Arch Dermatol Res DOI 10.1007/s00403-015-1570-2
ORIGINAL PAPER
Effect of lipid peroxidation, antioxidants, macro minerals and trace elements on eczema Mohammad Nurul Amin1 • Kaniz Fatema Liza1 • Md. Shahid Sarwar2 • Jamiuddin Ahmed1 • Md. Tareek Adnan1 • Manjurul Islam Chowdhury1 Mohammad Zahid Hossain3 • Mohammad Safiqul Islam1
•
Received: 9 February 2015 / Revised: 21 April 2015 / Accepted: 5 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The exact etiology and pathogenesis of eczema are not yet fully understood, although different factors are considered as pathogenic mechanisms in the development of eczema. Our study was designed to determine extent of serum lipid peroxidation, antioxidants, macro minerals and trace elements in patients with eczema, and thereby, find any pathophysiological correlation. The study was conducted as a case–control study with 65 eczema patients as cases and 65 normal healthy individuals as controls. Lipid peroxidation was assessed by measuring the serum level of malondialdehyde (MDA). Antioxidants- vitamin A and E concentration was determined by RP-HPLC method whereas vitamin C was evaluated for serum ascorbic acid by UV spectrophotometric method. Serum macro minerals (Na, K, Ca) and trace elements (Zn, Fe) were determined by Atomic Absorption Spectroscopy (AAS). This study found significantly higher level of MDA (p \ 0.001) and lower level of antioxidants (p \ 0.05) in patients in comparison to the control subjects. Analysis of serum macro minerals (Na, K and Ca) and trace elements (Zn, Fe) found that the mean values of Na, K, Ca, Zn and Fe were 2771.60 ± 75.64, 66.33 ± 3.03, 48.41 ± 2.50, 0.30 ± 0.02 and 0.29 ± 0.009 mg/L for the patient group and
M. N. Amin, K. F. Liza and M. S. Sarwar contributed equally. & Mohammad Safiqul Islam [email protected] 1
Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Bangladesh
2
Department of Pharmacy, Southeast University, Banani, Dhaka, Bangladesh
3
Department of Pharmacy, State University of Bangladesh, Dhanmondi, Dhaka, Bangladesh
3284.81 ± 34.51, 162.18 ± 3.72, 87.66 ± 2.10, 0.75 ± 0.06 and 0.87 ± 0.06 mg/L for the control group, accordingly. There was a significant difference for all the minerals between the patients and controls (p \ 0.001). This study suggests a strong association between the pathogenesis of eczema with the elevated level of MDA and depleted level of antioxidants, macro minerals, and trace elements.
Keywords Antioxidant Lipid peroxidation Macro minerals Trace elements Eczema MDA
Introduction Eczema or atopic dermatitis [34] is a common disease which is characterized by edema, erythema, vesicles and pruritus [32]. The histopathological changes are intercellular edema of the epidermis of skin and a dermal inflammatory infiltrate of lymphocytes and macrophages [32]. Eczema is defined clinically as an inflammatory, chronically relapsing, scratching and intense itching skin disorder with age-related distribution [8, 27]. Current epidemiological researches evaluating the frequency of atopic eczema in different countries have shown differences in prevalence [38]. The prevalence of atopic dermatitis has risen substantially in several countries of the world in recent decades, and this increase has been attributed to changes in nutrition, lifestyle and environmental factors [8]. One study has suggested the prevalence of eczema varies considerably from a very low prevalence in developing nations of about 1 % [46] to about 25 % of the population in different developed nations [32]. Besides, little is known about the causes of eczema, although it is a
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common skin disease [17]. However, in addition to occupational studies of eczema disease, some investigations addressing the risk factors for eczema among adults have found a relationship between family history of allergy and eczema [22, 23]. Such relationships between genetic factors and eczema are well reported. Less is also known about some other factors such as diet and environment [17]. There is extensive evidence of the link between allergic disorders such as eczema and oxidative stress. Inflammatory cells such as neutrophils, eosinophils, and macrophages produce reactive oxygen species (ROS) in human body that can cause epithelial damage and promote inflammation by reducing physiological antioxidant defenses and this may contribute positively to the pathogenesis of allergic disorders [31, 38]. Additionally, some drugs and toxins produce free radicals during their metabolism in the human body, and these may also deplete natural antioxidant defenses [5, 24]. Moreover, lipid peroxidation also produces free radicals. It is considered as a complex process involved in the oxidative damage to cell structures [7]. Actually, lipid peroxidation is a degenerative process involved in the production of a variety of lipid byproducts, some of which exert adverse effects [7]. Serum malondialdehyde (MDA) is the end product of lipid peroxidation and reflects the oxidative status of the human biological system [10]. Antioxidants inhibit lipid peroxidation by inactivating free radicals [20]. The molecules that are capable of hindering the oxidation of other molecules by counteracting ROS are known as antioxidants [9]. Synthetic antioxidants may have adverse effects on the human body; hence, much attention has been put toward various natural antioxidants [22]. Antioxidants from dietary sources which are also known as non-enzymatic antioxidants include lipid-soluble vitamins such as vitamin E (alphatocopherol) and vitamin A (carotenoids) as well as watersoluble vitamin C (ascorbic acid) [14–16, 29]. Vitamin E and A are considered as most important chain-breaking antioxidants. Vitamin E is a free radical terminator due to its lipophilic nature whereas vitamin C reacts directly with hydroxyl radicals, superoxides and various lipid hydroperoxides [31]. In addition, essential elements and minerals are key to nutrition and sound health [39]. The importance of macro minerals such as sodium, calcium and chloride in human nutrition has been recognized [37]. Trace elements or micro nutrients are essential to biochemical processes in our body and are involved in immunological reactions [21]. They play an important role in the normal functioning of the human immune system and antioxidant mechanisms [39]. Therefore, oxidative stress may occur due to the deficiency of trace elements such as zinc, selenium and copper [26]. But, oxidative stress is considered one of the major problems in patients with atopic dermatitis [39].
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Moreover, the development and phenotypic expression of atopic dermatitis depend on the interaction between genetic and environmental factors including nutrition [39, 43]. The purpose of the present study was to determine the status of antioxidants (vitamin A, E and C), lipid peroxidation and various minerals such as Na, K, Ca, Zn and Fe in serum of eczema patients and normal healthy individuals.
Materials and methods Study design and blood sample collection The study protocol was approved by the ethical committee of Noakhali Medical College Hospital (NMCH), Bangladesh and conducted by regular outpatient visit at Department of Dermatology, NMCH. There were two groups; comprising 65 eczema patients (30 males and 35 females) as cases and 65 healthy volunteer (40 males and 25 females) as controls. Both the cases and controls were diagnosed by a specialized dermatologist, and all study subjects were carefully briefed about the purpose of the study. Written informed consent was obtained from each of them prior to their inclusion in this study and all studies were conducted according to the Declaration of Helsinki Principles. Normal healthy individuals who matched their age with eczema patients and who had no smoking or alcoholic habits and were free from any other skin and systemic disorders were included as controls. The mean age was 28.33 ± 2.03 years (range 15–35 years) in the patient group and 28.86 ± 1.21 years (range 15-35 years) in the control group. The exclusion criteria included patients those with any other complications other than eczema like systemic diseases and other chronic diseases that might interfere with the study. For this purpose subjects had to undergo a routine physical checkup including their weight, nutritional condition, organ activity, blood pressure, chest X-ray and EGC. Furthermore, blood urea, creatinine, nitrogen, glucose and liver enzyme tests were also performed for all subjects to find out their actual pathological conditions. Individuals with antioxidant and nutrition supplementation also excluded. 5 ml of venous blood from each patient and control was collected after 8 h overnight. The blood sample was kept into a metal-free plastic tube and allowed to clot for almost 1 h at room temperature. Then, serum was separated from the blood sample by centrifugation at 3000 rpm for 15 min at room temperature, and the obtained serum were placed into Eppendorf tubes and stored at -20 °C until the study day. All steps were performed in a dust-free environment to avoid the possible interference in the test results.
Arch Dermatol Res
Chemicals and reagents The chemicals used for the study were of analytical grade from commercially available company and HPLC grade chemicals and reagents were obtained for HPLC-based experiments.
50 mM butylated hydroxyl toluene (BHT) had been added. This mixture was incubated at 60 °C for 15 min and kept in ice water for another 5 min. Then, the samples were centrifuged at 5000 rpm for 10 min. Finally, the absorbance of the supernatant was determined spectrophotometrically at 535 nm using 1,1,3,3-tetraethoxy-propane as standard.
Statistical analysis
Determination of serum minerals status
All data were presented as mean ± standard error mean (SEM). Pearson’s correlation analysis was applied to find the correlation among various study parameters. Comparison of all parameters of the eczema patients and controls were performed by cross table variables and independent sample t test. Statistical analysis was done using the statistical software package SPSS version 16.0 (SPSS, Inc. Chicago, IL).
Determination of serum minerals status was conducted by flame atomic absorption spectrometry (Varian Spectra AA 220) as well as graphite furnace following the method of Sarwar et al. [35]. The samples of patients and controls were diluted with deionized water by a dilution factor of 10. Different concentrations (0.5; 1.0, 2.0, 5.0 and 10.0 mg/ L) of minerals were applied for calibration of standard graphs. Absorbances were taken at 589.0, 766.5, 422.7, 213.9 and 248.3 nm for sodium, potassium, calcium, zinc and iron, respectively, in the atomic absorption spectrometer. To maintain quality and to verify the assay accuracy, the standard solutions were applied for every ten test samples. A software package (SpectrAA Software) was used to determine the concentration of sodium, potassium, calcium, zinc and iron.
Measurement of vitamin A, E, and C Retinol (vitamin A) and a-tocopherol (vitamin E) were determined from serum by liquid–liquid extraction using n-hexane and evaporated to dryness using Sample Concentrator (DB-3, Techne, UK) at 40 °C under a stream of nitrogen. Then, the dried extract was reconstituted in the mobile phase. Serum concentration of retinol and a-tocopherol were measured simultaneously at 291 nm by modified RP-HPLC method described by Bieri et al. [6] with UV detection. From the reconstituted sample, 20 lL was injected carefully into the chromatography on a C18 column with acetonitrile: methanol (75:25) mobile phase flowing at 1 ml/min. Standards (retinol, a-tocopherol, and a-tocopheryl acetate) were obtained from Sigma Chemical Co., USA; and HPLC grade solvents and chemicals were purchased from Active Fine Chemicals, Dhaka, Bangladesh. To analyze serum ascorbic acid (vitamin C), extracted serum was treated properly with 5 % trichloroacetic acid (TCA) in a test tube and centrifuged at 3000 rpm for 10 min. Clear supernatant thus obtained was kept at -80 °C for further study. The concentration of ascorbic acid was measured by UV-spectrophotometer (UV-1201, Shimadzu, Kyoto, Japan) by using phenyl hydrazine as indicator as the previously mentioned method by Islam et al. [19]. Quantification of serum MDA Serum malondialdehyde (MDA) concentration which is the end product of lipid peroxidation, was measured according to the method of Nahar et al. [29]. After properly mixing of 100 lL of serum with 900 lL of 0.9 % saline solution, 2 ml of thiobarbituric acid (TBA) reagent and 30 lL of
Results Serum antioxidant and MDA level Serum antioxidant vitamins and MDA levels in patient and control groups have been shown in Table 1. The mean values of vitamin A, E, C and MDA were 0.22 ± 0.02, 3.89 ± 0.06, 11.26 ± 1.56 and 4.82 ± 0.09 lg/ml for patient group and 0.38 ± 0.05, 5.40 ± 0.14, 15.232 ± 0.34 and 3.61 ± 0.315 lg/ml for the healthy control group, respectively. There was a statistically significant difference for antioxidants between two groups. At 5 % level of significance, it was found that the eczema patients had low level of antioxidant vitamins like vitamin A (p = 0.006), vitamin E (p = 0.000) and vitamin C (p = 0.014) than the healthy control. Moreover, it had also
Table 1 Serum antioxidants and MDA levels in eczema patients and control subjects Parameters (lg/ml) Vitamin A
Patient group
Control group
0.22 ± 0.02
0.38 ± 0.05
Vitamin E
3.89 ± 0.06
5.40 ± 0.14
Vitamin C
11.26 ± 1.56
15.232 ± 0.34
MDA
4.82 ± 0.09
3.61 ± 0.315
p value \0.05 \0.001 \0.05 \0.001
All values are expressed in mean ± SEM
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been found that the MDA content was significantly higher (p = 0.000) in the serum of the patients when compared with the controls. Serum macro minerals and trace elements level Analysis of serum minerals found that the mean values of Na, K, Ca, Zn and Fe were 2771.60 ± 75.64, 66.33 ± 3.03, 48.41 ± 2.50, 0.30 ± 0.02 and 0.29 ± 0.009 mg/L for the patient group and 3284.81 ± 34.51, 162.18 ± 3.72, 87.66 ± 2.10, 0.75 ± 0.06 and 0.87 ± 0.06 mg/L for the control group, accordingly (Table 2). There was a significant difference for all the minerals between the patients and controls (p \ 0.001). Correlation analysis among various macro minerals and trace elements
Table 3 Study of inter-element-correlations Correlation parameters
Patient group
Control group
r
r
p
p
Zn and Fe
0.168
0.182
0.071
Zn and Ca
0.037
0.770
0.073
0.576
Zn and K
0.024
0.847
-0.302
Zn and Na
0.015
0.906
0.006
Ca and Fe
0.005
0.967
0.015
0.905
Ca and K
-0.037
0.769
0.031
0.805
Ca and Na Fe and K
-0.066 -0.021
0.599 0.921
0.096 -0.127
0.446 0.314
0.563 0.014* 0.961
Fe and Na
0.154
0.221
-0.134
0.288
K and Na
-0.067
0.593
-0.113
0.368
Values with negative sign indicate an inverse correlation r correlation co-efficient, p significance * Correlation is significant at 0.05 level (two-tailed)
Pearson’s correlation analysis was carried out to determine the inter-element-correlations for the analyzed elements between patient and control subjects which exhibited a positive (direct) or negative (inverse) correlations for selected elements. The correlation coefficient and the statistical confidence levels at which the correlations were determined are presented in Table 3. In the patient group, there was a positive relationship between Zn and Fe (r = 0.168, p = 0.182); Zn and Ca (r = 0.037, p = 0.770); Zn and K (r = 0.024, p = 0.847); Zn and Na (r = 0.015, p = 0.906); Ca and Fe (r = 0.005, p = 0.967); Fe and Na (r = 0.154, p = 0.221) but an inverse relationship between Ca and K (r = -0.037, p = 0.769); Ca and Na (r = -0.066, p = 0.599); Fe and K (r = -0.021, p = 0.921) and K and Na (r = -0.067, p = 0.593). In the control group, there was a positive relationship between Zn and Fe (r = 0.071, p = 0.576); Zn and Ca (r = 0.073, p = 0.563); Zn and Na (r = 0.006, p = 0.961); Ca and Fe (r = 0.015, p = 0.905); Ca and K (r = 0.031, p = 0.805); Ca and Na (r = 0.096, p = 0.446) but an inverse relationship between Zn and K (r = -0.302, p = 0.014); Fe and K (r = -0.127, p = 0.314); Fe and Na (r = -0.134, p = 0.288) and K and Na (r = –0.113, p = 0.368). Table 2 Serum levels of Na, K, Ca, Zn and Fe in the study population Parameters (mg/L)
Patient group
Control group
p value
Na
2771.60 ± 75.64
3284.81 ± 34.51
\0.001
K
66.33 ± 3.03
162.18 ± 3.72
\0.001
Ca
48.41 ± 2.50
87.66 ± 2.10
\0.001
Zn
0.30 ± 0.02
0.75 ± 0.06
\0.001
Fe
0.29 ± 0.009
0.87 ± 0.06
\0.001
All values are expressed in mean ± SEM
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** Correlation is significant at 0.01 level (two-tailed)
Discussion Although reactive oxygen species (ROS) are essential for biological processes, they are potentially harmful [40]. Lipid peroxidation that is not beneficial for health occurs through a free radical chain reaction, and oxygen is a vital factor on the development of lipid peroxidation [4]. For proper maintaining of a healthy biological system, the balance between production and elimination of ROS is believed to be critical. And antioxidant plays an important role for maintaining this balance [40]. They scavenge and inhibit the formation of free radicals or oppose their actions [41]. Moreover, antioxidants are compound that also prevent lipid peroxidation by inactivating free radicals [20]. The present results showed significantly higher level of MDA (p = 0.000) and significantly lower level of vitamin A (p = 0.006), vitamin E (p = 0.000) and vitamin C (p = 0.014) in eczema patients in comparison with controls. These results indicate some extent of tissue damage in eczema patients due to oxidative stress. This oxidative stress is such a condition which is closely associated with an increased free radical burden. These free radicals can react with important cellular components like membrane lipids, DNA and proteins leading to the alteration of normal function of these components [31, 38]. Thus, cell damage may occur [36]. So, our study suggests that a significant rise in MDA with decreased antioxidants level may be a possible causative factor for the pathogenesis of eczema. Minerals are essential components that play a significant role in the biochemistry of our body as do vitamins [26]. The relationship between certain types of minerals and eczema or atopic dermatitis is a topic of ongoing
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investigation. To date, very few studies of minerals and atopic dermatitis are available [11]. Minerals are essential as co-factor for all enzymatic reactions in our body. Normal trace elements in our blood are crucial for proper maintenance of skin health [26]. They play a vital role in immune function [45]. Alteration of normal homeostasis of these minerals in the human body may adversely affect biological processes leading to various unexpected disorders [28]. Macro minerals have been used by human being since ancient periods for their therapeutic effects on the skin [26]. Zinc (Zn) is a macro mineral that is used as a vital nutrient for skin health. Its nutritional status is important for the activation of local skin hormone, control of skin inflammation and regeneration of skin cells [33]. Moreover, several proteins in the human body bind with Zn. These Zn bound protein depends on the concentration of Zn in our body for exhibiting their biological activities [12]. Zn deficiency that leads to dermatitis and decreased immune function [25] is common in patients with skin lesions and growth retardation [2]. This study also supports these findings [2, 25] by showing a significant decrease in the serum zinc concentration of eczema patients compared to the controls (p \ 0.001). Iron (Fe) is the most important trace mineral which has a significant role in immune function [35, 39]. It is essential for the synthesis of hemoglobin [35]. The myeloperoxidase activity of neutrophils and bactericidal activity of macrophages are decreased due to Fe deficiency [3]. Iron deficiency is the most frequent nutritional deficiency throughout the world accounting around 600–700 million people in the world [2]. Fe deficiency is also associated with a metabolic consequence of skin diseases like exfoliative dermatitis, erythroderma, psoriasis, eczema and so on. Our study found a significant decrease in the serum iron concentration of eczema patients compared to the controls (p \ 0.001), which supports the report of previous study [2]. Minerals such as sodium (Na), potassium (K), and calcium (Ca), etc. has a great importance to human health. These minerals must be in required amounts in the human diet to enjoy a healthy life [37]. Na regulates acid–base balance and maintains membrane potential. It is also activates muscle function [37]. K is another mineral that is essential for normal cell function. It helps in performing various cellular enzymatic reactions. The abnormality of K can profoundly affect the muscular system [37]. It may act against stroke and other cardiovascular diseases [18, 42]. A potassium deficit in the human body may occur due to low potassium diet [1]. Hence, in this case K supplementation may be beneficial for the body. Moreover, according to some researchers, supplementation with 60 mmol (2.5 g) of elemental K may indeed be effective in decreasing blood pressure significantly over a 12-week period [13, 44].
Adrogue et al. [1] in 2007 showed that the supplementation of K may reduce the need for antihypertensive medication. One research reported that with an increased dietary K intake in hypertensive individuals, 81 % of the subjects required less than half of the baseline medication and 38 % needed no antihypertensive medication for the control of blood pressure, as compared with 29 % and 9 %, accordingly, in the control group at 1 year of follow-up [1]. Ca is another macro mineral which plays a major role in the activation of different enzymes and also in the maintenance and formation of bone. It is an important component in blood clotting system. Moreover, Ca is involved in neuromuscular excitability [37]. Poor calcium nutrition or Ca deficiency is a risk factor for various chronic diseases. Actually, Ca deficiency is a condition that can lead to osteoporosis, various cancers, hypertension and many other cardiovascular diseases [30]. To our knowledge; no previous studies are available regarding the evaluation of the status of Na, K and Ca in patients with eczema. Our result found significantly lower level of these minerals in eczema patients when compared to control subjects (p \ 0.001). Thus, significant depletion of serum levels of these elements as reported in the current study may trigger the pathogenesis of eczema.
Conclusion The present study explored that eczema patients have high serum concentration of MDA and low serum concentration of macro minerals and trace elements than the healthy control. These patients also contain low concentration of antioxidants like vitamin A, E, and C. The study strongly suggests that increased level of serum MDA and decreased level of serum antioxidants, macro minerals, and trace elements may contribute to the pathogenesis of eczema. However, we did not examine the effect of dietary intake and socioeconomic status on the investigated parameters in eczema patients. Thus, further study may be needed to find out whether food habit and social class affect the level of these components in eczema patients or not. Acknowledgments The authors are thankful to all the staffs, nurses and physicians of Department of Dermatology, Noakhali Medical College Hospital (NMCH), Bangladesh and the participants of the research. The authors are also grateful to the Department of Pharmacy, Noakhali Science and Technology University, Bangladesh for providing the laboratory facilities.
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44. Whelton PK, He J, Cutler JA, Brancati FL, Appel IJ, Follmann D, Klag MJ (1997) Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials. J Am Med Assoc 277(20):1624–1632 45. Wintergerst ES, Maggini S, Hornig DH (2007) Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 51(4):301–323 46. Yemaneberhan H, Flohr C, Lewis SA, Bekele Z, Parry E, Williams HC, Britton J, Venn A (2004) Prevalence and associated factors of atopic dermatitis symptoms in rural and urban Ethiopia. Clin Exp Allergy 34(5):779–785
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ORIGINAL PAPER
Effect of lipid peroxidation, antioxidants, macro minerals and trace elements on eczema Mohammad Nurul Amin1 • Kaniz Fatema Liza1 • Md. Shahid Sarwar2 • Jamiuddin Ahmed1 • Md. Tareek Adnan1 • Manjurul Islam Chowdhury1 Mohammad Zahid Hossain3 • Mohammad Safiqul Islam1
•
Received: 9 February 2015 / Revised: 21 April 2015 / Accepted: 5 May 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract The exact etiology and pathogenesis of eczema are not yet fully understood, although different factors are considered as pathogenic mechanisms in the development of eczema. Our study was designed to determine extent of serum lipid peroxidation, antioxidants, macro minerals and trace elements in patients with eczema, and thereby, find any pathophysiological correlation. The study was conducted as a case–control study with 65 eczema patients as cases and 65 normal healthy individuals as controls. Lipid peroxidation was assessed by measuring the serum level of malondialdehyde (MDA). Antioxidants- vitamin A and E concentration was determined by RP-HPLC method whereas vitamin C was evaluated for serum ascorbic acid by UV spectrophotometric method. Serum macro minerals (Na, K, Ca) and trace elements (Zn, Fe) were determined by Atomic Absorption Spectroscopy (AAS). This study found significantly higher level of MDA (p \ 0.001) and lower level of antioxidants (p \ 0.05) in patients in comparison to the control subjects. Analysis of serum macro minerals (Na, K and Ca) and trace elements (Zn, Fe) found that the mean values of Na, K, Ca, Zn and Fe were 2771.60 ± 75.64, 66.33 ± 3.03, 48.41 ± 2.50, 0.30 ± 0.02 and 0.29 ± 0.009 mg/L for the patient group and
M. N. Amin, K. F. Liza and M. S. Sarwar contributed equally. & Mohammad Safiqul Islam [email protected] 1
Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Bangladesh
2
Department of Pharmacy, Southeast University, Banani, Dhaka, Bangladesh
3
Department of Pharmacy, State University of Bangladesh, Dhanmondi, Dhaka, Bangladesh
3284.81 ± 34.51, 162.18 ± 3.72, 87.66 ± 2.10, 0.75 ± 0.06 and 0.87 ± 0.06 mg/L for the control group, accordingly. There was a significant difference for all the minerals between the patients and controls (p \ 0.001). This study suggests a strong association between the pathogenesis of eczema with the elevated level of MDA and depleted level of antioxidants, macro minerals, and trace elements.
Keywords Antioxidant Lipid peroxidation Macro minerals Trace elements Eczema MDA
Introduction Eczema or atopic dermatitis [34] is a common disease which is characterized by edema, erythema, vesicles and pruritus [32]. The histopathological changes are intercellular edema of the epidermis of skin and a dermal inflammatory infiltrate of lymphocytes and macrophages [32]. Eczema is defined clinically as an inflammatory, chronically relapsing, scratching and intense itching skin disorder with age-related distribution [8, 27]. Current epidemiological researches evaluating the frequency of atopic eczema in different countries have shown differences in prevalence [38]. The prevalence of atopic dermatitis has risen substantially in several countries of the world in recent decades, and this increase has been attributed to changes in nutrition, lifestyle and environmental factors [8]. One study has suggested the prevalence of eczema varies considerably from a very low prevalence in developing nations of about 1 % [46] to about 25 % of the population in different developed nations [32]. Besides, little is known about the causes of eczema, although it is a
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common skin disease [17]. However, in addition to occupational studies of eczema disease, some investigations addressing the risk factors for eczema among adults have found a relationship between family history of allergy and eczema [22, 23]. Such relationships between genetic factors and eczema are well reported. Less is also known about some other factors such as diet and environment [17]. There is extensive evidence of the link between allergic disorders such as eczema and oxidative stress. Inflammatory cells such as neutrophils, eosinophils, and macrophages produce reactive oxygen species (ROS) in human body that can cause epithelial damage and promote inflammation by reducing physiological antioxidant defenses and this may contribute positively to the pathogenesis of allergic disorders [31, 38]. Additionally, some drugs and toxins produce free radicals during their metabolism in the human body, and these may also deplete natural antioxidant defenses [5, 24]. Moreover, lipid peroxidation also produces free radicals. It is considered as a complex process involved in the oxidative damage to cell structures [7]. Actually, lipid peroxidation is a degenerative process involved in the production of a variety of lipid byproducts, some of which exert adverse effects [7]. Serum malondialdehyde (MDA) is the end product of lipid peroxidation and reflects the oxidative status of the human biological system [10]. Antioxidants inhibit lipid peroxidation by inactivating free radicals [20]. The molecules that are capable of hindering the oxidation of other molecules by counteracting ROS are known as antioxidants [9]. Synthetic antioxidants may have adverse effects on the human body; hence, much attention has been put toward various natural antioxidants [22]. Antioxidants from dietary sources which are also known as non-enzymatic antioxidants include lipid-soluble vitamins such as vitamin E (alphatocopherol) and vitamin A (carotenoids) as well as watersoluble vitamin C (ascorbic acid) [14–16, 29]. Vitamin E and A are considered as most important chain-breaking antioxidants. Vitamin E is a free radical terminator due to its lipophilic nature whereas vitamin C reacts directly with hydroxyl radicals, superoxides and various lipid hydroperoxides [31]. In addition, essential elements and minerals are key to nutrition and sound health [39]. The importance of macro minerals such as sodium, calcium and chloride in human nutrition has been recognized [37]. Trace elements or micro nutrients are essential to biochemical processes in our body and are involved in immunological reactions [21]. They play an important role in the normal functioning of the human immune system and antioxidant mechanisms [39]. Therefore, oxidative stress may occur due to the deficiency of trace elements such as zinc, selenium and copper [26]. But, oxidative stress is considered one of the major problems in patients with atopic dermatitis [39].
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Moreover, the development and phenotypic expression of atopic dermatitis depend on the interaction between genetic and environmental factors including nutrition [39, 43]. The purpose of the present study was to determine the status of antioxidants (vitamin A, E and C), lipid peroxidation and various minerals such as Na, K, Ca, Zn and Fe in serum of eczema patients and normal healthy individuals.
Materials and methods Study design and blood sample collection The study protocol was approved by the ethical committee of Noakhali Medical College Hospital (NMCH), Bangladesh and conducted by regular outpatient visit at Department of Dermatology, NMCH. There were two groups; comprising 65 eczema patients (30 males and 35 females) as cases and 65 healthy volunteer (40 males and 25 females) as controls. Both the cases and controls were diagnosed by a specialized dermatologist, and all study subjects were carefully briefed about the purpose of the study. Written informed consent was obtained from each of them prior to their inclusion in this study and all studies were conducted according to the Declaration of Helsinki Principles. Normal healthy individuals who matched their age with eczema patients and who had no smoking or alcoholic habits and were free from any other skin and systemic disorders were included as controls. The mean age was 28.33 ± 2.03 years (range 15–35 years) in the patient group and 28.86 ± 1.21 years (range 15-35 years) in the control group. The exclusion criteria included patients those with any other complications other than eczema like systemic diseases and other chronic diseases that might interfere with the study. For this purpose subjects had to undergo a routine physical checkup including their weight, nutritional condition, organ activity, blood pressure, chest X-ray and EGC. Furthermore, blood urea, creatinine, nitrogen, glucose and liver enzyme tests were also performed for all subjects to find out their actual pathological conditions. Individuals with antioxidant and nutrition supplementation also excluded. 5 ml of venous blood from each patient and control was collected after 8 h overnight. The blood sample was kept into a metal-free plastic tube and allowed to clot for almost 1 h at room temperature. Then, serum was separated from the blood sample by centrifugation at 3000 rpm for 15 min at room temperature, and the obtained serum were placed into Eppendorf tubes and stored at -20 °C until the study day. All steps were performed in a dust-free environment to avoid the possible interference in the test results.
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Chemicals and reagents The chemicals used for the study were of analytical grade from commercially available company and HPLC grade chemicals and reagents were obtained for HPLC-based experiments.
50 mM butylated hydroxyl toluene (BHT) had been added. This mixture was incubated at 60 °C for 15 min and kept in ice water for another 5 min. Then, the samples were centrifuged at 5000 rpm for 10 min. Finally, the absorbance of the supernatant was determined spectrophotometrically at 535 nm using 1,1,3,3-tetraethoxy-propane as standard.
Statistical analysis
Determination of serum minerals status
All data were presented as mean ± standard error mean (SEM). Pearson’s correlation analysis was applied to find the correlation among various study parameters. Comparison of all parameters of the eczema patients and controls were performed by cross table variables and independent sample t test. Statistical analysis was done using the statistical software package SPSS version 16.0 (SPSS, Inc. Chicago, IL).
Determination of serum minerals status was conducted by flame atomic absorption spectrometry (Varian Spectra AA 220) as well as graphite furnace following the method of Sarwar et al. [35]. The samples of patients and controls were diluted with deionized water by a dilution factor of 10. Different concentrations (0.5; 1.0, 2.0, 5.0 and 10.0 mg/ L) of minerals were applied for calibration of standard graphs. Absorbances were taken at 589.0, 766.5, 422.7, 213.9 and 248.3 nm for sodium, potassium, calcium, zinc and iron, respectively, in the atomic absorption spectrometer. To maintain quality and to verify the assay accuracy, the standard solutions were applied for every ten test samples. A software package (SpectrAA Software) was used to determine the concentration of sodium, potassium, calcium, zinc and iron.
Measurement of vitamin A, E, and C Retinol (vitamin A) and a-tocopherol (vitamin E) were determined from serum by liquid–liquid extraction using n-hexane and evaporated to dryness using Sample Concentrator (DB-3, Techne, UK) at 40 °C under a stream of nitrogen. Then, the dried extract was reconstituted in the mobile phase. Serum concentration of retinol and a-tocopherol were measured simultaneously at 291 nm by modified RP-HPLC method described by Bieri et al. [6] with UV detection. From the reconstituted sample, 20 lL was injected carefully into the chromatography on a C18 column with acetonitrile: methanol (75:25) mobile phase flowing at 1 ml/min. Standards (retinol, a-tocopherol, and a-tocopheryl acetate) were obtained from Sigma Chemical Co., USA; and HPLC grade solvents and chemicals were purchased from Active Fine Chemicals, Dhaka, Bangladesh. To analyze serum ascorbic acid (vitamin C), extracted serum was treated properly with 5 % trichloroacetic acid (TCA) in a test tube and centrifuged at 3000 rpm for 10 min. Clear supernatant thus obtained was kept at -80 °C for further study. The concentration of ascorbic acid was measured by UV-spectrophotometer (UV-1201, Shimadzu, Kyoto, Japan) by using phenyl hydrazine as indicator as the previously mentioned method by Islam et al. [19]. Quantification of serum MDA Serum malondialdehyde (MDA) concentration which is the end product of lipid peroxidation, was measured according to the method of Nahar et al. [29]. After properly mixing of 100 lL of serum with 900 lL of 0.9 % saline solution, 2 ml of thiobarbituric acid (TBA) reagent and 30 lL of
Results Serum antioxidant and MDA level Serum antioxidant vitamins and MDA levels in patient and control groups have been shown in Table 1. The mean values of vitamin A, E, C and MDA were 0.22 ± 0.02, 3.89 ± 0.06, 11.26 ± 1.56 and 4.82 ± 0.09 lg/ml for patient group and 0.38 ± 0.05, 5.40 ± 0.14, 15.232 ± 0.34 and 3.61 ± 0.315 lg/ml for the healthy control group, respectively. There was a statistically significant difference for antioxidants between two groups. At 5 % level of significance, it was found that the eczema patients had low level of antioxidant vitamins like vitamin A (p = 0.006), vitamin E (p = 0.000) and vitamin C (p = 0.014) than the healthy control. Moreover, it had also
Table 1 Serum antioxidants and MDA levels in eczema patients and control subjects Parameters (lg/ml) Vitamin A
Patient group
Control group
0.22 ± 0.02
0.38 ± 0.05
Vitamin E
3.89 ± 0.06
5.40 ± 0.14
Vitamin C
11.26 ± 1.56
15.232 ± 0.34
MDA
4.82 ± 0.09
3.61 ± 0.315
p value \0.05 \0.001 \0.05 \0.001
All values are expressed in mean ± SEM
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been found that the MDA content was significantly higher (p = 0.000) in the serum of the patients when compared with the controls. Serum macro minerals and trace elements level Analysis of serum minerals found that the mean values of Na, K, Ca, Zn and Fe were 2771.60 ± 75.64, 66.33 ± 3.03, 48.41 ± 2.50, 0.30 ± 0.02 and 0.29 ± 0.009 mg/L for the patient group and 3284.81 ± 34.51, 162.18 ± 3.72, 87.66 ± 2.10, 0.75 ± 0.06 and 0.87 ± 0.06 mg/L for the control group, accordingly (Table 2). There was a significant difference for all the minerals between the patients and controls (p \ 0.001). Correlation analysis among various macro minerals and trace elements
Table 3 Study of inter-element-correlations Correlation parameters
Patient group
Control group
r
r
p
p
Zn and Fe
0.168
0.182
0.071
Zn and Ca
0.037
0.770
0.073
0.576
Zn and K
0.024
0.847
-0.302
Zn and Na
0.015
0.906
0.006
Ca and Fe
0.005
0.967
0.015
0.905
Ca and K
-0.037
0.769
0.031
0.805
Ca and Na Fe and K
-0.066 -0.021
0.599 0.921
0.096 -0.127
0.446 0.314
0.563 0.014* 0.961
Fe and Na
0.154
0.221
-0.134
0.288
K and Na
-0.067
0.593
-0.113
0.368
Values with negative sign indicate an inverse correlation r correlation co-efficient, p significance * Correlation is significant at 0.05 level (two-tailed)
Pearson’s correlation analysis was carried out to determine the inter-element-correlations for the analyzed elements between patient and control subjects which exhibited a positive (direct) or negative (inverse) correlations for selected elements. The correlation coefficient and the statistical confidence levels at which the correlations were determined are presented in Table 3. In the patient group, there was a positive relationship between Zn and Fe (r = 0.168, p = 0.182); Zn and Ca (r = 0.037, p = 0.770); Zn and K (r = 0.024, p = 0.847); Zn and Na (r = 0.015, p = 0.906); Ca and Fe (r = 0.005, p = 0.967); Fe and Na (r = 0.154, p = 0.221) but an inverse relationship between Ca and K (r = -0.037, p = 0.769); Ca and Na (r = -0.066, p = 0.599); Fe and K (r = -0.021, p = 0.921) and K and Na (r = -0.067, p = 0.593). In the control group, there was a positive relationship between Zn and Fe (r = 0.071, p = 0.576); Zn and Ca (r = 0.073, p = 0.563); Zn and Na (r = 0.006, p = 0.961); Ca and Fe (r = 0.015, p = 0.905); Ca and K (r = 0.031, p = 0.805); Ca and Na (r = 0.096, p = 0.446) but an inverse relationship between Zn and K (r = -0.302, p = 0.014); Fe and K (r = -0.127, p = 0.314); Fe and Na (r = -0.134, p = 0.288) and K and Na (r = –0.113, p = 0.368). Table 2 Serum levels of Na, K, Ca, Zn and Fe in the study population Parameters (mg/L)
Patient group
Control group
p value
Na
2771.60 ± 75.64
3284.81 ± 34.51
\0.001
K
66.33 ± 3.03
162.18 ± 3.72
\0.001
Ca
48.41 ± 2.50
87.66 ± 2.10
\0.001
Zn
0.30 ± 0.02
0.75 ± 0.06
\0.001
Fe
0.29 ± 0.009
0.87 ± 0.06
\0.001
All values are expressed in mean ± SEM
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** Correlation is significant at 0.01 level (two-tailed)
Discussion Although reactive oxygen species (ROS) are essential for biological processes, they are potentially harmful [40]. Lipid peroxidation that is not beneficial for health occurs through a free radical chain reaction, and oxygen is a vital factor on the development of lipid peroxidation [4]. For proper maintaining of a healthy biological system, the balance between production and elimination of ROS is believed to be critical. And antioxidant plays an important role for maintaining this balance [40]. They scavenge and inhibit the formation of free radicals or oppose their actions [41]. Moreover, antioxidants are compound that also prevent lipid peroxidation by inactivating free radicals [20]. The present results showed significantly higher level of MDA (p = 0.000) and significantly lower level of vitamin A (p = 0.006), vitamin E (p = 0.000) and vitamin C (p = 0.014) in eczema patients in comparison with controls. These results indicate some extent of tissue damage in eczema patients due to oxidative stress. This oxidative stress is such a condition which is closely associated with an increased free radical burden. These free radicals can react with important cellular components like membrane lipids, DNA and proteins leading to the alteration of normal function of these components [31, 38]. Thus, cell damage may occur [36]. So, our study suggests that a significant rise in MDA with decreased antioxidants level may be a possible causative factor for the pathogenesis of eczema. Minerals are essential components that play a significant role in the biochemistry of our body as do vitamins [26]. The relationship between certain types of minerals and eczema or atopic dermatitis is a topic of ongoing
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investigation. To date, very few studies of minerals and atopic dermatitis are available [11]. Minerals are essential as co-factor for all enzymatic reactions in our body. Normal trace elements in our blood are crucial for proper maintenance of skin health [26]. They play a vital role in immune function [45]. Alteration of normal homeostasis of these minerals in the human body may adversely affect biological processes leading to various unexpected disorders [28]. Macro minerals have been used by human being since ancient periods for their therapeutic effects on the skin [26]. Zinc (Zn) is a macro mineral that is used as a vital nutrient for skin health. Its nutritional status is important for the activation of local skin hormone, control of skin inflammation and regeneration of skin cells [33]. Moreover, several proteins in the human body bind with Zn. These Zn bound protein depends on the concentration of Zn in our body for exhibiting their biological activities [12]. Zn deficiency that leads to dermatitis and decreased immune function [25] is common in patients with skin lesions and growth retardation [2]. This study also supports these findings [2, 25] by showing a significant decrease in the serum zinc concentration of eczema patients compared to the controls (p \ 0.001). Iron (Fe) is the most important trace mineral which has a significant role in immune function [35, 39]. It is essential for the synthesis of hemoglobin [35]. The myeloperoxidase activity of neutrophils and bactericidal activity of macrophages are decreased due to Fe deficiency [3]. Iron deficiency is the most frequent nutritional deficiency throughout the world accounting around 600–700 million people in the world [2]. Fe deficiency is also associated with a metabolic consequence of skin diseases like exfoliative dermatitis, erythroderma, psoriasis, eczema and so on. Our study found a significant decrease in the serum iron concentration of eczema patients compared to the controls (p \ 0.001), which supports the report of previous study [2]. Minerals such as sodium (Na), potassium (K), and calcium (Ca), etc. has a great importance to human health. These minerals must be in required amounts in the human diet to enjoy a healthy life [37]. Na regulates acid–base balance and maintains membrane potential. It is also activates muscle function [37]. K is another mineral that is essential for normal cell function. It helps in performing various cellular enzymatic reactions. The abnormality of K can profoundly affect the muscular system [37]. It may act against stroke and other cardiovascular diseases [18, 42]. A potassium deficit in the human body may occur due to low potassium diet [1]. Hence, in this case K supplementation may be beneficial for the body. Moreover, according to some researchers, supplementation with 60 mmol (2.5 g) of elemental K may indeed be effective in decreasing blood pressure significantly over a 12-week period [13, 44].
Adrogue et al. [1] in 2007 showed that the supplementation of K may reduce the need for antihypertensive medication. One research reported that with an increased dietary K intake in hypertensive individuals, 81 % of the subjects required less than half of the baseline medication and 38 % needed no antihypertensive medication for the control of blood pressure, as compared with 29 % and 9 %, accordingly, in the control group at 1 year of follow-up [1]. Ca is another macro mineral which plays a major role in the activation of different enzymes and also in the maintenance and formation of bone. It is an important component in blood clotting system. Moreover, Ca is involved in neuromuscular excitability [37]. Poor calcium nutrition or Ca deficiency is a risk factor for various chronic diseases. Actually, Ca deficiency is a condition that can lead to osteoporosis, various cancers, hypertension and many other cardiovascular diseases [30]. To our knowledge; no previous studies are available regarding the evaluation of the status of Na, K and Ca in patients with eczema. Our result found significantly lower level of these minerals in eczema patients when compared to control subjects (p \ 0.001). Thus, significant depletion of serum levels of these elements as reported in the current study may trigger the pathogenesis of eczema.
Conclusion The present study explored that eczema patients have high serum concentration of MDA and low serum concentration of macro minerals and trace elements than the healthy control. These patients also contain low concentration of antioxidants like vitamin A, E, and C. The study strongly suggests that increased level of serum MDA and decreased level of serum antioxidants, macro minerals, and trace elements may contribute to the pathogenesis of eczema. However, we did not examine the effect of dietary intake and socioeconomic status on the investigated parameters in eczema patients. Thus, further study may be needed to find out whether food habit and social class affect the level of these components in eczema patients or not. Acknowledgments The authors are thankful to all the staffs, nurses and physicians of Department of Dermatology, Noakhali Medical College Hospital (NMCH), Bangladesh and the participants of the research. The authors are also grateful to the Department of Pharmacy, Noakhali Science and Technology University, Bangladesh for providing the laboratory facilities.
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