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Article
Article information:
Received on October 2019
Accepted on December 2019
DOI: https://doi.org/10.3329/
jbsp.v14i2.44790
Corresponding author:
Does Vitamin D3 supplementation affect
antioxidant enzymes of D3 deficient
patients with asthma COPD overlap
(ACO)? - A randomized controlled trial
Maksuda Bintey Mahmud, Department of
Physiology, Bangabandhu Sheikh Mujib
Medical University, Dhaka. email:
maksuda.lima999@gmail.com
Maksuda Bintey Mahmud1, Taskina Ali1, Kazi Saifuddin
Bennoor2, Md. Ali Hossain2, Mustafizur Rahman2,
Mohammad Abdus Shakur Khan2, Md. Saiful Islam1, Samia
Hassan3, Salsa Bil Nahar4, Sharkia Khanam Rosy5, Naznin
Sultana1, Salma Anjum1
Cite this article:
Does Vitamin D 3 supplementation affect
antioxidant enzymes of D 3 deficient patients
with asthma COPD overlap (ACO)? - A
randomized controlled trial. Mahmud MB, Ali
T, Bennoor KS, Hossain MA, Rahman M, Khan
MAS, Islam MS, Hassan S, Nahar SB, Rosy SK,
Sultana N, Anjum S
J Bangladesh Soc Physiol 2019;14(2): 89-98
1. Department of Physiology, Bangabandhu Sheikh Mujib Medical
University, Dhaka.
2. Department of Respiratory Medicine, National Asthma Center,
National Institute of the Diseases of Chest and Hospital, Dhaka.
3. Department of Physiology, Anwer Khan Modern Medical College, Dhaka
4. Department of Physiology, Abdul Malek Ukil Medical College, Noakhali.
5. Department of Physiology, Shaheed Suhrawardy Medical College, Dhaka
This article is open access licensed under
CC BY NC SA which allows readers copy,
distribute, display, and perform the work and
make derivative works based on it only for
noncommercial purposes.
Abstract
Background: Asthma COPD overlap (ACO) is a new disease
entity where respiratory tract is continuously exposed to oxidants.
Supplementation of vitamin D 3 have shown evidence of
increasing antioxidant enzymes level which neutralize these
oxidants. Objectives: To evaluate the effects of vitamin D3
supplementation on two antioxidant enzyme levels in D3
deficient ACO patients. Methods: A double blinded placebo
controlled randomized clinical trial (RCT) was carried out on 60
(sixty) D3 deficient [serum 25-hydroxycholecalciferol, 25(OH)
D<30 ng/ml], male, smoker, stable ACO patients of age 40 to 80
years. This RCT was registered at www.clinicaltrials.gov identifier
NCT03931889. After the final selection, all the patients were
randomly allocated to vitamin D3 supplemented ‘Study’ group
(n=30) or placebo treated ‘Control’ group (n=30). Two antioxidant
enzyme levels [plasma superoxide dismutase (SOD) and catalase
(CAT)] were measured at their baseline. Subsequently, along
with standard pharmacological treatment of ACO, ‘Study’
patients received 80,000 IU (2 oral capsules) of vitamin D3 per
Vitamin D3 supplementation & antioxidant enzymes in ACO patients
Mahmud et al
week for first 13 weeks. Thereafter, according to their serum
25(OH)D or calcium concentration, they received 40,000 IU (1
oral capsule) of D3 per 1 week or per 2 weeks or per 6 weeks or
no further supplementation, for another 13 weeks. Whereas, all
the ‘Control’ patients received two oral capsules of placebo
weekly, for consecutive 26 weeks. All patients of both groups
were also advised to have sunlight exposure (within 11 am to 4
pm) only for 20 minutes daily. After 26 weeks of follow up, both
enzyme levels of all patients were again measured. Both enzymes
were measured by ELISA method using spectrophotometry. Data
were analyzed by Student’s paired and unpaired ‘t’ test, where
p≤0.05 was accepted as significant. Results: Initially a total 60
patients were enrolled and randomized, but ultimately 40 of them
completed the trial. The baseline antioxidant enzymes levels of
two groups were not significantly different. However, the mean
level of both enzymes increased in both groups after 26 weeks
of follow up but it was statistically significant (p<0.001) only in
‘Study’ patients. In addition, SOD (p<0.05) and CAT (p<0.01)
were significantly higher in the vitamin D3 supplemented patients
than those of placebo treated patients after 26 weeks of follow
up. Conclusion: The present study reveals that vitamin D3
supplementation increases the antioxidant enzyme level in
vitamin D3 deficient stable ACO patients.
Keywords: Asthma COPD overlap (ACO), Vitamin D3, Superoxide
dismutase (SOD), Catalase (CAT)
Introduction
he obstructive lung disases (OLDs)
including asthma and COPD are very
common and are associated with
substantial morbidity. Asthma is characterized by
chronic airway inflammation with wheeze,
shortness of breath, chest tightness and cough,
but its airflow obstruction is fully reversible after
treatment with bronchodilator1. In contrast, COPD
is a progressive inflammatory disorder affecting
the airways and characterized by chronic airway
inflammation, increased airway resistance, fibrosis,
mucus hypersecretion, parenchymal lesions with
reduced elastic recoil and loss of alveolar
attachments, leading to airflow limitation, which
is not fully reversible with bronchodilator2.
T
However, it is evident that typical asthma and
COPD characteristics can both exist
simultaneously in one patient. Approximately
one in four patients with COPD have asthmatic
features consist of wheeze, airway hyperresponsiveness or atopy3. On the other hand,
patients with asthma may present with fixed
airway obstruction over time4. In 2015, a joint
project GINA and global standard of obstructed
lung disease(GOLD) described ACO as,
persistent airflow limitation with several features
usually associated with asthma and several
features usually associated with COPD5.
The patients with OLD are continuously exposed
to oxidants generated from endogenous or
exogenous source such as exposure to cigarette
smoking, dust particles and air pollutants such
as, allergens, bacterial or viral spores6. This
increment of oxidants is the main component of
J Bangladesh Soc Physiol. 2019, December; 14(2 ): 89-98
90
Vitamin D3 supplementation & antioxidant enzymes in ACO patients
oxidative stress (imbalance between reactive
oxygen species production and antioxidant
defenses)7.
For protection from oxidative stress, human body
possesses antioxidants, derived from both
endogenous and exogenous sources. They may
delay or prevent direct oxidation of substrates or
scavenge oxidative free radicals neutralizing the
oxidants 8. The major antioxidants enzymes
include superoxide dismutase (SOD), catalase
(CAT), glutathione peroxidase and glutathione
reductase9.
Recent research evidence showed role of vitamin
supplement on lung diseases10. Vitamin D3 is the
active form, synthesized from 7-dehydrocholesterol in the skin through the action of
ultraviolet B (UVB) radiation11. This vitamin is
now recognized for its classical role in bone
mineralization and calcium homeostasis12 .
Deficiency of this vitamin D might cause rickets,
osteomalacia, low bone mass, osteoporosis as
well as fractures13. In addition, in respiratory
health, vitamin D deficiency has also been shown
to increase the risk of upper respiratory tract
infections 14 and active tuberculosis15. This
vitamin deficiency frequently occurs in COPD
patients and correlates with severity of COPD16.
Moreover, association between vitamin D
deficiency and asthma has also been reported14.
Very recently it has been found that vitamin D3
supplementation can improve exercise tolerance
with D3 deficient stable COPD 17 as well as ACO18
patients.
Previous studies found that plasma antioxidant
enzyme was positively correlated with serum
vitamin D3 and erythrocyte SOD and CAT
activity19. Furthermore, both SOD and CAT were
found increased in diabetic mice20, hemodialysis
patient21 and preeclamptic women22 after vitamin
D3 supplementation.
Nevertheless, the volume of data on effect of
vitamin D 3 supplementation on plasma
antioxidant enzymes is not enough for conclusive
remarks.
Mahmud et al
On the basis of this background, this study was
designed to observe the effect of vitamin D3
supplementation on plasma SOD and CAT level
in vitamin D3 deficient stable ACO patients.
Methods
Subjects. This double blinded placebo controlled
RCT was carried out in the Department of
Physiology, Bangabandhu Sheikh Mujib Medical
University (BSMMU) and National Institute of
the Diseases of Chest and Hospital (NIDCH),
Dhaka from March, 2018 to August, 2019. This
clinical
trial
was
registered
at
www.clinicaltrials.gov, ID: NCT03931889 and
approved by Institutional Review Board of
BSMMU. For this purpose, 60 (sixty) vitamin D3
deficient (serum 25-hydroxycholecalciferol <30
ng/ml)23, male, smoker, stable5 patients with
asthma COPD overlap (ACO) of age 40 to 80 years
were selected by pulmonologists through clinical,
physical and radiological signs of chronic airway
disease, usually with spirometric evidence of
chronic airflow limitation (post bronchodilator
FEV1/FVC<0.7) 5 , but its absence did not
absolutely exclude ACO. The ultimate diagnosis
was confirmed by ‘tick box’ approach advocated
by joint committee of GINA and GOLD (2019)5.
The inclusion criteria were duration of ACO (1 to
5 years), duration of smoking (>10 pack years)24,
body mass index (18.6 to 24.9 kg/m2)25, mid upper
arm circumference (>25.1 cm)26, serum total
calcium (8.5 to 10.5 mg/dl)27, serum inorganic
phosphate (2.3 to 4.7 mg/dl) 27 and serum
parathormone (10 to 65 pg/ml)27. In addition,
patients with uncontrolled systemic
hypertension (systolic blood pressure ≥140 mm
Hg and/or diastolic blood pressure ≥90 mm Hg,
with anti-hypertensive medication) 28 ,
uncontrolled diabetes mellitus (fasting blood
sugar ≥7 mmol/l and/or HbA1c ≥6.5%) 29 ,
dyslipidemia (total cholesterol ≥240 mg/dl and/
or HDL <40 mg/dl and/or LDL ≥160 mg/dl and/or
triglyceride ≥200 mg/dl and/or with use of any
lipid lowering drug)30, renal insufficiency (serum
creatinine >1.36 mg/dl)31 as well as H/O any
J Bangladesh Soc Physiol. 2019, December; 14(2 ): 89-98
91
Vitamin D3 supplementation & antioxidant enzymes in ACO patients
pulmonary, liver, endocrine or cardiac disease,
malignancy or with consumption of any drug
known to affect vitamin D metabolism
(phenytoin, carbamazepine, clotrimazole,
rifampicin, nifedipine, spironolactone) within 1
month prior to study, were excluded.
Sampling and Data collection. An informed
written consent was taken from each preliminarily
selected patient and his serum 25(OH)D was
estimated. When serum 25(OH)D was <30 ng/ml
(D3 deficiency) but >10 ng/ml23, then he was
finally selected and randomly assigned as
‘Study’ (n=30) or ‘Control’ (n=30) patient (Figure
1). The baseline plasma level of SOD and CAT of
all patients were measured. Then along with the
standard pharmacological treatment of ACO
(according to GOLD criteria)32, ‘Study’ patients
received 80,000 IU (2 oral capsules) of vitamin D3
per week for first 13 weeks. Detail of the dose
schedule for D3 supplementation for last 13
weeks23 are shown in Table I. Whereas, all the
‘Control’ patients received two oral capsules of
placebo weekly for consecutive 26 weeks.
Mahmud et al
Additionally, all the patients of both groups were
also advised to have sunlight exposure (within
11 am to 4 pm) only for 20 minutes daily33. On the
other hand, if serum 25(OH)D was <10 ng/ml
(severely deficiency)23 of any patient, then he
was dropped out (Figure 1) from the study (for
ethical purpose). After 26th week of follow up,
both the enzyme levels were again measured.
Preparation of vitamin D3 and placebo capsules.
All capsules were prepared and supplied by
Beximco Pharmaceuticals Limited, Bangladesh.
Ingredients of vitamin D 3 capsules were
cholecalciferol (40,000 IU), microcrystalline
cellulose (58.1 gm), butylated hydroxy toluene
(0.2 mg), magnesium stearate (3 mg), gelatin
capsule shell (1 mg). Ingredients of placebo were
same as vitamin D3 except Cholecalciferol.
Assessment of serum vitamin D3 and antioxidant
enzymes. Serum 25(OH)D was assessed by
Chemiluminescent microparticle immunoassay
(CMIA) method (Abbot Laboratory, Ireland).
Plasma SOD and CAT enzymes level were
Pulmonologist diagnosed stable
ACO patients with vitamin D3 deficiency
n = 75
Excluded, n = 15
Randomized
n = 60
Allocated to intervention
(Vitamin D3 )
n = 30
Lost in follow up, n =10
• discontinued intervention, n = 3
• refused to continue study, n = 7
Analysed,
n = 20
Allocation
Follow up
(after 26 weeks)
Analysis
•
•
Not meeting selection criteria, n = 13
Declined to participate, n = 2
Allocated to intervention
(Placebo)
n = 30
Lost in follow up, n =10
• became severely D3 deficient, n = 2
• refused to continue study, n =8
Analysed,
n = 20
Figure 1: CONSORT (Consolidated Standards of Reporting Trials) diagram; ACO: Asthma COPD
Overlap
92
J Bangladesh Soc Physiol. 2019, December; 14(2 ): 89-98
Vitamin D3 supplementation & antioxidant enzymes in ACO patients
assessed by colorimetric method using SOD
assay kit (Elabscience, USA) and CAT assay kit
(Elabscience, USA).
Statistical Analysis. The results were expressed
as mean±SD and the data were analyzed by SPSS
Mahmud et al
(Version 16), and for statistical analysis,
independent sample ‘t’ test as well as paired
Student’s ‘t’ test was used. In the interpretation
of results, ≤0.05 level of probability (p) was
accepted as significant.
Table I: D3 Supplementation schedule for D3 deficient ACO patients23
A t 1s t visit / at day 1:
Vitamin D3 80,000 IU (2 capsules of 40,000 IU) / week, for consecutive 13 weeks
At 2n d visit / after 13 weeks:
If,
serum 25 (OH)D
and/or
serum Ca2+ =
30-40 ng/ml
and/or
8.5-10.5 mg/ml
40-50 ng/ml
and/or
8.5-10.5 mg/ml
Then,
for next 13 weeks,
dose was -
4600 IU/day
3000 IU/day
60-80 ng/ml
and/or
8.5-10.5 mg/ml
So,
for next 13 weeks,
dose schedule was 4600 IU X 7
= 32,200 IU / 7 days
= 1 cap (40,000 IU) / week
3000 X 15
= 45,000 IU / 15 days
= 1 cap (40,000 IU) / 2 weeks
1 cap (40,000 IU) / 6 weeks
> 80 ng/ml and/or
8.5-10.5 mg/ml
stop taking drug &
symptom analysis
>150 ng/ml
and/or
>10.5 mg/ml
close monitoring and ask for –
l
l
l
l
l
l
l
l
l
l
feeling sick or being sick
poor appetite or loss of appetite
feeling very thirsty
passing urine often
constipation or diarrhea
abdominal pain
muscle weakness and pain
bone pain
feeling confused
feeling tired
no dose for
further 13 weeks
no dose for further 13 weeks
At 3rd visit / after 26 weeks:
Patients were referred to pulmonologist and suggested to follow the above-mentioned schedule
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Vitamin D3 supplementation & antioxidant enzymes in ACO patients
Results
A total of 60 patients were initially randomized
and 40 of them ultimately completed the study
(20 in each group was dropped out). There was
no significant difference in the baseline
characteristics including antioxidant enzymes
(SOD and CAT) between vitamin D 3
supplemented and placebo groups (Table II).
However, the plasma level of both enzymes
increased after 26 weeks of their follow up in the
Mahmud et al
‘Study’ as well as in ‘Control’ groups in
comparison to their corresponding baseline
values, but these differences were statistically
significant (p<0.001) only is ‘Study’ patients
(Figure 2). In addition, the mean plasma levels of
SOD (p<0.05) and CAT (p<0.01) were
significantly higher in the vitamin D 3
supplemented patients than those of placebo
after 26 weeks of follow up (Figure 2).
Table II: Baseline characteristics of ACO patients in both groups (N=60)
Parameters
Vitamin D3
Placebo
group
group
(n=30)
(n=30)
Age (years)
60.13±9.75
57.66±10.90
Duration of ACO (years)
3.63±0.80
3.53±0.81
Duration of smoking (pack years)
14.62±4.46
16.28±5.72
Body Mass Index (kg/m2)
22.51±3.34
21.75±3.01
Mid Upper Arm
26.73±2.88
26.93±3.43
116±7.23
116±7.23
Systolic blood pressure (mm of Hg)
75.33±7.76
75.33±7.76
Diastolic blood pressure (mm of Hg)
86.80±17.93
83.02±16.97
FEV1/FVC (%) FEV1 (% of PV)
62.88±21.11
58.22±21.93
25-hydroxcholecalciferol (ng/ml) serum
19.20±4.44
19.58±3.79
parathormone (pg/ml)
53.29±9.28
49.93±10.92
Total calcium (mg/dl)
9.15±0.33
9.39±0.4
Inorganic Phosphate (mg/dl)
3.15±0.63
3.27±0.39
Fasting blood sugar (mmol/l)
5.09±0.79
5.14±0.77
Glycosylated hemoglobin (%)
6.14±0.44
6.12±0.49
Plasma Superoxide dismutase (U/ml)
14.13±5.34
12.29±5.55
Plasma Catalase (U/ml)
11.90±6.81
17.16±7.30
Circumference (cm)
Data were expressed as mean±SD; Statistical analysis was done by independent sample t test; n:
number of subjects; Pack year: (number of cigarette smoked per day ÷ 20) X no. of year smoked; ACO:
Asthma COPD Overlap; FEV1: Forced expiratory volume in 1st second; FVC: Forced Vital Capacity;
PV: Predicted Value.
94
J Bangladesh Soc Physiol. 2019, December; 14(2 ): 89-98
Vitamin D3 supplementation & antioxidant enzymes in ACO patients
Mahmud et al
30
19.89
25
60
37.85
20
15
10
5
0
Figure 2: Antioxidant enzymes level on pre and post intervention in both groups. Each bar symbolizes
mean±SD of 20 patients; A1: Patients with vitamin D3 on day 1; A2: Patients with vitamin D3 after 26th
week; B1: Patients with placebo on day 1; B2: Patients with placebo after 26th week; ***: p<0.001 in
A1 vs A2; #: p<0.05 in A2 vs B2; ##: p<0.01 in A2 vs B2
Discussion
The present study observed the effects of vitamin
D3 supplementation on antioxidant enzymes in
vitamin D3 deficient Asthma COPD overlap (ACO)
patients. In the present study, both the
antioxidant enzyme levels at their baseline status
were almost similar to other studies19,21.
In this study, SOD was significantly higher in
vitamin D3 supplemented patients compared to
placebo treated patients after 26th week of follow
up. Similar higher SOD in erythrocytes of atopic
dermatitis patients on 60th day19, plasma of
neonates with hypoxic-ischemic encephalopathy
on 5th day34 and serum of preeclamptic pregnant
women on 8th week of vitamin D3 supplementation 22 were reported. In addition, this
antioxidant enzyme was found higher in cardiac
tissue and liver tissue of vitamin D 3
supplemented rats on 5th week35 and 28th day36
of follow up, respectively.
In addition, CAT was also significantly increased
in ACO patients with vitamin D3 supplementation in comparison to that of patients with
placebo after 26th week of follow up. Similar result
was reported, where CAT was significantly
higher in erythrocytes of patients with atopic
dermatitis after 60th day19 and serum of preeclamptic pregnant women after 8th week of
vitamin D3 supplementation22. In addition, this
antioxidant enzyme was found higher in
hippocampus of vitamin D3 supplemented rats
with multiple sclerosis on 21st day37 and in liver
tissue of diabetic rats on 28th day36 of follow up,
respectively.
In the present study, all of our ACO patients were
long standing smoker (≥ 10 pack year). It is well
known that cigarette contains reactive oxygen
species (ROS)38 which can damage epithelial cells
lining the airways by inducing peroxidation of
lipids and other cell membrane constituents and/
or by activating oxidant-sensitive cellular
pathways and/or by inducing DNA damage39.
These ROS also activate epithelial cell
intracellular signaling cascades leading to gene
activation for inflammatory cytokines
production40. These mediators promote chronic
immune cell (neutrophils, macrophages, T cell)
recruitment to produce more ROS or oxidants41
and ultimately increase the consumption of
antioxidant enzymes42 followed by decrement of
J Bangladesh Soc Physiol. 2019, December; 14(2 ): 89-98
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Vitamin D3 supplementation & antioxidant enzymes in ACO patients
their plasma concentration 43. In addition,
cigarette smoke could also reduce the antioxidant
defenses of the lung by irreversibly modifying
glutathione (GSH) and various redox-sensitive
signaling proteins. Smoking also could
compromises transcription factors, such as the
nuclear factor-erythroid 2-related factor 2 (Nrf2),
which could activate an antioxidant response
element (ARE) that regulates antioxidant8 .
However, the activities of these enzymes could
also be increased44 to combat the over burden of
oxidants. Nevertheless, it has been proposed that
vitamin D3, structurally having a steroid
nucleus 11 might induce the mRNA gene
expression of the antioxidant enzymes, SOD and
CAT45 by its genomic action to regulate one or
more of the mitogen activated protein kinase
(MAPK) signaling pathways46. This vitamin
might also increase Sirtuin1 (SIRT1) expression
through phosphorylation of the extracellular
signal-regulated kinases (REK1/2)47, which is
induce the expression of the antioxidant enzymes
(SOD, CAT).
Conclusion
The present study reveals that vitamin D 3
supplementation increases the antioxidant
enzymes in D3 deficient ACO patients. However,
further experimental study is needed to elucidate
the exact component and mechanism responsible
for these effects. In addition, vitamin D 3
supplementation may be recommended to ACO
patients with D 3 deficiency to raise their
antioxidant status to protect them from oxidative
stress.
Conflict of interest: None
Acknowledgement: This study was supported
by an unrestricted educational grant from
Beximco Pharmaceuticals Ltd. Bangladesh.
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