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Vitamin B6 supplementation increases immune response in critically ill patients

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To investigate whether vitamin B6 supplementation has a beneficial effect on immune responses in critically ill patients. A single-blind intervention study. The study was performed at the Taichung Veterans General Hospital, the central part of Taiwan. Fifty-one subjects who stayed over 14 days in the intensive care unit completed the study. Subjects were not treated with any vitamin supplement before the intervention. Patients were randomly assigned to one of three groups, control (n = 20), a daily injection of 50 mg vitamin B-6 (B6 -50, n=15), or 100 mg vitamin B-6 (B6 -100, n = 16) for 14 days. Plasma pyridoxal 5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (4-PA), erythrocyte alanine (EALT-AC) and aspartate (EAST-AC) aminotransaminase activity coefficient, and urinary 4-PA were measured. The levels of serum albumin, hemoglobin, hematocrit, high-sensitivity C-reactive protein (hs-CRP) and immune responses (white blood cell, neutrophils, total lymphocytes count (TLC), T- (CD3) and B-(CD19) lymphocytes, T-helper (CD4) and suppressor (CD8) cells) were determined. Plasma PLP, PL, 4-PA and urinary 4-PA concentrations significantly increased in two treated groups. T-lymphocyte and T-helper cell numbers and the percentage of T-suppressor cell significantly increased on day 14 in the B6 -50 group. Total lymphocyte count, T-helper and T-suppressor cell numbers, the percentage of T-lymphocyte cells and T-suppressors significantly increased in the B6 -100 group at the 14th day. There were no significant changes with respect to immune responses in the control group over 14 days. A large dose of vitamin B6 supplementation (50 or 100 mg/day) could compensate for the lack of responsiveness of plasma PLP to vitamin B6 intake, and further increase immune response of critically ill patients. This study was supported by the National Science Council, Taiwan, Republic of China (NSC-92-2320-B-040-026).
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ORIGINAL ARTICLE
Vitamin B
6
supplementation increases immune
responses in critically ill patients
C-H Cheng
1
, S-J Chang
2
, B-J Lee
3
, K-L Lin
4
and Y-C Huang
5
1
Critical Care and Respiratory Therapy, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China;
2
Department of
Nutrition, St Martin De Porres, Hospital, Chia-Yi, Taiwan, Republic of China;
3
Intensive Care Unit, Taichung Veterans General
Hospital, Taichung, Taiwan, Republic of China;
4
Department of Clinical Laboratory, Chung Shan Medical University Hospital,
Taichung, Taiwan, Republic of China and
5
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan, Republic of China
Objective: To investigate whether vitamin B
6
supplementation has a beneficial effect on immune responses in critically ill
patients.
Design: A single-blind intervention study.
Setting: The study was performed at the Taichung Veterans General Hospital, the central part of Taiwan.
Subjects: Fifty-one subjects who stayed over 14 days in the intensive care unit completed the study. Subjects were not treated
with any vitamin supplement before the intervention.
Interventions: Patients were randomly assigned to one of three groups, control (n¼20), a daily injection of 50 mg vitamin B-6
(B
6
-50, n¼15), or 100 mg vitamin B-6 (B
6
-100, n¼16) for 14 days.
Main outcome measures: Plasma pyridoxal 50-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (4-PA), erythrocyte alanine
(EALT-AC) and aspartate (EAST-AC) aminotransaminase activity coefficient, and urinary 4-PA were measured. The levels of serum
albumin, hemoglobin, hematocrit, high-sensitivity C-reactive protein (hs-CRP) and immune responses (white blood cell,
neutrophils, total lymphocytes count (TLC), T- (CD3) and B-(CD19) lymphocytes, T-helper (CD4) and suppressor (CD8) cells)
were determined.
Results: Plasma PLP, PL, 4-PA and urinary 4-PA concentrations significantly increased in two treated groups. T-lymphocyte and
T-helper cell numbers and the percentage of T-suppressor cell significantly increased on day 14 in the B
6
-50 group. Total
lymphocyte count, T-helper and T-suppressor cell numbers, the percentage of T-lymphocyte cells and T-suppressors significantly
increased in the B
6
-100 group at the 14th day. There were no significant changes with respect to immune responses in the
control group over 14 days.
Conclusions: A large dose of vitamin B
6
supplementation (50 or 100 mg/day) could compensate for the lack of responsiveness
of plasma PLP to vitamin B
6
intake, and further increase immune response of critically ill patients.
Sponsorship: This study was supported by the National Science Council, Taiwan, Republic of China (NSC-92-2320-B-040-026).
European Journal of Clinical Nutrition (2006) 60, 1207–1213. doi:10.1038/sj.ejcn.1602439; published online 3 May 2006
Keywords: pyridoxal 50-phosphate; pyridoxal; immune responses; vitamin B
6
supplementation; critically ill
Introduction
Although the mechanism of plasma pyridoxal 50phosphate
(PLP), the physiological active coenzyme form of vitamin B
6
,
on immune responses has not yet been ascertained, the
deficiency of PLP has been demonstrated to significantly
impair both humoral and cell-mediated immunity
(Kumar and Axelrod, 1968; Axlerod, 1971; Sergeev et al.,
1978; Willis-Carr and St Pierre, 1978; Ha et al., 1984).
Casciato et al. (1984) indicated that eight hemodialysis
patients supplemented with 50 mg/day of vitamin B
6
Received 30 August 2005; revised 9 December 2005; accepted 23 January
2006; published online 3 May 2006
Correspondence: Dr Y-C Huang, No. 110 Sec 1 Chien-Kuo N. Rd., School of
Nutrition, Chung Shan Medical University, Taichung, Taiwan, ROC 402.
E-mail: ych@csmu.edu.tw
Guarantor: YC Huang.
Contributors: C-HC was responsible for the screening and intervention of
subjects and interpretation of the results. S-JC was responsible for data coding,
sample analyses, and statistical analyses. B-JL was responsible for the screening
and intervention of subjects. K-LL was responsible for the hematological
measurements. Y-CH was responsible for the development of intellectual
content and the study design, interpretation of the results, and manuscript
drafting.
European Journal of Clinical Nutrition (2006) 60, 1207– 1213
&
2006 Nature Publishing Group All rights reserved 0954-3007/06 $
30.00
www.nature.com/ejcn
(pyridoxine hydrochloride (HCl)) for 3–5 weeks showed an
improvement in their nitroblue tetrazolium reduction test,
the generation of chemotactic factors from plasma, lympho-
cyte subpopulation and lymphocyte transformation in
response to mitogens. Lymphocyte proliferation signifi-
cantly increased in response to phytohemagglutinin, pokwe-
weed and Staphylococcus aureus after 11 healthy elderly were
supplemented with 50 mg/day of vitamin B
6
(pyridoxine) for
2 months; Talbott et al. (1987), therefore, indicated that
increasing vitamin B
6
intake could improve immune respon-
siveness of both T and B cells. Folkers et al. (1993) treated
nine healthy subjects with 300 mg/day of pyridoxine,
consequently their T4 lymphocytes and T4/T8 ratio signifi-
cantly increased over 2 months. The improvements of
immune response seemed to occur after high doses of
vitamin B
6
supplements (450 mg/day pyridoxine) even
though subjects had no any evidence of vitamin B
6
deficiency.
Our previous study (Huang et al., 2002) indicated that
although critically ill patients had an adequate vitamin B
6
intake (1.6 mg/day for men and women who are older than
51 years, Taiwan Dietary Reference Intakes, Department of
Health, Taiwan, 2002), their plasma PLP and pyridoxal (PL)
still significantly decreased during their stay in the intensive
care unit (ICU). Critically ill patients were under severe
stress, inflammation, and clinical conditions, which may
increase the utilization and metabolic turnover of plasma
PLP or even cause the redistribution of PLP from plasma to
erythrocyte (Louw et al., 1992; Talwar et al., 2003a; Huang
et al., 2005). It thus would be interesting to know whether a
high dose of vitamin B
6
supplement would increase the
immune response of critically ill patients. The purpose of
this study was to investigate whether vitamin B
6
supple-
mentation has a beneficial effect on immune responses in
critically ill patients.
Materials and methods
Patients
A single-blind study was conducted at the Taichung Veteran
General Hospital, which is a teaching hospital in the central
part of Taiwan. One hundred and twelve patients were
admitted or transferred to the ICU screened from December
2003 to December 2004. Patients were excluded if they were
uremic or clinically unstable or unconscious at the time of
entry to the study. Patients were also excluded if they were
given additional multivitamin supplements based on a
physician’s decision. All patients received either enteral,
total parenteral, or combined (enteral plus total parenteral)
nutritional support based on the physician’s recommenda-
tions. Daily macronutrients (carbohydrate, fat, and protein)
and vitamin B
6
intake from nutritional support and
intravenous crystalloid infusions were recorded routinely
by the ICU nurses and dietitians. The diagnoses, age, sex,
and height were obtained from the medical records. Patient’s
weight, body mass index (BMI; kg/m
2
), and the severity of
illness (by using APACHE II score) on admission were
assessed within 24 h of admission and again on day 14 in
the ICU. Only patients requiring at least 14 days of
mechanical ventilation were included; therefore, 51 patients
(41 men and 10 women) with the mean age of 70.2714.5
years successfully completed the study after informed
consent was obtained. The study was approved by the
Committee for Ethics of Chung Shan Medical University.
Experimental protocol
Patients were randomly assigned to either the control (no
vitamin B
6
injection, n¼20), 50 mg vitamin B
6
(B
6
-50)
(n¼16), or 100 mg vitamin B
6
group (B
6
-100) (n¼15).
Patients in the groups of B
6
-50 and B
6
-100 were receiving
the injection of vitamin B
6
daily by the ICU nurse for 14
days. The vitamin B
6
injection (pyridoxine HCl) was
commercially available (Ying Yuan Chemical Pharmaceutical
Co., Ltd, Tainan, Taiwan).
Fasting venous blood samples were collected in Vacutainer
tubes (Becton Dickinson, Rutherford, NJ, USA) containing an
ethylenediaminetetraacetic acid as an anticoagulant or no
anticoagulant as required to determine hematological (i.e,
white blood cell (WBC), total lymphocyte count (TLC),
neutrophils, hemoglobin, hematocrit, albumin, prealbumin,
creatinine, alkaline phosphatase, high-sensitivity C-reactive
protein (hs-CRP), vitamin B
6
status (i.e., plasma PLP, PL, 4-
pyridoxic acid (4-PA), erythrocyte alanine aminotransferase,
and erythrocyte aspartate aminotransferase activity coeffi-
cient (EALT-AC and EAST-AC), and T-cell subsets (i.e., CD3,
CD4, CD8, and CD19 antigens). During the intervention
period, blood samples were taken on the 1st and 14th days in
the ICU. Blood samples were transported on ice and
separated into plasma (or serum) and red blood cells within
1 h by low-speed centrifugation (2500 r.p.m., 15min). Sam-
ples were then stored frozen (801C) until analysis.
Biochemical measurements
Plasma PLP, PL, and 4-PA were determined by high-
performance liquid chromatography as previously described
(Talwar et al., 2003b). The fluorescence detector’s excitation
and emission wavelengths were 320 and 420 nm, respec-
tively. The intra-assay of plasma PLP, PL, and 4-PA variabil-
ities were 2.6% (n¼5), 3.8% (n¼5), and 1.5% (n¼5),
respectively. The inter-assay of plasma PLP, PL, and 4-PA
variabilities were 4.2% (n¼8), 4.8% (n¼8), and 2.1% (n¼8),
respectively. EALT and EAST with and without PLP stimula-
tion in vitro were measured by the method of Woodring and
Storvick (1970). All EALT and EAST activity measurements
were performed by using fresh erythrocyte samples collected
on the day of analysis. Plasma B
6
concentrations and
transaminase activity measurements were carried out under
yellow light to prevent photodestruction. All analyses were
performed in duplicate. Vitamin B
6
deficiency was defined as
Vitamin B
6
supplementation increases immune responses
C-H Cheng et al
1208
European Journal of Clinical Nutrition
plasma PLP concentration o20 nmol/l, EALT-AC 41.25 and/
or EAST-AC 41.8 (Leklem, 1990; Food and Nutrition Board,
1998).
Lymphocyte subsets were analyzed by flow cytometry
(FACS Calibur, Becton Dickinson, San Jose, CA, USA) using
fluorescent-labeled antibodies specific to the cell markers. All
tests were performed within 48 h of sampling. T-lymphocyte
(CD3
þ
) and B-lymphocyte (CD19
þ
) percentages were
determined with fluorescein isothiocyanate (FITC)-labeled
CD3 (Leu 4), clone SK7 and phycoerythrin (PE)-labeled CD
19 (Leu-12), clone 4G7 (Becton Dickinson, Immunocyto-
metry Systems, San Diego, CA, USA). T-helper (CD4
þ
) and
T-suppressor (CD8
þ
) lymphocyte percentages were deter-
mined with FITC-labeled CD4 (Leu 3a), clone SK3 and
PE-labeled CD8 (Leu-2a), clone SK1 (Becton Dickinson,
Immunocytometry Systems, San Diego, CA, USA). The
following values were considered as the reference ranges
for our laboratory: WBC, 5000–10000/mm
3
; neutrophil,
3000–7000/mm
3
or 60–70%; TLC, 1000–4000/mm
3
or
20–40%; T lymphocyte, 61–76%; B lymphocyte (CD 19),
6–22%; T-helper cell, 27–43%; and T-suppressor cell (CD8),
24–35% (Huppert et al., 1998).
Statistical analyses
Data was analyzed using the SigmaStat statistical software
(version 2.03; Jandel Scientific, San Rafael, CA, USA). The
paired t-test or Wilcoxon signed rank test was used to
compare significant differences in demographic and health
characteristics and the data for biochemical measurements
within each group between the 1st and the 14th day. Among
groups, one-way analysis of variance (ANOVA) or Kruskal–
Wallis one-way analysis on ranks was used to compare
differences with values at day 1 and day 14. Spearmen
correlation coefficients were used to assess the relationship
between vitamin B
6
status parameters and immune indices.
Statistical results were considered to be significant at
Po0.05. Values presented in the text are means7standard
deviation (s.d.).
Results
Characteristics of subjects
Demographic and health characteristics of subjects in each
group are shown in Table 1. There were 37 surgical and 14
medical patients. Patients’ age ranged from 24 to 91 years,
with a mean age of 70.2 years. The three groups of patients
were well matched for age, weight, and severity of illness
(APACHE II score). However, patients in the control group
were significantly taller; therefore, the BMI value was
expected to be significantly lower than patients in the other
two groups. The APACHE II score of patients in the B
6
-50
group significantly decreased on the 14th day when
compared with the value on the 1st day. However, there
were no significant changes for ACPACHE II score when we
compared the value of day 1 and day 14 in the control and
B
6
-100 groups. The most common diagnoses were gastro-
intestinal disorders (i.e., gastric ulcer, peptic ulcer, acute
pancreatitis, cholecystitis, peritonitis, inflammatory bowel
disease, and intestinal obstruction), malignant neoplasms
(i.e., esophagus, lung, breast, stomach, duodenal, prostate,
rectum and colon cancer), infection (i.e., deep neck infection
and sepsis), respiratory diseases (i.e., adult respiratory distress
syndrome and pneumonia), and multiple organ failure.
Nutrient intakes
The mean intakes of carbohydrate, lipid, and protein for 14
days were 309.2785.9, 63.6735.0, and 61.2724.4 g in the
control group; 262.8753.9, 53.5718.3, and 47.5715.3 g in
the B
6
-50 group; and 290.0750.7, 50.9712.5, and
54.4724.0 g in the B
6
-100 group. There were no significant
differences in macronutrient and vitamin B
6
intake (Table 3)
Table 1 Demographic and health characteristics of critically ill patients on the 1st and 14th d of admission to the intensive care unit
a
Characteristics Control (n¼20) B
6
-50 (n¼16) B
6
-100 (n¼15)
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
Sex (male/female) 16/4 12/4 13/2
Surgical/medical (n) 16/4 6/8 13/2
Age (y) 73.0714.1 65.4711.8 71.7717.2
Weight (kg) 60.1710.7 63.6710.2
b
62.4710.4 62.6711.6 64.8710.7 66.0710.4
Height (cm) 167.078.0
c
159.776.5
d
162.378.3
d
Body mass index (kg/m
2
) 21.873.8
c
22.973.8
b
24.473.6
d
24.773.3 24.572.6
d
25.072.3
APACHE II score 15.973.8 14.873.6 17.674.4 14.974.4
b
15.773.6 14.074.1
Predicted mortality (%) 63.1715.3 73.3712.0 66.9719.8
a
Values are means7s.d.
b
Values are significantly different between the 1st d and 14th d within the group; Po0.05.
c
Values within a row with different superscript symbols are significantly different among the control, B
6
-50, and B
6
-100 groups on the first day admission to the
intensive care unit; Po0.05.
d
Values within a row with different superscript symbols are significantly different among the control, B
6
-50 and B
6
-100 groups on the first day admission to the
intensive care unit; Po0.05.
Vitamin B
6
supplementation increases immune responses
C-H Cheng et al
1209
European Journal of Clinical Nutrition
among the three groups. Total vitamin B
6
intake (dietary
plus supplementation) significantly correlated with plasma
PLP concentration in all subjects (r¼0.56, Po0.001).
Measurements response to vitamin B
6
supplementation
The results of hematological measurement are shown in
Table 2. On day 1, there were no significant differences
with respect to serum hemoglobin, hematocrit, albumin,
prealbumin, alkaline phosphatase, creatinine, and hs-CRP
among the three groups. The hematological measurements
(i.e., hemoglobin, hematocrit, albumin, prealbumin,
alkaline phosphatase, creatinine, and hs-CRP), on average,
were either below or over normal measurements for
patients in all three groups on day 1, and the values
showed no significant changes by day 14. However,
prealbumin in the control and B
6
-100 groups, alkaline
phosphatase in the B
6
-100 group, and hs-CRP in the control
and B
6
-50 groups either significantly increased or decreased
by day 14.
Table 3 shows responses of vitamin B
6
status and immune
parameters to two different doses of vitamin B
6
supplements
for 14 days in the critically ill patients. There were no
significant differences in the values of vitamin B
6
status
indicators (i.e., plasma PLP, EALT-AC and EALT-AC, and
urinary 4-PA) among the three groups on day 1. Mean
plasma PLP level showed a marginal PLP-deficient status (20–
30 nmol/l) on day 1. Plasma PLP, PL, and 4-PA and urinary
4-PA significantly increased, EAST-AC and EALT-AC signifi-
cantly decreased in response to 14 days of vitamin B
6
supplementation in the B
6
-50 and B
6
-100 groups. It is worth
noting that 100 mg/day of vitamin B
6
for 14 days did not
show twofold increases in plasma PLP concentration when
compared with the value in the B
6
-50 group.
Critically ill patients had abnormal immune responses
parameters (i.e., WBC, neutrophils, TLC, T and B lymphocyte
and T-suppressor cell) on the first day of admission to
the ICU. Critically ill patients in the B
6
-50 group showed
a significant increase in T lymphocytes, T-helper-cell
numbers and the percentage of T-suppressor cells; the
B
6
-100 group showed significant increases in TLC, the
percentage of T lymphocytes, T-helper-cell numbers, and
the percentage of T-suppressor cell (Table 3). There were
no significant changes in all immune parameters except
for the percentage of neutrophils in the control group
when compared with the values between day 1 and
day 14.
Associations with immune responses
Spearman correlation coefficients were performed to
understand the relation between immune responses and
vitamin B
6
status indicators (Table 4). Plasma PLP
concentration was inversely associated with neutrophil
cell numbers, but positively associated with total lympho-
cytes, T lymphocytes, and T-suppressor cell numbers.
Plasma PL concentration was positively correlated with total
lymphocytes and T-suppressor-cell numbers. Plasma 4-PA
only negatively correlated with neutrophil cell numbers. The
values of EALT-AC and EAST-AC were negatively correlated
with total lymphocytes, T lymphocytes and T-suppressor-cell
numbers.
Table 2 Responses of hematological measurements to different vitamin B
6
supplements on the 1st and 14th day of admission to the intensive care unit
a
Variables Control (n¼20) B
6
-50 (n¼16) B
6
-100 (n¼15) ANOVA ANOVA
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
P-value P-value
Hemoglobin (g/dl) 9.871.6 9.571.0 9.872.4 8.772.6 9.871.2 9.771.4 0.997 0.207
(normal: 11–18 g/dl)
Hematocrit (%) 28.674.7 30.273.9 28.676.7 29.773.8 28.474.8 25.674.5 0.992 0.006
(normal: 38–54%)
Albumin (g/dl) 2.770.8 2.770.8 2.571.9 2.572.2 2.670.7 2.970.8 0.886 0.568
(normal: 3.5–5.0 g/dl)
Prealbumin (g/dl) 9.873.7 14.776.6
b
11.376.0 14.677.9 8.972.6 13.778.2
b
0.487 0.631
(normal: 18–43 g/dl)
Phosphorus (mg/dl) 2.871.6 3.070.8 2.471.4 3.771.8
b
2.370.9 3.771.3
b
0.560 0.109
(normal: 11–18 g/dl)
Alkaline phosphatase (U/l) 151.7793.8 167.07106.8 298.07339.5 389.37323.3 113.8764.3 219.3790.9
b
0.465 0.098
(normal: 50–190 g/dl)
Creatinine (mg/dl) 1.971.8 1.871.8 2.671.9 2.672.3 1.670.6 1.871.2 0.108 0.362
(normal: 0.7–1.4 g/dl)
hs-CRP (mg/l) 13.0710.1 4.573.1
b
13.6710.5 8.176.7
b
15.1713.0 7.675.3 0.707 0.146
(normal: o0.3 mg/dl)
a
Values are means7s.d.
Abbreviations: ANOVA, analysis of variance; hs-CRP, high-sensitivity C-reactive protein.
b
Values are significantly different between the 1st and 14th day within the group, Po0.05.
Vitamin B
6
supplementation increases immune responses
C-H Cheng et al
1210
European Journal of Clinical Nutrition
Table 3 Responses of vitamin B
6
status indicators and immune parameters to different vitamin B
6
supplements on the 1st and 14th day of admission to
the intensive care unit
a
Variables Control (n ¼20) B
6
-50 (n ¼16) B
6
-100 (n ¼15) ANOVA
ANOVA
Day 1 Day 14 Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
P-value P-value
Vitamin B
6
status indicators
Vitamin B-6 intake (mg/day)
(without supplementation) 2.571.4 2.471.0 2.871.3
Plasma
PLP (nmol/l) 30.2737.5 33.5722.1 19.4712.4 67.9744.1
b
24.4722.2 66.9735.5
b
0.709 0.002
Pyridoxal (nmol/l) 24.8723.7 42.6730.3
b
14.9715.7 763.87910.5
b
40.6736.0 1064.371036.5
b
0.015 o0.001
4-pyridoxic acid (mmol/l) 0.270.4 0.470.8 0.270.3 9.8713.4
b
0.470.4 9.9714.2
b
0.043 o0.001
Erythrocyte
EAST-AC 1.470.2 1.470.3 1.470.3 1.270.2
b
1.670.5 1.270.1
b
0.223 o0.001
EALT-AC 1.270.2 1.170.2 1.270.2 1.170.1
b
1.170.1 1.070.1 0.121 0.006
Urine
4-pyridoxic acid (mmol/l) 21.5719.3 28.6717.4 24.3721.7 42.8739.2 25.4714.9 158.37115.0
b
0.847 0.003
4-pyridoxic acid/creatinine (mmol/g) 21.2712.9 34.3726.5 20.7711.4 71.4758.2
b
31.5726.2 313.77263.4
b
0.347 o0.001
Immune responses
White blood cell (10
3
/mm
3
) 13.475.2 12.977.2 12.177.5 10.675.3 10.375.3 12.576.6 0.327 0.605
Neutrophil (%) 89.275.2 84.079.0
b
85.579.3 81.978.2 85.479.1 80.479.9 0.249 0.501
Neutrophil (10
3
/mm
3
) 12.074.5 11.077.0 10.376.0 8.674.2 8.374.9 9.275.8 0.02 0.386
Total lymphocyte (%) 7.074.7 8.675.5 6.874.1 9.976.8 8.377.6 13.177.7 0.717 0.136
Total lymphocyte (10
3
/mm
3
)1.071.0 1.070.5 0.871.1 1.070.8 0.870.8 1.471.0
b
0.219 0.329
T lymphocyte (CD3) (%) (normal
range: 61–76%)
51.0728.4 54.1722.7 51.5724.7 60.6717.8 39.9724.4 46.6730.7
b
0.376 0.279
T lymphocyte (CD3) (cells/ml) 518.27484.9 520.97412.4 453.17793.8 633.47505.7
b
392.47603.7 667.57696.0 0.164 0.695
B lymphocyte (CD19) (%) (normal
range: 6–22%)
9.7712.4 9.978.9 13.6712.1 9.277.9 14.879.9 7.276.6 0.253 0.730
B lymphocyte (CD19) (cells/ml) 60.6762.2 90.9798.3 67.4758.7 92.4785.3 78.4780.2 78.1765.0 0.617 0.993
T-helper cell (CD4) (%) (normal
range: 27–43%)
35.0722.7 34.3719.2 33.2719.4 34.1712.7 22.2715.0 21.2711.4 0.147 0.029
T-helper cell (CD4) (cells/ml) 292.9749.5 247.37151.5 301.37558.2 342.77254.7
b
169.27202.9 267.97209.5
b
0.171 0.606
T-suppressor cell (CD8) (%) (normal
range: 24–35%)
15.1711.4 18.477.8 13.979.3 23.8711.4
b
15.6717.1 23.5719.5
b
0.697 0.432
T suppressor (CD8) (cells/ml) 94.1755.3 134.1780.1 123.47208.4 266.97294.4 244.67398.9 363.87441.7
b
0.182 0.681
a
Values are means7s.d.
b
Values are significantly different between the 1st and 14th day within the group, Po0.05.
Abbreviations: ANOVA, analysis of variance; EALT-AC, erythrocyte alanine aminotransaminase activity coefficient; EAST-AC, erythrocyte aspartate aminotransa-
minase activity coefficient.
Table 4 Correlation coefficients between vitamin B
6
status indicators and immune responses
a
Pyridoxal 50-phosphate
(nmol/l)
Pyridoxal
(nmol/l)
4-Pyridoxic
acid
(mmol/l)
EALT-AC EAST-AC Urine 4-PA/creatinine
(mmol/g)
WBC (10
3
/mm
3
)0.114 0.115 0.163 0.045 0.044 0.052
Neutrophil (10
3
/mm
3
)0.208* 0.183 0.211* 0.034 0.002 0.07
Total lymphocyte (10
3
/mm
3
) 0.203* 0.226* 0.117 0.314* 0.273** 0.019
T lymphocyte (CD3) (cells/ml) 0.225* 0.165 0.118 0.225* 0.290** 0.201
B lymphocyte (CD19) (cells/ml) 0.086 0.003 0.066 0.116 0.101 0.231
T helper (CD4) (cells/ml) 0.164 0.105 0.041 0.149 0.271** 0.262*
T suppressor (CD8) (cells/ml) 0.271** 0.242* 0.149 0.233* 0.251* 0.001
a
Spearman correlation coefficient (r) between measures for all subjects. Abbreviations: EALT-AC, erythrocyte alanine aminotransaminase activity coefficient; EAST-
AC, erythrocyte aspartate aminotransaminase activity coefficient; WBC, white blood cells.
*Po0.05; ** Po0.01.
Vitamin B
6
supplementation increases immune responses
C-H Cheng et al
1211
European Journal of Clinical Nutrition
Discussion
Plasma PLP has been shown to be a significant indicator of
immune responses in critically ill patients in our recent
study (Huang et al., 2005). However, the effect of vitamin B
6
supplementation on immune responses in immunocom-
promised subgroups within the population (i.e., elderly, ill
patients) has been seldom reported. Only a few studies have
shown that 50–300 mg/day vitamin B
6
supplementation in
either healthy elderly or hemodialysis patients significantly
improved immune responses of subjects (Casciato et al.,
1984; Talbott et al., 1987; Folkers et al., 1993). In the present
study, our critically ill patients had abnormal immune
responses even though their vitamin B
6
intake was higher
than Taiwan DRI recommendations (Department of Health,
Taiwan, 2002) on the first day of admission to the ICU. In
agreement with the previous studies (Casciato et al., 1984;
Talbott et al., 1987; Folkers et al., 1993), several cellular
immune response parameters (i.e., T lymphocyte, T-helper
and T-suppressor cells) significantly increased after the
supplementation of either 50 or 100 mg/day of vitamin B
6
for 14 days; whereas immune responses showed no signifi-
cant changes in the control group. This suggests that vitamin
B
6
supplementation could increase immune responsiveness
of only T cells but not B cells. The increase in the percentage
of T3
þ
and T4
þ
cells has been suggested to affect the
differentiation of immature T cells to mature T cells by
vitamin B
6
supplementation in healthy elderly (Talbott
et al., 1987).
In the study of Gray et al. (2004), patients who underwent
an elective knee arthroplasty had a significant increase in
circulatory CRP concentrations and there was a significant
fall in plasma PLP concentration but red cell PLP remained
stable. This may be that critically ill patients were under
severe stress during the systemic inflammatory response,
which may have increased the turnover and utilization of
plasma PLP, decreased hepatic PLP reserves (Louw et al.,
1992), or redistributed PLP from plasma to erythrocyte
(Talwar et al., 2003a; Gray et al., 2004; Quasim et al., 2005).
Quasim et al. (2005), therefore, suggested that direct
measurements of red cell PLP are more responsive to
supplementation than plasma measurements in the critically
ill patients. That might be the reason why there was no
correlation between vitamin B
6
intake and plasma PLP
concentration in our two previous studies (Huang et al.,
2002; Huang et al., 2005). Critically ill patients consumed
approximately 4 mg/day of vitamin B
6
, and a marginal
plasma PLP deficiency (B20 nmol/l) and abnormal immune
responses were still observed (Huang et al., 2005). We,
therefore, gave a large amount of vitamin B
6
to our critically
ill patients, finding total vitamin B
6
intake (dietary plus
supplementation) significantly correlated with plasma PLP
concentration. It seemed that a large dose of vitamin B
6
supplementation (50 or 100 mg/day) could compensate for
the lack of responsiveness of plasma PLP to vitamin B
6
intake
and plasma PLP concentrations increased in the critically ill
patients. The significant increased plasma PLP concentration
may further increase the responses of T cells in our critically
patients, although the correlation between plasma PLP and
immune cells was relatively weak.
Two doses of vitamin B
6
supplements (50 and 100 mg)
were given daily to our critically ill patients. However,
plasma PLP concentration did not correlate with dose
response, which meant mean plasma PLP level of the B
6
-
100 group did not increase two times more than plasma PLP
level of the B
6
-50 group. In addition, parameters of immune
function in the B
6
-100 group did not show more improve-
ment than in the B
6
-50 group. We, therefore, suspected that
50 mg/day of vitamin B
6
might be the saturation level for
critically ill patients, who could not efficiently utilize the
higher dose (i.e., 100 mg/day) of vitamin B
6
.
In the control group, plasma PLP concentration remained
unchanged during the study period, but plasma PL signifi-
cantly increased on day 14 in the ICU. A possible explana-
tion could be that plasma PLP is bound to serum albumin
while being transported by the blood; however, low serum
albumin in our critically ill patients caused the dephos-
phorylation of plasma PLP into PL (Merrill and Henderson,
1987).
In conclusion, 50 mg/day or higher of vitamin B
6
supple-
mentation could compensate for the lack of responsiveness
of plasma PLP to vitamin B
6
intake, and further increase
immune response of critically ill patients. Erythrocyte PLP
may be more responsive to supplementation than plasma
measurements in the critically ill patients (Quasim et al.,
2005), and we did not measure erythrocyte PLP when
assessing vitamin B
6
status in this study; however, our results
provide more information in the clinical practice for
considering using vitamin B
6
supplementation to increase
the immune function of critically ill patients.
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European Journal of Clinical Nutrition
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Cellular antibody synthesis was determined by the Jerne agar-plaque technique in normal and vitamin Be-deficientrats immunized with sheep erythrocytes. A severe reduction in the number of individual antibody-forming cells was observed in spleens from immunized deficient animals. This decreased cellular immune re sponse was independent of the inanition associated with the deficiency and was restored to normal by the administration of pyridoxine shortly before immunization. Accumulation of antigen by rat spleen did not appear to be deranged in vitamin B6 deficiency.
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The effect of pyridoxine deficiency on the proliferation and cytotoxicity of BALB/c mouse lymphocytes stimulated in vitro with irradiated spleen cells from C3H mice was studied. Cytotoxicity was measured by Na51CrO4 release from L cells which have the same histocompatibility loci as C3H mouse cells. Pyridoxal-5′-phosphate (PLP) content in the spleen and liver of pyridoxine-deficient animals was determined with Escherichia coli B/1 t7A apotryptophanase. Maintenance of animals on a pyridoxine-deficient diet for 1 to 3 weeks affected neither proliferation of lymphocytes in vitro nor their cytotoxicity. Lymphocytes from mice fed a pyridoxine-deficient diet for 5 to 6 weeks had a reduced capacity to respond to foreign lymphoid cells in vitro. The Cytotoxicity of these lymphocytes was also significantly decreased. PLP, but not pyridoxal, added directly to the medium in vitro partially restored the impaired functions of T lymphocytes.
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To investigate the effect, if any, of the acute-phase response on blood vitamin concentrations and to test the hypothesis that these concentrations may change during stress. Open study, utilizing a volunteer sample of patients. Tertiary care center. Twenty-six healthy adult volunteers (14 female and 12 male); 25 volunteers underwent uncomplicated orthopedic surgery and one suffered traumatic limb fractures. None. The presence of a systemic acute-phase response was documented by the determination of serum C-reactive protein concentrations. Blood vitamin concentrations were determined from sequentially collected blood samples over a 7-day period, and compared with entry values. The presence of the acute-phase response was documented by significant and transient increases in C-reactive protein values. This response was accompanied by significant and transient decreases in the concentrations of leukocyte vitamin C, and in plasma concentrations of vitamin A, retinol-binding protein, vitamin E, total lipids, pyridoxal-5'-phosphate, and albumin. Blood concentrations of pyridoxal-5'-phosphate, retinol-binding protein, and leukocyte vitamin C decreased to values below the respective normal ranges. These concentrations normalized without any therapeutic interventions. We demonstrated transient, but significant, decreases in blood vitamin concentrations during the acute-phase response. Recommendations regarding daily supplementation with these vitamins in clinical practice cannot be made on the basis of these results, as the functional importance of these observations is not, at present, clear. However, what is clear is that biochemical vitamin concentrations, determined during the acute-phase response, should be interpreted with care.
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It is clear that many diseases are known to involve defects in vitamin B6 metabolism, but that even more await definitive studies. Furthermore, some functions of vitamin B6, such as its role in glucocorticoid action (21), have been discovered so recently that the medical implications have not yet been fully explored.
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Studies conducted in our laboratory, relating to the development of immune processes in vitamin-deficient experimental animals, have been reviewed. 1) The significant participation of these nutritional factors in the production of circulating antibodies to a variety of antigens, and in the manifestation of delayed hypersensitivity reactions, including the rejection of tissue transplants, has been described. 2) Investigations on the mode of action of vitamin B6 and pantothenic acid have demonstrated a marked reduction in the production of antibody-forming cells following antigenic stimulation in both deficiency states. The metabolism of antigen appeared to be normal. However, these two vitamins seem to function at different loci in the development of the immune process. Whereas vitamin B6 appears to be necessary for the production of “C1” units from serine, which are required for the biosynthesis of nucleic acids, it seems likely that pantothenic acid is involved in the secretion of newly-synthesized proteins into the extracellular compartment.