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Journal of Infection (2016) xx, 1e9

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11 Evaluation of vitamin status in patients with 72
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pulmonary tuberculosis 74
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16 Q3 Jongwon Oh a,c, Rihwa Choi a,c, Hyung-Doo Park a, Hyun Lee b, 78
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18 Byeong-Ho Jeong b, Hye Yun Park b, Kyeongman Jeon b, 79
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19 O. Jung Kwon b, Won-Jung Koh b,**, Soo-Youn Lee a,* 81
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Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University 84
23 School of Medicine, Seoul, Republic of Korea 85
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Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, 86
25 Sungkyunkwan University School of Medicine, Republic of Korea 87
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Accepted 19 October 2016 89
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Available online - - - 90
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KEYWORDS Summary Objective: Vitamins are known to be associated with immunity and nutrition. 94
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Nutrition; Moreover, vitamin deficiency can affect host immunity to various infectious diseases, including 95
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Tuberculosis; tuberculosis. Although patients with tuberculosis often have vitamin D deficiency, little is 96
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Vitamin known about the levels of other vitamins. Here, we aimed to investigate the status of vitamins 97
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A, B12, D, and E in patients with tuberculosis. We also aimed to investigate the clinical and lab- 98
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oratory variables related to vitamin status in patients with tuberculosis. 99
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Methods: We performed a case-control study to investigate the serum vitamin concentrations 100
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in 152 patients with tuberculosis and 137 control subjects. The concentrations of vitamin A, 101
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vitamin D, vitamin E, homocysteine, and methylmalonic acid were measured using high- 102
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performance liquid chromatography (HPLC) or HPLC-tandem mass spectrometry. Patient de- 103
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mographic data and other biochemical parameters were also analyzed. 104
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Results: The serum concentrations of vitamins A, D, and E were significantly lower in patients 105
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with tuberculosis than in control subjects (1.4 vs. 2.0 mmol/L, P < 0.001; 10.6 vs. 19.3 ng/mL, 106
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P < 0.001; and 22.8 vs. 30.6 mmol/L, P < 0.001, respectively). In contrast, the methylmalonic 107
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acid levels were higher in patients with tuberculosis (134.9 vs. 110.8 nmol/L, P < 0.001). The 108
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prevalences of vitamin deficiencies were significantly higher in patients with tuberculosis. 109
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Moreover, multiple vitamin deficiencies were only observed in patients with tuberculosis 110
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(22.4% of all patients with tuberculosis vs. 0% of all control subjects). Positive correlations 111
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53 * Corresponding author. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of
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54 Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea. Fax: þ82 2 3410 2719.
** Corresponding author. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, 116
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Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea. Fax: þ82 2 3410 3849. 117
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E-mail addresses: wjkoh@skku.edu (W.-J. Koh), sy117.lee@samsung.com (S.-Y. Lee). 118
57 c
These authors contributed equally to this work. 119
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http://dx.doi.org/10.1016/j.jinf.2016.10.009 121
60 0163-4453/ª 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved. 122

Please cite this article in press as: Oh J, et al., Evaluation of vitamin status in patients with pulmonary tuberculosis, J Infect (2016),
http://dx.doi.org/10.1016/j.jinf.2016.10.009
 YJINF3834_proof ■ 14 November 2016 ■ 2/9

2 J. Oh et al.

1 among vitamin A, D, and E concentrations were observed (vitamins A and D, r Z 0.395; vita- 63
2 mins D and E, r Z 0.342; and vitamins A and E, r Z 0.427, P < 0.001). Body mass index, total 64
3 cholesterol, low-density lipoprotein, iron, and total iron-binding capacity all showed positive 65
4 correlations with vitamin A, D, and E concentrations. 66
5 Conclusions: Vitamin deficiencies are common in patients with tuberculosis. Further research 67
6 investigating the clinical importance of vitamin and nutritional status in patients with tuber- 68
7 culosis is needed. 69
8 ª 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved. 70
9 71
10 72
11 Introduction be better indicators of nutritional status.19,20 Assays for 73
12 directly measuring vitamin B12 levels have many limita- 74
13 tions, such as poor agreement between laboratories, 75
14 Tuberculosis (TB) is an infectious disease caused by the 76
different methods or platforms, and low sensitivity and
15 bacterium Mycobacterium tuberculosis.1 Although a num- 77
specificity. To more efficiently diagnose vitamin B12 defi-
16 ber of treatments are available, TB remains a major global 78
ciency, a combination of several markers associated with
17 concern.2 The latest 2015 World Health Organization (WHO) 79
vitamin B12 metabolism could be used in place of a single
18 global TB report estimated that 1.5 million of the approxi- 80
vitamin B12 measurement. For example, measurement of
19 mately 9.6 million people who developed TB in 2014 died.2 81
methylmalonic acid (MMA), homocysteine, or a combination
20 In South Korea, the notified TB rate was 84.9 per 100,000 82
thereof is often used to confirm vitamin B12 deficiency in
21 persons in 2014.3 Many factors are needed for adequate dis- 83
untreated patients. The levels of MMA and total homocyste-
22 ease control, including orchestration of rapid, sensitive, 84
ine are both markedly elevated in the vast majority (>98%)
23 and reliable diagnosis; appropriate treatment; and timely 85
of patients with clinical vitamin B12 deficiency, including
24 monitoring.2 Undernutrition increases the risk of TB; 86
patients who have only neurologic manifestations of defi-
25 conversely, TB can also lead to malnutrition. Undernutri- 87
ciency (i.e., no anemia).20 Importantly, an elevated level
26 tion is a risk factor for progression from TB infection to 88
of MMA has been shown to be more sensitive and specific
27 active TB disease, and undernutrition at the time of diag- 89
for the diagnosis of vitamin B12 deficiency compared with
28 nosis of active TB is a predictor of increased risk of death 90
measurement of serum vitamin B12.20
29 and TB relapse.4 In this context, nutritional care and sup- 91
No study has yet performed an estimate of multiple
30 port of patients with TB are both important in regular TB 92
vitamin statuses using reliable biomarkers in patients with
31 care.4 93
pulmonary TB. Therefore, in this study, we simultaneously
32 Vitamins have an important relationship with immunity 94
measured the serum levels of multiple vitamins, MMA, and
33 and nutrition, and vitamin deficiencies are known to affect 95
homocysteine in patients with TB. We also aimed to
34 host immunity to various infectious diseases.5 Altered 96
investigate the clinical and laboratory variables related to
35 vitamin statuses have been reported to be associated 97
vitamin status in patients with TB.
36 with various viral infections such as influenza, human im- 98
37 munodeficiency virus, and hepatitis C, helminth infections, 99
and bacterial infections such as dental caries and TB.1,5e12 Methods
38 100
39 The consistency of these findings is striking, considering 101
40 that different groups have defined vitamin deficiency Ethics statement 102
41 and/or inadequate vitamin status using a range of bio- 103
42 markers and different cutoffs. Vitamin D is associated This study was conducted according to the guidelines of the 104
43 with macrophage function, proper phagocytosis, and lyso- Declaration of Helsinki, and all procedures involving human 105
44 somal fusion.13 Vitamin A regulates innate immunity, main- subjects were approved by the Institutional Review Board 106
45 tains the mucosal epithelium, and is associated with T and B of Samsung Medical Center (IRB No: SMC-2013-07-155-018). 107
46 lymphocyte function.14,15 Vitamin E is the most effective All subjects provided written consent for participation in 108
47 natural free radical scavenger and is found in cell mem- this study. 109
48 branes. Moreover, vitamin E deficiency impairs cellular 110
49 and humoral immunity and can also reduce oxidative stress Study populations, diagnosis, and definition 111
50 on T lymphocytes due to its antioxidant properties.16 112
51 Several vitamins are also known to be essential for the sur- This case-control study enrolled 152 adult patients with TB 113
52 vival and virulence of most organisms, including mycobac- and 137 control subjects without active TB at Samsung 114
53 teria, and help maintain host immune processes involved Medical Center (Seoul, Korea), a tertiary care hospital. All 115
54 in killing of mycobacteria.17 While several studies have patients with TB met the diagnostic criteria for pulmonary 116
55 identified an association between inadequate vitamin D TB according to the guidelines of the American Thoracic 117
56 status and TB, little is known regarding the levels of other Society.21 A control group of 137 subjects without prior 118
57 vitamins.18 diagnosis of TB was recruited from the group of individuals 119
58 Although the concentrations of most vitamins are usually who visited a health promotion center for a medical 120
59 measured in serum, serum measurements have certain checkup without any clinical symptoms or signs of illness 121
60 limitations. For example, serum measurements are thought due to active TB. Patients with TB were matched with con- 122
61 to reflect recent intake and to be poor indicators of tissue trols by age and sex. Information about demographic data 123
62 stores; other biologic markers have been demonstrated to including age, sex, and body mass index (BMI) was obtained 124

Please cite this article in press as: Oh J, et al., Evaluation of vitamin status in patients with pulmonary tuberculosis, J Infect (2016),
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Vitamin status in tuberculosis patients 3

1 from electronic medical records. Underweight status was of the data using the KolmogoroveSmirnov test. The chi- 63
2 defined as a BMI <18.5 kg/m2 according to the WHO guide- square test was used to assess equality of proportions. P 64
3 lines for Asian populations.22 To assess biochemical status, values less than 0.05 were considered statistically signifi- 65
4 serum chemistry parameters and lipid profiles including to- cant. Spearman’s correlations were calculated to evaluate 66
5 tal protein, albumin, C-reactive protein (CRP), total choles- the relationships between vitamin status, demographic 67
6 terol, low-density lipoprotein (LDL), high-density data, and biochemical results. According to the classifica- 68
7 lipoprotein (HDL), iron, and total iron-binding capacity tion system proposed by Hebel et al., r values below 0.2 69
8 (TIBC) were measured. indicate a negligible relationship, r values between 0.2 70
9 and 0.5 indicate a weak correlation, r values between 0.5 71
10 Analytical procedures and definitions and 0.8 indicate a moderate correlation, and r values be- 72
11 tween 0.8 and 1.0 indicate a strong correlation.31 Logistic 73
12 regression analysis was performed in patients with TB and 74
Serum samples were drawn for analysis after the initiation
13 controls for factors affecting TB. A multivariable linear 75
of antituberculosis treatment (during treatment). Blood
14 regression analysis was used to investigate factors associ- 76
samples for vitamin levels were collected from both cases
15 ated with serum vitamin levels. 77
and controls in the fasting state during the first visit. The
16 78
serum concentrations of vitamins A and E were measured by
17 Results 79
high-performance liquid chromatography (HPLC) using an
18 80
Agilent 1200 instrument (Agilent Technologies, Waldbronn,
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Germany) with commercially available reagent kits (Chrom- Baseline study population characteristics
20 €nchen, Ger- 82
systems Instruments & Chemicals GmbH, Mu
21 83
many). The serum vitamin D level was calculated as the The study included 152 patients with TB (101 men and 51
22 84
sum of the serum 25-hydroxyvitamin D2 (25[OH]D2) and women) and 137 healthy controls (90 men and 47 women).
23 85
25(OH)D3 concentrations. Serum 25(OH)D2 and 25(OH)D3 Among the 152 patients with TB 111 (73.0%) patients were
24 86
concentrations were measured by LC-MS/MS with an Agilent sputum culture-positive and 75 (49.3%) patients were
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1200 LC 2D system connected to an Agilent 6460 Triple Quad sputum smear-positive for tuberculosis. Forty-eight
26 88
MS (Agilent Technologies, Waldbronn, Germany). Commer- (31.6%) patients had a cavitary lesion on their chest
27 89
cially available reagent kits (Chromsystems Instruments & radiograph and 56 (36.8%) patients had bilateral lesions
28 90
Chemicals GmbH) were used.23 As vitamin B12 status indica- on their chest radiograph. Table 1 shows the demographic
29 91
tors, serum homocysteine and MMA concentrations were and biochemical results of the patients with TB and con-
30 92
measured on an Acquity UPLC system (Waters Corporation, trols. The age and sex distributions were not significantly
31 93
Milford, MA, USA) connected to a Xevo TQ-S tandem mass different between the patients with TB vs. controls. How-
32 94
spectrometer (Waters Corporation) by the modified method ever, significant differences were observed between pa-
33 95
described by Hempen et al.24 The accuracy of serum tients with TB and controls regarding body weight
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vitamin A, D, E, and B12 measurements was assured using (60.3  11.0 kg vs. 65.6  11.3 kg, P < 0.05) and BMI
35 97
the Proficiency Testing/Quality Management program of (21.7 vs. 23.9 kg/m2, P < 0.01).
36 98
the United States College of American Pathologists survey. Due to the increased globulin level, the median total
37 99
The assay detection ranges were 0.5e10 mmol/L for vitamin protein level was higher in patients with TB than in healthy
38 100
A, 4.0e500.0 ng/mL for vitamin D, 2.0e100.0 mmol/L for controls (7.4 vs. 7.1 g/dL, P < 0.001). Similarly, the median
39 101
vitamin E, 45.0e49270.0 nmol/L for MMA, and CRP level was significantly higher in the TB group than in
40 102
5.0e910.0 mmol/L for homocysteine. The measurements healthy controls (0.14 vs. 0.04 mg/dL, P < 0.001). In
41 103
of intra-assay and inter-assay imprecision of all assays contrast, the total cholesterol and LDL levels were signifi-
42 104
were <10% of the coefficients of variation. cantly lower in patients with TB than in healthy controls
43 105
Vitamin A and E deficiencies were defined as previously (171.0 vs. 198.0 mg/dL, P < 0.001, 102.0 mg/dL vs.
44 106
described (serum vitamin A concentration <1.05 mmol/L 123.0 mg/dL, P < 0.001, respectively), as were the iron
45 107
and vitamin E concentration <11.6 mmol/L).25,26 Vitamin D and TIBC levels (100.5 vs. 120.0 mg/dL, P < 0.001 and
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deficiency was defined as a serum 25(OH)D concentration 278.5 mg/dL vs. 309.0 mg/dL, P < 0.001, respectively).
47 109
<20 ng/mL.27,28 Vitamin B12 deficiency was defined as an
48 110
MMA concentration >300 nmol/L and a homocysteine con- Vitamin status of patients with TB and controls
49 111
centration >15 mmol/L.29,30 Serum chemistry parameters
50 112
and lipid profiles were determined using a Roche modular
51 The serum vitamin concentrations are summarized in 113
analyzer (Roche Diagnostics Corp., Indianapolis, IN, USA)
52 Table 2 and Fig. 1. The serum concentrations of vitamins 114
according to the manufacturer’s instructions.
53 A, D, and E were significantly lower in patients with TB 115
54 than in control subjects (1.4 vs. 2.0 mmol/L, P < 0.001 for 116
55 Statistical analysis vitamin A; 10.6 vs. 19.3 ng/mL, P < 0.001 for vitamin D; 117
56 and 22.8 vs. 30.6 mmol/L, P < 0.001 for vitamin E). In 118
57 Data were analyzed using SPSS software v23.0 (SPSS Inc. contrast, the median serum MMA level was higher in pa- 119
58 233 S. Chicago, IL, USA) and SAS version 9.4 (SAS Institute, tients with TB than in control subjects (134.9 vs. 120
59 Cary, NC, USA). Student’s t-test and the Wilcoxon Man- 110.8 nmol/L, P < 0.001). The serum homocysteine levels 121
60 neWhitney test were used to assess the significance of dif- were not significantly different between the two groups 122
61 ferences in vitamin status and biochemical results of (9.5 vs. 9.7 mmol/L, P > 0.05). The vitamin statuses based 123
62 patients with TB vs. controls, after assessment of normality on the concentrations described above are summarized in 124

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4 J. Oh et al.

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Table 1 Baseline study population characteristics.
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3 Patients with tuberculosis (n Z 152) Controls (n Z 137) P-value 65
4 Demographic characteristics 66
5 Age, years, median (range) 48 (18e80) 45 (21e80) 0.192 67
6 Sex, number (%) M 101 (66.4) M 90 (65.7) 0.893 68
7 F 51 (33.6) F 47 (34.3) 69
8 BMI, kg/m2 21.7 (15.8e30.7) 23.9 (16.4e32.0) <0.001 70
9 BMI <18.5 kg/m2, number (%) 16 (11.8) 6 (4.4) 71
10 BMI 18.5 kg/m2, number (%) 120 (88.2) 131 (95.6) 72
11 Serum chemistry results, median (range) 73
12 Total protein (g/dL) 7.4 (5.7e9.0) 7.1 (6.3e8.4) <0.001 74
13 Albumin (g/dL) 4.4 (2.8e5.0) 4.4 (3.9e7.5) 0.098 75
14 Albumin/globulin ratio 1.6 (1.2e2.8) 1.5 (0.6e2.1) <0.001 76
15 CRP (mg/dL) 0.14 (0.03e18.74) 0.04 (0.03e0.30) <0.001 77
16 Total cholesterol (mg/dL) 171.0 (103.0e249.0) 198.0 (134.0e274.0) <0.001 78
17 LDL (mg/dL) 102.0 (47.0e167.0) 123.0 (57.0e195.0) <0.001 79
18 HDL (mg/dL) 57.0 (34.0e103.0) 55.0 (30.0e97.0) 0.119 80
19 Iron (mg/dL) 100.5 (28.0e281.0) 120.0 (8.0e340.0) <0.001 81
20 TIBC (mg/dL) 278.5 (161.0e426.0) 309.0 (221.0e448.0) <0.001 82
21 83
BMI, Body mass index; CRP, C-reactive protein; LDL, Low-density lipoprotein; HDL, High-density lipoprotein; TIBC, Total iron-binding
22 84
capacity.
23 85
24 86
25 87
26 Table 2 Serum concentrations of vitamins and vitamin B12 status indicators in the study population. 88
27 Patients with tuberculosis (n Z 152) Controls (n Z 137) Odds ratio (95% CI) P-valuea 89
28 90
29 Vitamin A (mmol/L) 1.4 (0.5e4.3) 2.0 (1.1e4.1) 0.257 (0.165e0.400) <0.001 91
30 Vitamin D (ng/mL) 10.6 (0.49e52.3) 19.3 (6.2e60.5) 0.904 (0.876e0.932) <0.001 92
31 Vitamin E (mmol/L) 22.8 (11.5e50.12) 30.6 (17.0e88.6) 0.869 (0.835e0.905) <0.001 93
32 Methylmalonic acid (nmol/L) 134.9 (22.3e1762.7) 110.8 (49.6e501.7) 1.005 (1.001e1.009) <0.001 94
33 Homocysteine (mmol/L) 9.5 (4.9e31.5) 9.7 (5.3e17.3) 1.057 (0.685e1.135) 0.121 95
34 CI, Confidence interval. 96
a Q1
35 Results are presented as medians (ranges) with p-values from logistic regression analysis. 97
36 98
37 99
Table 3. Vitamin A and D deficiencies were significantly observed in the study population. Moreover, a positive cor-
38 100
more prevalent in patients with TB than in control subjects relation between MMA and homocysteine was observed
39 101
(P < 0.001). Multiple vitamin deficiencies were observed (r Z 0.241, P < 0.05).
40 102
only in the TB group (22.4% of all patients with TB), with BMI, total cholesterol, and LDL showed positive correla-
41 103
combined vitamin A and D deficiency most commonly tions with vitamin A, vitamin D, and/or vitamin E levels.
42 104
observed (19.1% of all patients with TB). In the bivariate lo- Vitamin E and total cholesterol showed the strongest
43 105
gistic regression analysis, the serum levels of vitamin A, correlation in the study population (r Z 0.635, P < 0.05),
44 106
vitamin D, vitamin E, and methylmalonic acid were all asso- while iron and TIBC also showed positive correlations with
45 107
ciated with TB (Table 2). According to the above definitions vitamin A (r Z 0.433, P < 0.05, r Z 0.317, P < 0.05, respec-
46 108
of vitamin deficiency, vitamin D deficiency was the only tively). MMA and homocysteine did not exhibit any signifi-
47 109
vitamin deficiency group that was associated with TB cant correlations with any other vitamin, demographic
48 110
(odds ratio 3.769, P < 0.001). Vitamin A, vitamin E, and variable, or biochemical indicator. Multivariable regression
49 111
vitamin B12 deficiencies were not significantly associated analysis revealed factors associated with vitamin concen-
50 112
with TB; this finding could be due to the low numbers of pa- trations. BMI, CRP, and iron were associated with vitamin
51 113
tients with these deficiencies. A. Total cholesterol, LDL and HDL were associated with
52 114
vitamin D. In addition, age, CRP and total cholesterol
53 115
Factors associated with vitamin levels were associated with vitamin E (Supplementary Table S1).
54 116
55 117
56 The correlations between the concentrations of vitamin A, Discussion 118
57 vitamin D, vitamin E, and vitamin B12 indicators (MMA and 119
58 homocysteine) and demographic data or other biochemical This is the first comprehensive comparative analysis of 120
59 results are shown in Table 4 and Supplementary Table S1. the statuses of vitamins A, B12, D, and E in patients with 121
60 Positive correlations between vitamins A, D, and E (vitamins TB vs. controls. We also investigated potential associa- 122
61 A and D, r Z 0.395, P < 0.05; vitamins D and E, r Z 0.342, tions between clinical data, laboratory results, and 123
62 P < 0.05; vitamins A and E, r Z 0.427, P < 0.05) were vitamin status in patients with TB, in addition to 124

Please cite this article in press as: Oh J, et al., Evaluation of vitamin status in patients with pulmonary tuberculosis, J Infect (2016),
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Vitamin status in tuberculosis patients 5

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Concentrations of vitamin A, vitamin D, vitamin E, methylmalonic acid, and homocysteine in control patients and patients with tuberculosis.
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Figure 1

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6 J. Oh et al.

1 63
Table 3 Vitamin deficiencies in the study population.
2 64
3 Patients with tuberculosis (n Z 152) Controls (n Z 137) P-value 65
4 Vitamin A deficiency 34 (22.4%) 0 (0.0%) <0.001 66
5 Vitamin D deficiency 124 (81.6%) 74 (54.0%) <0.001 67
6 Vitamin E deficiency 3 (2.0%) 0 (0.0%) 0.098 68
7 Vitamin B12 deficiency 4 (2.6%) 0 (0.0%) 0.124 69
8 Vitamin A and D deficiency 29 (19.1%) 0 (0.0%) <0.001 70
9 Vitamin A and E deficiency 1 (0.7%) 0 (0.0%) 1.000 71
10 Vitamin D and B12 deficiency 4 (2.6%) 0 (0.0%) 0.124 72
11 73
Results are presented as numbers and percentages with p-values from the chi-square test.
12 74
No concomitant deficiencies of vitamins D & E, vitamins B12 & E, or vitamins A & B12 were observed.
13 75
14 76
15 77
16 reviewing vitamin status in patients with TB of other eth- supplementation during the early stages of TB treatment, 78
17 nicities (Table 5). although a consistent benefit on TB treatment outcomes 79
18 We found that serum vitamin A, D, and E concentrations or nutritional recovery has not been demonstrated.43 80
19 were significantly lower in patients with TB than in Future well-designed randomized controlled trials with es- 81
20 controls. According to the above definitions of vitamin tablished definitions of treatment outcomes are needed to 82
21 deficiencies, vitamin A and vitamin D deficiencies were clarify this issue. 83
22 significantly more frequent in patients with TB than in We used serum MMA and homocysteine as biomarkers of 84
23 controls. The frequency of multiple vitamin deficiencies vitamin B12 status because the levels of these molecules are 85
24 was 22.4%; all affected subjects were patients with TB. increased in vitamin B12 deficiency.20 We found that the 86
25 Vitamin D is the most widely studied vitamin in the median MMA level was higher in patients with TB than in 87
26 context of TB. Most previous studies have reported lower controls, while the homocysteine level was not. MMA has 88
27 concentrations in patients with TB than in controls been demonstrated to be a more sensitive and specific 89
28 (Table 5). Our results are consistent with previous studies biomarker of vitamin B12 deficiency than homocysteine.20 90
29 reporting lower vitamin D concentrations in patients with Interestingly, M. tuberculosis has the capacity to regulate 91
30 TB than controls and that vitamin D deficiency was more core metabolic functions according to B12 availability, 92
31 common in patients with TB than controls. Similarly, a num- i.e., whether B12 is acquired via endogenous synthesis or 93
32 ber of reviews have reported an association of low vitamin through uptake from the host environment. This finding im- 94
33 D levels with TB infection.32e37 Reduced concentrations of plies that vitamin B12 has a role in pathogenesis, although 95
34 vitamin A and of the antioxidant vitamin E have also been this role remains poorly understood.17 Although the serum 96
35 previously reported in patients with TB in other ethnic pop- levels of vitamin B12 in patients with TB have been reported 97
36 ulations.25,38e40 Our result is consistent with previous to fall within the normal range, we found significantly 98
37 studies reporting lower concentrations of vitamins A and E different proportions of patients with vitamin B12 defi- 99
38 in patients with TB than in controls.25,38e41 One study in ciency (defined as increased levels of both MMA and homo- 100
39 Timor reported an association of severe TB with vitamin A cysteine) in the TB vs. control groups.44 This result may be 101
40 deficiency.42 However, studies of the clinical impact of due to the different sensitivity of biomarkers used to assess 102
41 vitamin supplementation on treatment outcomes have vitamin B12 deficiency.20 Future studies are needed to 103
42 yielded inconsistent results, and the evidence is limited.43 assess the roles and clinical implications of vitamin B12 in 104
43 A recent systematic review reported that the plasma level TB infection. 105
44 of vitamin A appeared to increase following initiation of We analyzed correlations between multiple vitamins and 106
45 TB treatment, regardless of supplementation. However, observed positive correlations between vitamins A and D 107
46 plasma levels of vitamins D and E can be improved by (r Z 0.395, P < 0.05), D and E (r Z 0.342, P < 0.05), and A 108
47 109
48 110
49 111
50 Table 4 Correlations between vitamin concentrations, basal characteristics, and other biochemical results of the study 112
51 population. 113
52 Age BMI Total protein Albumin CRP Total cholesterol LDL HDL Iron TIBC 114
53 Vitamin A 0.127) 0.391) 0.141) 0.217) 0.253) 0.333) 0.315) 0.121 0.433) 0.317) 115
54 Vitamin D 0.127) 0.320) 0.156) 0.003 0.194) 0.267) 0.283) 0.160) 0.177) 0.143 116
55 Vitamin E 0.199) 0.219) 0.087 0.002 0.247) 0.635) 0.527) 0.008 0.134 0.293) 117
56 Methylmalonic acid 0.151) 0.061 0.054 0.142) 0.158) 0.075 0.076 0.011 0.045 0.163) 118
57 Homocysteine 0.022 0.161) 0.103 0.118) 0.159) 0.025 0.073 0.313) 0.061 0.092 119
58 120
59 BMI, Body mass index; CRP, C-reactive protein; LDL, Low-density lipoprotein; HDL, High-density lipoprotein; TIBC, Total iron-binding ca- 121
pacity.
60 122
)p-value <0.05.
61 123
Results are presented as Spearman’s correlation coefficients.
62 124

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Vitamin status in tuberculosis patients 7

1 Q2 63
Table 5 Previous studies about vitamin status in patients with tuberculosis.
2 64
3 References Studied Number Studied region Case vs. control results (mean or median) 65
4 vitamins (cases/controls) 66
5 This study Vitamins A, D, 152/137 Korea Vitamin A, 1.4 vs. 2.0 mmol/L (P < 0.001) 67
6 E, and B12 Vitamin D, 10.6 vs. 19.3 ng/mL (P < 0.001) 68
7 Vitamin E, 22.8 vs. 30.6 mmol/L (P < 0.001) 69
8 Methylmalonic acid, 134.9 vs. 110.8 nmol/L 70
9 (P < 0.001) 71
10 Homocysteine, 9.5 vs 9.7 mmol/L (not 72
11 significant) 73
12 Koo, 201239 Vitamin D 116/86 Korea Vitamin D, 13.9 vs. 13.2 ng/mL (not 74
13 significant) 75
14 Kim, 201430 Vitamin D 165/192 Korea Vitamin D, 13.2 vs. 18.7 ng/mL (P < 0.001) 76
15 Hong, 201431 Vitamin D 94/182 Korea Vitamin D, 9.86 vs. 16.03 ng/mL (P < 0.001) 77
16 Ustianowski, 200532 Vitamin D 210a India, Somalia, Vitamin D, 76% < 8.8 ng/mL 78
17 Pakistan etc. 79
18 Wejse, 200733 Vitamin D 36/494 West Africa Vitamin D, 31.0 vs. 33.2 ng/mL (P < 0.001) 80
19 Ho-Pham, 201034 Vitamin D 166/219 Vietnam Vitamin D, 35.4% vs. 19.5% < 30 ng/mL 81
20 (P < 0.001) 82
21 Mastala, 201335 Vitamin D 161/157 Malawi Vitamin D, 23.9 vs. 33.7 ng/mL (P < 0.001) 83
22 Venturini, 201436 Vitamin D 44/814 Asia, Latin America, Vitamin D, 11.1 vs. 21.0 ng/mL (P < 0.001) 84
23 children Europe, 85
24 Nord Africa, and 86
25 sub-Saharan Africa 87
26 Rwangabwoba, 199823 Vitamin A 94a Rwanda Vitamin A, 1.38 mmol/L 88
27 Ali, 201443 Vitamin A 208a India Vitamin A, 0.77 mmol/L 89
28 Srinivasan, 201337 Vitamins A, D 22/22 India Vitamin A, 1.51 vs. 6.67 nmol/L (P < 0.001) 90
29 Vitamin D, 27.0 vs. 47.0 ng/mL (P < 0.001) 91
30 Pilt, 199841 Vitamins C, E 41/20 South Africa Vitamin C, 7.5 vs. 10.2 mg/mL 92
31 Vitamin E, 4.5 vs. 9.6 mg/mL 93
32 Madebo, 200342 Vitamins A, C, E 125/45 Ethiopia Vitamin A, 0.90 vs. 2.49 mmol/L (P < 0.001) 94
33 Vitamin C, 2.91 vs. 7.14 mmol/L (P < 0.001) 95
34 Vitamin E, 21.10 vs. 24.35 mmol/L (P < 0.01) 96
35 Edem, 201538 Vitamins A, C, 24/20 Nigeria Vitamin A, 72.9 vs. 84.6 mg/dL (P < 0.05) 97
36 D, E Vitamin C, 0.74 vs. 0.87 mg/dL (P < 0.05) 98
37 Vitamin D, 58.1 vs. 68.5 pg/mL (P < 0.05) 99
38 Vitamin E, 1.1 vs. 1.27 mg/dL (P < 0.05) 100
39 a 101
Only patients with tuberculosis were included in the study.
40 102
41 103
42 104
43 and E (r Z 0.427, P < 0.05). These results might explain the correlation with serum iron, and vitamin E only showed a 105
44 multiple vitamin deficiencies previously noted in some pa- correlation with TIBC. These results could be due to the in- 106
45 tients with TB.4 We also compared vitamin status in pa- teractions of these vitamins with iron and the involvement 107
46 tients with TB vs. controls in relation to other markers. of iron homeostasis.47 Since anemia is frequently observed 108
47 BMI, total protein, total cholesterol, and LDL, all of which in patients with TB, our results could be helpful for under- 109
48 are indicators of protein-energy malnutrition status, were standing the relationships between vitamins and iron ho- 110
49 significantly lower in patients with TB than in controls; meostasis.4,47 However, since relatively few patients had 111
50 this finding is consistent with a previous study.45 Iron and vitamin E and B12 deficiency, our results should be inter- 112
51 TIBC were also significantly lower in patients with TB than preted with caution. 113
52 in controls, which is also in agreement with a previous This study did have some limitations. All patients with 114
53 study.46 These results could indicate anemia due to inflam- TB in this study were initially treated at community 115
54 mation in TB and/or malnutrition.46 Correlation analysis be- hospitals before their transfer to Samsung Medical Center, 116
55 tween vitamins and other nutritional status-associated since Samsung Medical Center is a tertiary hospital. Thus, 117
56 parameters showed that BMI, total cholesterol, and LDL pretreatment samples could not be obtained for these 118
57 were correlated with vitamins A, D, and E, suggesting an as- patients. Moreover, few data were obtained regarding 119
58 sociation between vitamin deficiency and malnutrition.39 dietary supplementation of vitamins. Serum vitamin con- 120
59 This result could be due to the fat solubility of these vita- centrations measured at a single point in time may not 121
60 mins and the known associations of BMI, cholesterol, and reflect long-term vitamin status. Future prospective studies 122
61 LDL with lipid metabolism.19 Vitamin A showed positive cor- with large patient cohorts addressing these issues are 123
62 relations with serum iron and TIBC, vitamin D showed a needed to clarify the significance of vitamins in TB. 124

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 YJINF3834_proof ■ 14 November 2016 ■ 8/9

8 J. Oh et al.

1 In conclusion, here we simultaneously compared the 12. de Gier B, Campos Ponce M, van de Bor M, Doak CM, Polman K. 63
2 statuses of multiple vitamins in patients with TB vs. con- Helminth infections and micronutrients in school-age children: 64
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higher frequencies of single vitamin deficiencies and of 99:1499e509.
4 66
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