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Antioxidant Vitamins and Brain Dysfunction in Alcoholics

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Alcohol induces cytokine secretion by Kupffer cells, which may exert also deleterious effects on distant organs, mediated in part by cytokine-derived increased production of reactive oxygen species (ROS). It is therefore important to assess antioxidant levels. The objective of this study is to analyse the relation of antioxidant vitamins with brain atrophy and cognitive dysfunction. In 77 alcoholic patients admitted for withdrawal syndrome, subjected to brain computed tomography (CT), and 19 controls, we determined antioxidant vitamin levels and analysed their relationships with data of brain atrophy and dysfunction. Searching for causes of altered vitamin levels, we also assessed liver function, nutritional status, eating habits, alcohol intake, proinflammatory cytokine (TNF-α, IL-6, IL-8) levels and malondialdehyde (MDA) levels. Both retinol (vitamin A) and tocopherol (vitamin E) levels were decreased in alcoholics, the former in relation with liver failure, and the latter in relation with triglyceride levels and fat mass. Both were related to data of brain atrophy and cerebellar shrinkage (to which also IL-6 was significantly related). Among alcoholics, liver function impairment leads to altered serum vitamin A levels, which are related to brain alterations. Vitamin E levels are also decreased, but although in relation with liver function impairment, its decrease seems to be more dependent on nutritional status and irregular eating habits. Both vitamins are lower in patients with cerebellar atrophy and other features related to brain atrophy.
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Antioxidant Vitamins and Brain Dysfunction in Alcoholics
Emilio González-Reimers1,*, Camino M. Fernández-Rodríguez1, M. Candelaria Martín-González1, Iván Hernández-Betancor1,
Pedro Abreu-González2, María José de la Vega-Prieto3, Oswaldo Elvira-Cabrera1and Francisco Santolaria-Fernández1
1
Servicio de Medicina Interna, Hospital Universitario de Canarias, Universidad de La Laguna, Tenerife, Canary Islands, Spain,
2
Dpto. de Fisiología, Hospital
Universitario de Canarias, Universidad de La Laguna, Tenerife, Canary Islands, Spain and
3
Servicio de Laboratorio, Hospital Universitario de Canarias,
Universidad de La Laguna, Tenerife, Canary Islands, Spain
*Corresponding author: Servicio de Medicina Interna, Hospital Universitario, Ofra s/n. Tenerife, Canary Islands, Spain.
Tel: +34-922-678600; E-mail egonrey@ull.es
(Received 18 April 2013; first review notified 24 June 2013; in revised form 7July 2013; accepted 29 August 2013)
Abstract Aims: Alcohol induces cytokine secretion by Kupffer cells, which may exert also deleterious effects on distant organs,
mediated in part by cytokine-derived increased production of reactive oxygen species (ROS). It is therefore important to assess
antioxidant levels. The objective of this study is to analyse the relation of antioxidant vitamins with brain atrophy and cognitive
dysfunction. Methods: In 77 alcoholic patients admitted for withdrawal syndrome, subjected to brain computed tomography (CT),
and 19 controls, we determined antioxidant vitamin levels and analysed their relationships with data of brain atrophy and dysfunc-
tion. Searching for causes of altered vitamin levels, we also assessed liver function, nutritional status, eating habits, alcohol intake,
proinflammatory cytokine (TNF-α, IL-6, IL-8) levels and malondialdehyde (MDA) levels. Results: Both retinol (vitamin A) and
tocopherol (vitamin E) levels were decreased in alcoholics, the former in relation with liver failure, and the latter in relation with tri-
glyceride levels and fat mass. Both were related to data of brain atrophy and cerebellar shrinkage (to which also IL-6 was significantly
related). Conclusion: Among alcoholics, liver function impairment leads to altered serum vitamin A levels, which are related to
brain alterations. Vitamin E levels are also decreased, but although in relation with liver function impairment, its decrease seems to
be more dependent on nutritional status and irregular eating habits. Both vitamins are lower in patients with cerebellar atrophy and
other features related to brain atrophy.
INTRODUCTION
Ethanol increases intestinal wall permeability, allowing gram-
negative bacteria to reach the liver via the portal system
(Su et al., 2002). These bacteria activate Kupffer cells, trigger-
ing an inflammatory response, in which macrophage-derived
cytokines, especially TNF-α, IL-1βand IL-6 play outstanding
roles (Fujimoto et al., 2000;McClain et al., 2004). These cyto-
kines can cross the bloodbrain barrier, and activate brain
microglial cells, endothelial cells and vagal afferents, leading
to neuroinflammation (Crews et al., 2006). In fact, in experi-
mental conditions, microglia can be activated after a single
intraperitoneal lipopolysaccharide injection (Qin et al., 2007),
with a marked and protracted increase in TNF-αlocal produc-
tion (Qin et al., 2008) and increased oxidative stress (Qin and
Crews, 2012), which leads to neuronal damage and brain
atrophy. Indeed, any inflammatory response is accompanied
by an increased production of reactive oxygen species (ROS).
This may be especially dangerous in the alcoholic, given the
reduced activity of glutathione peroxidase and superoxide dis-
mutase, as well as the decreased levels of antioxidant micronu-
trients such as retinol, ascorbic acid and α-tocopherol
(Faizallah et al., 1986;Van de Casteele et al., 2002), selenium
and zinc (Menzano and Carlen, 1994;Gueguen et al., 2003;
González-Reimers et al., 2008) described in these patients,
although normal antioxidant vitamin levels have also been
reported (Fernández-Solà et al., 1998). Since oxidative stress
is related to a proinflammatory cytokine response, and, as
mentioned before, it may lead to neuronal damage and brain
atrophy, it is important to assess the behaviour of antioxidant
vitamins in alcoholic patients with brain dysfunction, to
discern which factor(s) may be involved in their (eventually)
altered levels, and which are their relations with brain atrophy
and cognitive impairment.
Based on these facts, in the present study we analyse the rela-
tionships of serum levels of vitamins A, C and E and the intensity
of brain atrophy and globally assessed cognitive impairment. As
a secondary objective, we also try to discern the relative roles of
liver function derangement, dietary habits, ethanol intake and
nutritional status, on altered vitamin levels.
PATIENTS AND METHODS
The study protocol was approved by the local ethical committee
of our Hospital (number 2012-01), and conforms to the ethical
guidelines of the 1975 Declaration of Helsinki. Included patients
gave informed consent to the work
We included a total of 77 alcoholics (69 men and 8 women),
drinkers of more than 150 g ethanol/day for a long time
(Table 1), aged 52.47 ± 11.06 years, and compared them with
19 age- (47.16 ± 12.23 years, t=1.83) and sex-matched con-
trols (3 women; P= 0.45). The patients were consecutively ad-
mitted with major symptoms of withdrawal syndrome, and were
included in the study if a brain computed tomography (CT) was
necessary for medical reasons. None of them was affected by any
other organic or psychiatric disorder, and they did not report ad-
diction to any other illicit drug. Based on clinical examination and
ultrasonography (liver morphology, splenomegaly, collateral cir-
culation) patients were classified in cirrhotics and non-cirrhotics.
Also, in order to get a global assessment of liver function, all the
patients were classified according to ChildPughs scoring system
(Child and Turcotte, 1964).
Following a previously reported protocol (Santolaria et al.,
2000), we recorded the eating habits of the patients, asking
them where do they usually eat (at home or in bars or taverns),
how many times a day and what they eat (sandwiches or
snacks, or normal dishes) classifying them in three categories
(normal, irregular habits (loss of some meals) and poor eating
Alcohol and Alcoholism Vol. 49, No. 1, pp. 4550, 2014 doi: 10.1093/alcalc/agt150
Advance Access Publication 25 September 2013
© The Author 2013. Medical Council on Alcohol and Oxford University Press. All rights reserved
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habits (usually in bars or taverns, in form of sandwiches or
snacks, once or twice daily)). Since only few patients fell in
this third category, we further grouped the alcoholics included
in this study in only two groups (normal vs irregular eating
habits).
Whole body densitometric composition
After informed consent, patients and controls underwent
densitometric evaluation with a Lunar Prodigy Advance
device (General Electric, Piscataway, NJ, USA). We per-
formed a whole body densitometric analysis, recording fat and
lean mass at different parts of the body, such as upper limbs,
ribs, pelvis, lower limbs, spine and total body. Total lean mass
and total fat mass were used in this study in the assessment of
nutritional status. Body mass index (as weight (in kg)/height
2
(in m)) was also recorded.
Biochemical assessment
Blood samples were taken at 8.00 a.m. in fasting conditions,
12 days before hospital discharge (about 1015 days after ad-
mission), when patients were already stable from clinical point
of view. Blood samples were immediately frozen at 20. In
addition to routine laboratory evaluation (which included,
among other variables, serum triglycerides, cholesterol, biliru-
bin, prothrombin activity and albumin), we performed the fol-
lowing biochemical determinations:
Serum vitamin A (retinol) and Vitamin E (α-tocopherol), by
high performance liquid chromatography (HPLC) Loinc
®
(Urbanek et al., 2006); serum ascorbic acid, by spectrophotom-
etry (Loinc
®
); serum tumour necrosis factor (TNF)-αby immuno-
metric chemiluminiscent assay (intra-assay variation coefficient
ranging 46.5%, interassay variation coefficient ranging 2.6
3.6%, recovery 92112%, Diagnostic Products Corporation
(DPC), Los Angeles, CA, USA); interleukin (IL)-6, by chemi-
luminiscent assay (interassay variation coefficient ranging
5.37.5%, recovery = 85104%, DPC, Los Angeles, CA, USA);
and IL-8, by chemiluminiscent assay (interassay variation coeffi-
cient ranging 5.37.5%, DPC, Los Angeles, CA, USA; Berthier
et al., 1999). As shown in Table 1,somevitaminsandcytokines
were not determined to all cases.
Lipid peroxidation products
Serum malondialdehyde (MDA) levels, referred to as thiobar-
bituric acid-reactive substance (TBARS), were measured
according to the method described by Kikugawa et al. (1992).
A volume sample of 0.2 ml of plasma was added to 0.2 ml of
H
3
PO
4
(0.2 M) and the colour reaction was initiated by the
addition of 25 µl of 0.11 M thiobarbituric acid (TBA) solu-
tion. Samples were placed in a 90°C heating block for 45 min.
After the samples were cooled, the TBARS (pink complex
colour) were extracted with 0.4 ml of n-butanol. Butanol
phase was separated by centrifugation at 6000×gfor 10 min.
Aliquots of the n-butanol phase were placed in a 96-well plate
and read at 535 nm in a microlate spectrophotometer reader
(Benchmark Plus, Bio-Rad, Hercules, CA, USA). The calibra-
tion curve was prepared with authentic MDA standards
ranging from 0 to 20 µM. The intra- and inter-assay variation
coefficients were 1.82 and 4.01, respectively.
Assessment of brain atrophy
Patients underwent a whole brain CT scan due to medical reasons
(mostly because of traumatism, convulsion, confusion). Besides
evaluation by a neuroradiologist, who recorded the presence or
not of cortical atrophy and cerebellar atrophy, the following para-
meters (Meese et al., 1980) were determined (Figs 1and 2):
Maximum width of the anterior horns of the lateral ventri-
cles (HLV) in relation to the inner skull width at the same
level (Bifrontal index).
Minimum width of the lateral ventricles (MLV) in relation
to the inner skull at the same level (Bicaudate index).
Width of both cellae media in relation to the inner skull at
the same level, which corresponds to the maximum inner
skull diameter (MISD) (Cella media index)
Evans index ( = HLV/MISD)
Ventricular index ( = MLV/HLV)
Fig. 1. Several indices utilized in this study that estimate ventricular dilatation.
Table 1. Differences in vitamins, cytokines and MDA among patients and controls
Patients Controls
T;Pn Mean ± SD nMean ± SD
Vitamin A (mg/l ) 73 0.258 ± 0.232 18 0.467 ± 0.135 T= 3.67; P< 0.001
Vitamin E (μg/ml) 67 8.775 ± 4.718 18 13.983 ± 5.303 T= 4.04; P< 0.001
Vitamin C (mg/dl) 58 0.986 ± 0.598 19 1.248 ± 0.575 T= 1.67; NS
Age (years) 77 52.01 ± 11.19 19 47.16 ± 12.23 T= 1.66; NS
MDA (μmol/l) 50 6.94 ± 6.1 5.53 (2.297.37) 19 1.39 ± 0.89 0.959 (0.7422.206) Z= 5.04; P< 0.001
TNF-α(pg/ml ) 46 13.01 ± 9.03 11.00 (7.7316.58) 19 5.75 ± 1.85 5.10 (4.07.87) Z= 4.74; P< 0.001
IL-6 ( pg/ml) 46 21.72 ± 46.95 7.23 (4.9819.50) 19 5.97 ± 1.62 5.00 (5.006.70) Z= 1.30; NS
IL-8 ( pg/ml) 40 41.20 ± 55.91 23.3 (12.0044.78) 17 6.71 ± 1.82 6.80 (5.007.75) Z= 4.46; P< 0.001
46 González-Reimers et al.
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Assessment of cognitive functions
This was performed by means of the minimental test (Folstein
et al., 1975), to 51 individuals at the day at which blood was
extracted.
Statistics
The KolmogorovSmirnov test was used to test normality, a
condition not fulfilled by several variables. Therefore, non-
parametric tests, such as MannWhitneys U test and Kruskall
Wallis were used to analyse between-group differences in these
variables. Spearmans correlation analysis was used to compare
quantitative variables. Otherwise, Studentst-test, ANOVA and
eventually Pearsons correlation analysis were used with the
normally distributed parameters, and χ
2
test to analyse the asso-
ciation between two or more qualitative variables.
RESULTS
Antioxidant vitamins in patients and controls
Marked differences were observed between patients and
controls regarding vitamin A and E (lower in patients,
t=3.67andt= 4.04, respectively; P< 0.001 in both cases),
whereas a trend was observed for ascorbic acid levels,
higher among controls (t= 1.67, Table 1). Significant corre-
lations were observed between Vitamin A and Vitamin E
(ρ=0.46; P< 0.001) and between Vitamin E and vitamin C
levels (ρ= 0.28; P= 0.026).
Relationships of altered vitamin levels and clinical features
Relationships with liver function
Vitamins A (t=3.65)and E (t=2.89;P< 0.001 in both cases)
were lower in cirrhotics, whereas no differences were observed
regarding ascorbic acid (Table 2). In addition, vitamin A and
vitamin E levels were significantly related to liver function im-
pairment (assessed by prothrombin, albumin and bilirubin).
Vitamin A was related to prothrombin activity (r=0.70),
albumin (r= 0.56) and, inversely, with bilirubin (r=0.59).
Vitamin E was related to prothrombin activity (r= 0.39,
P= 0.001) and albumin (r=0.36, P= 0.002), whereas no rela-
tions were observed between ascorbic acid and liver function
impairment. Patients with ascites showed lower vitamin A
values (t= 2.73; P= 0.008), whereas patients with encephalop-
athy showed both lower vitamin A (t= 3.13; P=0.003) and
vitamin E (t= 3.03; P= 0.004) levels. Classifying all the
patients according to Childs score (which includes bilirubin,
albumin and prothrombin activity, and the presence and char-
acteristics of ascites and encephalopathy), both vitamin A
and vitamin E were significantly lower among ChildsBand
C patients than among Childs A patients (Figs 3and 4). No
relationship was observed between ascorbic acid and liver
function.
Relationships with nutritional parameters
Both vitamin A and vitamin E showed significant relationships
with triglyceride (r= 0.29; P= 0.014 and r= 0.44; P<0.001,
respectively) and cholesterol levels (r=0.42; P< 0.001 and
r= 0.44; P= 0.001, respectively).
Vitamin E was inversely correlated with total fat (r=0.31,
P= 0.018) and, especially, with trunk fat (r=0.34, P=0.008),
whereas no relationships were observed between vitamin C and
fat parameters. A significant correlation was also observed
between vitamin A and right arm lean mass (r= 0.29; P=0.018).
Vitamin A also showed weak, inverse correlations with trunk fat
(r=0.27; P= 0.026), and total fat mass (r=0.24; P= 0.051).
Patients with irregular eating habits showed lower vitamin E
levels (Z= 2.07; P= 0.039) and a non-significant trend to lower
vitamin C values.
Relationships with ethanol intake and related parameters
No relations were observed between vitamin E, A or C and in-
tensity of ethanol consumption, duration of drinking habit,
MCV (mean corpuscular volume) or GGT (gamma glutamyl-
transferase).
Relationship with cytokines and MDA
Vitamin A showed significant, inverse relationships with
TNF-α(ρ=0.29; P= 0.045), IL-6 (ρ=0.47; P=0.001),
Fig. 2. Cella index.
Table 2. Serum vitamins in cirrhotics and non-cirrhotics
Cirrhotics Non-cirrhotics
T;Pn Mean ± SD nMean ± SD
Vitamin A (mg/l) 48 0.183 ± 0.151 25 0.403 ± 0.284 T= 3.61; P< 0.001
Vitamin E (μg/ml) 44 7.659 ± 3.881 23 10.967 ± 5.374 T= 2.89; P= 0.005
Vitamin C (mg/dl) 38 0.928 ± 0.542 20 1.063 ± 0.702 T= 1.04; NS
Antioxidant vitamins in alcoholics 47
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IL-8 (ρ=0.50; P= 0.001) and MDA (ρ=0.33; P=0.028).
Vitamin E levels also showed negative correlations with TNF-α
(ρ=0.47; P= 0.001), IL-6 (ρ=0.37; P= 0.011), but not
with IL-8 (ρ=0.09) or MDA (ρ=0.27)
Factors involved in decreased levels of vitamin A and E. In
order to discern which of the analysed variables was inde-
pendently related to vitamin levels, we performed stepwise
multiple correlation analyses, introducing liver function tests
(such as prothrombin, albumin and bilirubin), nutritional para-
meters (lean mass, trunk fat mass, cholesterol, triglyceride
levels), eating habits and daily drinking amount. We found
that serum triglyceride levels and trunk fat mass (inverse cor-
relation) displaced liver function parameters from their correl-
ation with vitamin E. On the contrary, in the case of vitamin
A, prothrombin activity was the firstand onlyvariable that
entered the multiple regression analysis.
Relationships between antioxidant vitamins and brain
alterations
Antioxidant vitamins and brain CT alterations
Vitamin E showed a significant correlation with ventricular
index (r= 0.31; P= 0.013) and also with bicaudate index
(r= 0.29; P= 0.019). Using Spearmans analysis, a correlation
was also observed vitamin A and ventricular index (ρ= 0.24;
P= 0.049) and between vitamin C and Evans index. Patients
with cerebellar atrophy showed lower levels of both vitamin A
(t= 2.41; P= 0.019) and vitamin E (t= 2.05, P= 0.045)
(Table 3). Brain atrophy data showed no relationship with
MDA, liver function tests, TNF-α, IL-8 or nutritional para-
meters, but several relationships were observed with IL-6:
patients with cerebellar atrophy showed higher values of IL-6
(Z= 2.60; P= 0.009), and IL-6 was directly correlated with
Evansindex (ρ= 0.43; P= 0.003) and bifrontal index
(ρ= 0.31; P= 0.035). By logistic regression analysis, introdu-
cing IL-6, serum vitamins and liver function tests, only
vitamin A was independently related to cerebellar atrophy, but
vitamin A was displaced by the variable age when this last
was also introduced in the analysis.
Antioxidant vitamins and cognitive dysfunction
A trend was observed between minimental test and bicaudate
index (ρ=0.30, P= 0.055), and also, nearly significant
Fig. 4. Significant differences in vitamin E levels among the three Childs
groups. KruskallWallis (KW) test was used, and, in addition to boxes and
whiskers, outliers (circles) and extreme values (asterisks) are also shown.
Table 3. Vitamins and interleukin-6 (the only interleukin which showed differences) among patients with or without cerebellar or frontal atrophy
Cerebellar atrophy Non-cerebellar atrophy
T;Pn Mean ± SD nMean ± SD
Vitamin A (mg/l) 55 0.222 ± 0.185 18 0.368 ± 0.313 T= 2.40; P= 0.019
Vitamin E (μg/ml) 49 7.659 ± 3.881 18 10.681 ± 5.822 T= 2.06; P= 0.043
Vitamin C (mg/dl) 47 1.010 ± 0.627 11 0.821 ± 0.453 T= 1.02; NS
Age (years) 58 54.00 ± 10.97 19 45.95 ± 9.79 T= 2.88; P= 0.005
IL-6 ( pg/ml) 35 26.39 ± 52.91 9.12 (5.0022.40) 11 6.86 ± 8.95 5.00 (2.005.70) Z = 2.60; P= 0.009
Frontal atrophy Non-frontal atrophy
nMean ± SD nMean ± SD T;P
Vitamin A (mg/l) 58 0.243 ± 0.226 16 0.317 ± 0.242 T= 1.12; NS
Vitamin E (μg/ml) 53 8.435 ± 4.577 14 10.158 ± 5.008 T= 1.24; NS
Vitamin C (mg/dl) 47 0.990 ± 0.635 11 0.907 ± 0.428 T= 0.48; NS
Age (years) 61 53.28 ± 11.15 16 47.19 ± 10.26 T= 1.96; P= 0.054
IL-6 ( pg/ml) 37 23.76 ± 51.93 7.84 (5.0019.05) 9 13.33 ± 12.73 5.00 (2.5526.60) Z = 0.63; NS
Fig. 3. Marked differences in vitamin A levels among the three Childs
groups. KruskallWallis (KW) test was used, and, in addition to boxes and
whiskers, outliers (circles) and extreme values (asterisks) are also shown.
48 González-Reimers et al.
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relationships with ventricular index (ρ=0.27) and bifrontal
index (ρ=0.26, 0.1 > P> 0.05 in both cases). However, no
relationships were observed between serum vitamins and cog-
nitive function (assessed by minimental test). Also, no rela-
tionships were observed between minimental test, cytokines,
MDA or liver function.
DISCUSSION
This study shows that serum levels of vitamin E and vitamin A
are lower in alcoholics than in controls. This finding is in
accordance with the results obtained by most (Bjørneboe
et al., 1987), but not all the authors (Fernández-Solá et al.,
1998) who have analysed this item. In alcoholics diverse
mechanisms may cause a decrease in antioxidant vitamins,
such as poor diet (Gueguen et al., 2003), malnutrition (Leo
et al., 1993), malabsorption (Krasner et al., 1976), liver failure
(Van de Casteele et al., 2002), inflammation (Santolaria et al.,
2000) or even increased urinary excretion (Faizallah et al.,
1986). Our results suggest that different mechanisms may be
involved. Both serum α-tocopherol and vitamin A levels were
significantly lower among cirrhotics. The relation between
both vitamins and liver function was also underscored by the
strong correlations observed between vitamin A and prothrom-
bin activity, serum albumin, serum bilirubin and Childs
score. However, alcoholics are also malnourished, and mal-
nourishment could account, theoretically, for low vitamin
levels. Indeed, both vitamin A (especially with parameters
related to lean mass) and vitamin E (with parameters related to
fat mass) were related to nutritional variables. In the case of
vitamin A, liver function parameters displaced nutritional
ones by stepwise multivariate analysis, suggesting an out-
standing importance of liver function on vitamin A levels, a
result in accordance with others reported (Van de Casteele
et al., 2002). On the contrary, nutritional parameterstrunk
fat and triglyceride levelsdisplaced liver function in the case
of vitamin E, suggesting a greater importance of nutritional
changes on vitamin E levels. In this last case it is also note-
worthy that vitamin E levels were lower among those who ate
irregularly, suggesting that dietary deficiency may also
account for low vitamin E levels, in accordance with other
authors who also reported a relation between tocopherol levels
and altered intake (Gueguen et al., 2003), altered absorption
(Krasner et al., 1976) or poor nutrition in general (Leo et al.,
1993;Santolaria et al., 2000). Therefore, the mechanisms
leading to deficiency in retinol and α-tocopherol may differ
among alcoholics.
However, it is important to consider that the relation of
vitamin E (and A) with fat parameters were inverse ones; i.e.
both vitamins showed higher levels when trunk fat mass was
lower. Although explanation of these results may be problem-
atic, it is possible that a greater fat mass in a setting of
increased lipid peroxidation may also lead to an enhanced con-
sumption of antioxidant vitamins. However, this is specula-
tive, since, for instance, MDA did not show any correlation
with fat parameters (ρ= 0.12; P> 0.40).
The principal objective of this study was to analyse if there
was a relationship between brain atrophy and antioxidant
vitamin levels. We did find that low levels of vitamin A and
vitamin E are related to several parameters that indicate brain
alteration. These results are in agreement with other
observations. In experimental setting, the addition of
α-tocopherol increases brain glutathione levels (Bondy et al.,
1996); an acute ethanol load produces an increase in lipid per-
oxidation in the rat cerebellum, together with a decrease in as-
corbate and alpha-tocopherol levels (Rouach et al., 1987), and,
in other studies, deficiency in antioxidant vitamins was related
to brain alterations, which reverted after vitamin E supplemen-
tation (Shirpoor et al., 2009). However, evidence of a benefi-
cial effect of vitamin E supplementation on brain alterations in
human beings is lacking (Isaac et al., 2008), and it also
remains unclear whether antioxidant supplements are useful or
not in other forms of alcohol-mediated damage, such as liver
disease (Bjelakovic et al., 2010).
Cerebellar atrophy is a common finding among alcoholics
(Nicolás et al., 2000). We observed that patients with cerebel-
lar atrophy showed lower values of serum vitamin A and toc-
opherol. Other authors also report a relation between vitamin
E deficiency and cerebellar atrophy (Battisti et al., 1998).
However, in this study, vitamin A, but not tocopherol, was the
biochemical parameter which showed an independent relation
with cerebellar atrophy, only displaced by age. Following the
same reasoning as other authors (Rouach et al., 1987), this
result could be interpreted as related to increased oxidative
stress: the more intensely decreased levels of both retinol and
tocopherol in those with cerebellar atrophy possibly reflect the
consumption of these antioxidants trying to counteract an ex-
cessive ROS production. Raised MDA levels reported in this
study lend support to this hypothesis. Several other drugs,
which consumption is frequently associated with ethanol ad-
diction in some groups of alcoholics, may also lead to
increased ROS production and neurotoxicity (Gutowicz et al.,
2006;Vitcheva, 2012). However, this was not the case in the
patients included in this study, most of them inhabitants of
rural areas, who solely reported ingestion of ethanol.
We also found in this study inverse relations between proin-
flammatory cytokines and tocopherol and vitamin A, especially
with this last. Raised levels of these proinflammatory cytokines
have been well described in the alcoholics (Fujimoto et al.,
2000;Taieb et al., 2000;Su et al., 2002;McClain et al., 2004).
It seems that the initial event in cytokine secretion is stimulation
of Kupffer cells by gram-negative bacteria reaching the liver in
the context of ethanol-mediated increased intestinal permeabil-
ity (Crews et al., 2006). As commented, these cytokines may be
also involved in oxidative stress and neuroinflammation (Qin
and Crews, 2012). We failed to find direct relationships with
TNF, IL-8 or MDA and brain alterations, but indeed between
IL-6 and cerebellar atrophy, Evans index and bifrontal index,
suggesting the existence of a relation between this cytokine on
brain alterations observed in alcoholics. Interestingly, we also
found significant, inverse relations of IL-6 with both vitamin A
(ρ=0.47) and vitamin E (ρ=0.37) levels, i.e. inverse rela-
tionship between increased neuroinflammation and decreased
antioxidant levels. Other authors have also reported an inverse
relation of IL-6 and age-related brain atrophy (Jefferson et al.,
2007), supporting the view that IL-6 may be a factor involved
in the development of brain atrophy in different settings, not
only in alcoholics.
Therefore, we conclude that among alcoholics, liver func-
tion impairment is related to altered serum vitamin A levels.
Vitamin E levels are also decreased, but although related to
liver function impairment, its decrease seems to be more de-
pendent on nutritional status and irregular eating habits. Both
Antioxidant vitamins in alcoholics 49
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vitamins are lower in patients with cerebellar atrophy and
other brain alterations, and show inverse correlations with
proinflammatory cytokines, especially with IL-6, which is
also related to brain alterations.
Acknowledgements We are indebted to the nurses and sanitary workers of the Internal
Medicine Unit, who helped us in blood extraction and patients care.
Conflict of interest statement. Authors declare that there are no conflicts of interest.
AUTHORSCONTRIBUTIONS
E.G.-R. designed the study, performed statistical analysis and
wrote the manuscript. M.C.M.-G., C.M.F.-R., I.H.-B., O.E.-C.
collected the data and analysed the brain CT. P.A.-G. per-
formed MDA analysis. M.J.V.-P. performed cytokine analysis
and F.S.-F. participated in the study design and revised the
manuscript. All the authors approved the final version of the
manuscript and state that the manuscript, including related
data, figures and tables, has not been previously published and
is not under consideration for publication elsewhere
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50 González-Reimers et al.
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