Dr Kinder).

© 2011 American College of Chest Physicians Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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Chest

Original ResearchDiffuse Lung DiseaseVitamin D Deficiency and Reduced Lung Function in Connective Tissue-Associated Interstitial Lung Diseases

Background

Methods

Results

Conclusions

Section snippets

Study Subjects, Clinical Evaluation, and Radiographic Evaluation

Subjects

Discussion

J Nutr

J Nutr

Arch Biochem Biophys

J Nutr

Autoimmun Rev

Clin Chest Med

Autoimmun Rev

Mol Aspects Med

Chest

J Steroid Biochem Mol Biol

Vitamin D deficiency

N Engl J Med

Vitamin D: its role and uses in immunology

FASEB J

1,25-Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice

Autoimmunity

Vitamin D and autoimmunity: new aetiological and therapeutic considerations

Ann Rheum Dis

Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia

J Rheumatol

[Bone density and 25-OH vitamin D serum level in patients with systemic lupus erythematosus]

Z Rheumatol

Vitamin D in systemic lupus erythematosus

Curr Opin Rheumatol

Vitamin D deficiency in undifferentiated connective tissue disease

Arthritis Res Ther

Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study

Arthritis Rheum

Vitamin D deficiency is associated with anxiety and depression in fibromyalgia

Clin Rheumatol

Hypovitaminosis D among rheumatology outpatients in clinical practice

Rheumatology (Oxford)

Original Research
Diffuse Lung Disease
Vitamin D Deficiency and Reduced Lung Function in Connective Tissue-Associated Interstitial Lung Diseases