Vitamin D, micro-nutritional deficiencies and poor diet: prevention and effects of
supplementation.
Wim Janssens
Search strategy
Pubmed was searched using the following search criteria: (‘Chronic Obstructive Pulmonary
disease’ OR ‘Emphysema’ OR ‘COPD’) and (‘Nutrients’ OR ‘antioxidant’ OR ‘retinoid’ OR
‘vitamin’ OR ‘vitamin D’ OR ‘deficiency’) and (‘diet’ or ‘intervention’ or ‘prevention’). We
limited our search to human studies and English language. Additional retrieval from
systematic reviews and frequently cited papers from reviews. 43 papers were selected.
Vitamin D and calcium intake
Vitamin D may have an important anti-inflammatory potential in different respiratory diseases
(1). Most population-based studies which explored cross-sectional associations between
serum 25-hydroxyvitamin D levels (25-OHD) and pulmonary function, found strong
relationships with FEV1, FVC and Peak Expiratory Flow rate (2-4). Conflicting evidence has
been reported on relationship between 25-OHD and FEV1/FVC ratio, lung function decline as
well as with respiratory tract infections (2;5-7). In COPD cohorts, 25-OHD levels are
correlating with disease severity and deficiency (25-OHD <20ng/ml) may occur in
approximately 75% of the more severe stages (GOLD III and IV) (8;9). Again, conflicting
evidence is found on relationships with exacerbations frequency (10-12). One randomized
controlled trial could not demonstrate benefits of supplementation on exacerbation frequency
in severe COPD patients with exception of the most deficient subgroup (13). Overall,
evidence for non-calcemic anti-inflammatory effects of vitamin D in COPD is limited and
recommendations on minimal daily intake - together with calcium intake - are and should be
only based on its proven skeletal effects in the general population (14-17). In addition,
different meta-analyses have shown a significant effect of vitamin D supplementation of fall
reduction in elderly (18-20). Whether this is directly related to an increase in muscle strength
or rather to neuromuscular control is still not clear (21;21-24). Similarly, it remains to be
shown whether these benefits of vitamin D and calcium supplementation are also true for
COPD patients. So far, one intervention trial showed mild additional benefits of vitamin D
supplementation on top of training program in COPD(25), but these data need to be confirmed
with other studies.
Micro-nutritional deficiencies and poor diet
Oxidative stress has a key role in the pathogenesis of COPD (26). Different large populationbased studies have associated a low dietary intake of anti-oxidant vitamins (vitamin C, E, A,
carotene) or higher intake of oxidative nitrogens, with impaired pulmonary function,
increased lung function decline, increased risk of COPD and readmission (27-34). Similar
effects have been attributed to wine and resveratrol intake (35). Two recent studies also report
that relationships with lung function are not only determined by food intake but directly
correlate with anti-oxidant levels in the serum, thereby highlighting its potential mechanism
(36-38). Together, most epidemiological evidence strongly suggest that a prudent dietary
pattern (rich in fresh vegetables, fruit, oily fish, wine and cereals, the so-called
‘Mediterranean diet’) may protect against COPD especially in smokers(39). A recent post-hoc
analysis in 38000 subjects of the Women’s Health Study, a randomized controlled trial with
600 IU of vitamin E every other day, found a 10% reduction in the risk of incident lung
disease (40). When it comes to benefits of micronutrient supplementation in COPD patients,
only small studies are available reporting no or limited benefits (39;41-43). Therefore, dietary
interventions in the management of COPD should target a healthy pattern with sufficient fruit
and vegetables intake. At this stage insufficient evidence is supporting the intake of high
doses of single supplements.
Reference List
(1) Janssens W, Lehouck A, Carremans C, Bouillon R, Mathieu C, Decramer M. Vitamin
D beyond bones in chronic obstructive pulmonary disease: time to act. Am J Respir
Crit Care Med 2009 April 15;179(8):630-6.
(2) Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and
pulmonary function in the third national health and nutrition examination survey.
Chest 2005 December;128(6):3792-8.
(3) Shaheen SO, Jameson KA, Robinson SM, Boucher BJ, Syddall HE, Sayer AA et al.
Relationship of vitamin D status to adult lung function and COPD. Thorax 2011
August;66(8):692-8.
(4) van Schoor NM, de Jongh RT, Daniels JM, Heymans MW, Deeg DJ, Lips P. Peak
expiratory flow rate shows a gender-specific association with vitamin D deficiency. J
Clin Endocrinol Metab 2012 June;97(6):2164-71.
(5) Ginde AA, Mansbach JM, Camargo CA, Jr. Association between serum 25hydroxyvitamin D level and upper respiratory tract infection in the Third National
Health and Nutrition Examination Survey. Arch Intern Med 2009 February
23;169(4):384-90.
(6) Kunisaki KM, Niewoehner DE, Singh RJ, Connett JE. "Vitamin D Status and
Longitudinal Lung Function Decline in the Lung Health Study". Eur Respir J 2010
July 1.
(7) Lange NE, Sparrow D, Vokonas P, Litonjua AA. Vitamin D deficiency, Smoking, and
Lung Function in the Normative Aging Study. Am J Respir Crit Care Med 2012 July
19.
(8) Janssens W, Bouillon R, Claes B, Carremans C, Lehouck A, Buysschaert I et al.
Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the
vitamin D-binding gene. Thorax 2010 March;65(3):215-20.
(9) Persson LJ, Aanerud M, Hiemstra PS, Hardie JA, Bakke PS, Eagan TM. Chronic
obstructive pulmonary disease is associated with low levels of vitamin D. PLoS One
2012;7(6):e38934.
(10) Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. Vitamin-D deficiency is
associated with chronic bacterial colonisation and disease severity in bronchiectasis.
Thorax 2012 October 16.
(11) Kunisaki KM, Niewoehner DE, Connett JE. Vitamin D levels and risk of acute
exacerbations of chronic obstructive pulmonary disease: a prospective cohort study.
Am J Respir Crit Care Med 2012 February 1;185(3):286-90.
(12) Quint JK, Donaldson GC, Wassef N, Hurst JR, Thomas M, Wedzicha JA. 25hydroxyvitamin D deficiency, exacerbation frequency and human rhinovirus
exacerbations in chronic obstructive pulmonary disease. BMC Pulm Med 2012;12:28.
(13) Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van EJ et al. High doses
of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a
randomized trial. Ann Intern Med 2012 January 17;156(2):105-14.
(14) Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ et al.
Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a
meta-analysis of randomized controlled trials. Arch Intern Med 2009 March
23;169(6):551-61.
(15) Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P.
Need for additional calcium to reduce the risk of hip fracture with vitamin d
supplementation: evidence from a comparative metaanalysis of randomized controlled
trials. J Clin Endocrinol Metab 2007 April;92(4):1415-23.
(16) Ross AC. The 2011 report on dietary reference intakes for calcium and vitamin D.
Public Health Nutr 2011 May;14(5):938-9.
(17) wson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D
supplementation on bone density in men and women 65 years of age or older. N Engl J
Med 1997 September 4;337(10):670-6.
(18) Bischoff-Ferrari HA, wson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R et
al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis
of randomised controlled trials. BMJ 2009;339:b3692.
(19) Kalyani RR, Stein B, Valiyil R, Manno R, Maynard JW, Crews DC. Vitamin D
treatment for the prevention of falls in older adults: systematic review and metaanalysis. J Am Geriatr Soc 2010 July;58(7):1299-310.
(20) Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM et
al. Clinical review: The effect of vitamin D on falls: a systematic review and metaanalysis. J Clin Endocrinol Metab 2011 October;96(10):2997-3006.
(21) Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW et al. Higher
25-hydroxyvitamin D concentrations are associated with better lower-extremity
function in both active and inactive persons aged > or =60 y. Am J Clin Nutr 2004
September;80(3):752-8.
(22) Dawson-Hughes B. Serum 25-hydroxyvitamin D and muscle atrophy in the elderly.
Proc Nutr Soc 2012 February;71(1):46-9.
(23) Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on muscle
strength, gait and balance in older adults: a systematic review and meta-analysis. J Am
Geriatr Soc 2011 December;59(12):2291-300.
(24) Sohl E, de Jongh RT, Heijboer AC, Swart KM, Brouwer-Brolsma EM, Enneman AW
et al. Vitamin D status is associated with physical performance: the results of three
independent cohorts. Osteoporos Int 2012 September 8.
(25) Hornikx M, Van RH, Lehouck A, Mathieu C, Maes K, Gayan-Ramirez G et al.
Vitamin D supplementation during rehabilitation in COPD: a secondary analysis of a
randomized trial. Respir Res 2012;13:84.
(26) Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary
disease. Oxidative Stress Study Group. Am J Respir Crit Care Med 1997
August;156(2 Pt 1):341-57.
(27) de BJ, Mendez M, Romieu I, Balcells E, Benet M, Donaire-Gonzalez D et al. Cured
meat consumption increases risk of readmission in COPD patients. Eur Respir J 2012
September;40(3):555-60.
(28) Hu G, Cassano PA. Antioxidant nutrients and pulmonary function: the Third National
Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol 2000 May
15;151(10):975-81.
(29) Jiang R, Paik DC, Hankinson JL, Barr RG. Cured meat consumption, lung function,
and chronic obstructive pulmonary disease among United States adults. Am J Respir
Crit Care Med 2007 April 15;175(8):798-804.
(30) McKeever TM, Scrivener S, Broadfield E, Jones Z, Britton J, Lewis SA. Prospective
study of diet and decline in lung function in a general population. Am J Respir Crit
Care Med 2002 May 1;165(9):1299-303.
(31) Siedlinski M, Postma DS, van Diemen CC, Blokstra A, Smit HA, Boezen HM. Lung
function loss, smoking, vitamin C intake, and polymorphisms of the glutamatecysteine ligase genes. Am J Respir Crit Care Med 2008 July 1;178(1):13-9.
(32) Varraso R, Fung TT, Barr RG, Hu FB, Willett W, Camargo CA, Jr. Prospective study
of dietary patterns and chronic obstructive pulmonary disease among US women. Am
J Clin Nutr 2007 August;86(2):488-95.
(33) Varraso R, Fung TT, Hu FB, Willett W, Camargo CA. Prospective study of dietary
patterns and chronic obstructive pulmonary disease among US men. Thorax 2007
September;62(9):786-91.
(34) Varraso R, Willett WC, Camargo CA, Jr. Prospective study of dietary fiber and risk of
chronic obstructive pulmonary disease among US women and men. Am J Epidemiol
2010 April 1;171(7):776-84.
(35) Siedlinski M, Boer JM, Smit HA, Postma DS, Boezen HM. Dietary factors and lung
function in the general population: wine and resveratrol intake. Eur Respir J 2012
February;39(2):385-91.
(36) Nicks ME, O'Brien MM, Bowler RP. Plasma antioxidants are associated with
impaired lung function and COPD exacerbations in smokers. COPD 2011
August;8(4):264-9.
(37) Lin YC, Wu TC, Chen PY, Hsieh LY, Yeh SL. Comparison of plasma and intake
levels of antioxidant nutrients in patients with chronic obstructive pulmonary disease
and healthy people in Taiwan: a case-control study. Asia Pac J Clin Nutr
2010;19(3):393-401.
(38) McKeever TM, Lewis SA, Smit HA, Burney P, Cassano PA, Britton J. A multivariate
analysis of serum nutrient levels and lung function. Respir Res 2008;9:67.
(39) Tsiligianni IG, van der Molen T. A systematic review of the role of vitamin
insufficiencies and supplementation in COPD. Respir Res 2010;11:171.
(40) Agler AH, Kurth T, Gaziano JM, Buring JE, Cassano PA. Randomised vitamin E
supplementation and risk of chronic lung disease in the Women's Health Study.
Thorax 2011 April;66(4):320-5.
(41) Baldrick FR, Elborn JS, Woodside JV, Treacy K, Bradley JM, Patterson CC et al.
Effect of fruit and vegetable intake on oxidative stress and inflammation in COPD: a
randomised controlled trial. Eur Respir J 2012 June;39(6):1377-84.
(42) Keranis E, Makris D, Rodopoulou P, Martinou H, Papamakarios G, Daniil Z et al.
Impact of dietary shift to higher-antioxidant foods in COPD: a randomised trial. Eur
Respir J 2010 October;36(4):774-80.
(43) Roth MD, Connett JE, D'Armiento JM, Foronjy RF, Friedman PJ, Goldin JG et al.
Feasibility of retinoids for the treatment of emphysema study. Chest 2006
November;130(5):1334-45.