Abstract
Psoriasis is a common and an inflammatory skin disease. Trace elements play an important role in the skin metabolism such as keratinisation and melanin formation as well as immunological and inflammatory reactions. Henceforth, the present study was aimed to evaluate the essential metals with special reference to Cu and Zn. In this study, 72 psoriatic patients and 50 controls were enrolled. On the basis of PASI score psoriatic group comprising of 48 mild and 24 severe psoriatic patients were grouped. The serum trace elements analysis in the subjects revealed that serum Cu levels and Cu/Zn ratio was significantly higher in the psoriatic patients as compared to controls. Interestingly, severity of the psoriasis was well correlated with the serum Cu levels. Taking together, all these findings suggest that Cu may be a major culprit in the pathogenesis as well as in the severity of the disease.
Keywords: Psoriasis, Trace elements, Copper, Zinc, Oxidative stress, PASI score
Introduction
Psoriasis is a common, chronic inflammatory disease with the prevalence of approximately 2–3% of the world population [1]. Psoriasis is characterized by chronic sharply demarcated dull red scaly plaques particularly on the extensor prominences and in the scalp. The pathogenesis of psoriasis is poorly understood, although it results from the interaction between genetic predisposition and large spectrum of environmental risk factors viz stress, alcohol consumption and smoking [2], Over expression of pro-inflammatory cytokines proceeded to elevated generation of reactive oxygen species which led to an immune mediated skin lesions viz psoriasis [2, 3].
Micronutrients and natural antioxidant molecules play an important role to maintain a balance between oxidative and antioxidant status in organisms, particularly, micronutrients with special reference to Zn and Cu which are indispensable elements for cellular metabolism via acting as a cofactor for the specific enzymes, receptors and metalloprotein [4]. Zinc is required as a cofactor for the catalytic activity of more than 200 enzymes which plays an important role in immune function, wound healing, protein synthesis, DNA synthesis and cell division. Acrodermatitis entropathica is a rare genetic autosomal recessive disorder of mutations in zinc transporter gene (SLC39A4) which is characterized by periorificial dermatitis, alopecia and diarrhoea [5]. These findings are suggestive of role of zinc in skin pathophysiology. Furthermore, zinc supplementation is used in the treatment of some diseases viz acrodermatitis enteropathica, necrolytic, acral erythema, rosacea, and ache vulgaris. On the other hand, copper is also an essential trace element which acts as a cofactor for various enzymes for instances superoxide dismutase, lysyl oxidase, dopamine- β-hydroxylase, tyrosinase, cytochrome-c-oxidase and ceruloplasmin [4]. Thus, copper is involved in the melanin pigmentation as well as in maturation of collagen and elastin. Notably, the excess copper in the body is notorious owing to under oxido-reduction reactions which lead to production of free hydroxyl radicals. These hydroxyl free radicals are well known to oxidize plasma membrane, cellular mitochondrial and DNA damage. As both the trace elements are utmost important in immunological and inflammatory reactions. The keratinization and melanin formation are enzyme dependent processes which could be altered by the deficiencies and excess accumulation of copper in free form. There are few reports on the role of trace elements viz Cu and Zn. However, there are few contradictory findings.
In view of these facts, in this study we hypothesized that aberrant levels of copper, zinc and their ratio could be plausibly responsible for the patho-physiology of psoriasis. Hence the present study was planned to assess the blood copper and zinc levels and their ratio from the psoriasis patients.
Methods
The present study was carried out in the Departments of Biochemistry and Dermatology, in a tertiary care centre of North India after the approval of institutional ethical committee. This was a case–control study involving 72 subjects diagnosed with psoriasis in the dermatology OPD. Fifty age and sex matched healthy volunteers were enrolled as controls. Psoriasis patients were further divided into two groups by using Psoriasis Area and Severity Index Score (PASI SCORE) (Group T1: PASI < 10—mild psoriasis whereas Group T2: PASI > 10—severe psoriasis) [6].
Subjects with autoimmune disorders, metabolic disorders, malignancies, or on any medications known to affect Zn, Cu levels such as penicillamine and mineral supplements were excluded from the study. Lactating and pregnant women were also excluded from this study. Venous blood samples were collected and analysed for serum copper and Zinc levelsusing a colorimetric kit from Erba 5 plus.
In this study, the serum Zn measurement procedure is based on the method of Homster and Zak. This method involved the reaction of nitro-PAPS, a sensitivity complexing agent with the zinc in alkaline medium. The intensity of the complex form is the directly proportional to the amount of Zn present in the serum sample. Similarly, the serum Cu was measured by a colorimetric method. This method is based on interaction of the Cu based di-br-PAESA to form a coloured complex in acidic medium. Where, the intensity of the complex forms is directly proportional to the amount of Cu present in serum sample. The serum Cu and Zn levels were expressed as µgm/dl of the serum. Further, Serum Cu/Zn ratio was also ascertained.
Statistical Analysis
Results are presented as mean ± standard deviation. The unpaired ‘t’ test was used to compare the levels of the test and control group. One way ANOVA was done to find out the difference between the groups. Post hoc analysis was further done to see the difference and association of the parameters with the severity of the disease. All p values < 0.05 were considered significant. All analyses were performed using the SPSS version 20.0.
Results
Total 72 patients of psoriasis were enrolled having with mean age (mean ± SD; 42.65 ± 13.48 years) including 54 males and 18 females. As controls 50 subjects were included in this study having mean age (40.96 ± 12.39 years). The severity of the psoriasis was evaluated using PASI score. PASI score in severe form of psoriasis was significantly higher (11.55 ± 1.59) to that of mild form of psoriasis (5.03 ± 2.53).
The serum copper levels and Cu/Zn ratio were significantly higher in psoriatic patients to that of controls. The serum zinc analysis revealed non significant difference between psoriatic and control groups.
One way ANOVA (Table 1) and Post-hoc analysis (Multiple comparisons-Scheffe) was further done to establish the association of these parameters with the severity of the disease and interestingly, the serum Cu levels were found to be significantly associated with the PASI score, thus, indicating severity of the disease. Correlation coefficient was also determined using Pearson correlation analysis, which demonstrated a positive correlation (r = 0.85) between Cu and severity of psoriasis (Fig. 1).
Table 1.
Serum Cu, Zn and Cu/Zn ratio in psoriatic and control group
| Parameters | Control | Mild disease | Severe disease | F value | p value |
|---|---|---|---|---|---|
| Mean ± SD | Mean ± SD | Mean ± SD | |||
| Cu (µg/dl) | 122.59 ± 14.07 | 169.81 ± 18.78 | 186.83 ± 19.34 | 148.749 | .0001 |
| Zn (µg/dl) | 97.87 ± 15.54 | 99.81 ± 20.80 | 103.63 ± 24.90 | .688 | .505 |
| Cu/Zn | 1.27 ± .15 | 1.77 ± .39 | 1.92 ± .59 | 34.283 | .0001 |
| PASI | 5.03 ± 2.53 | 11.55 ± 1.59 |
Values are expressed as mean ± S.D. The significance was determined using ANOVA test. p < 0.05 was considered as significant
Fig. 1.
Correlation between Cu and PASI score. The correlation was done by Pearson Correlation and the correlation coefficient came out to be (r) = 0.85
Discussion
In the present study, we have demonstrated an alternation in essential trace element status with special reference to Cu in blood from psoriatic patients. However, there are contradictory findings regarding serum levels of essential trace elements. The elevated levels of the Cu could be a culprit in the pathogenesis of psoriasis. Since, an excess Cu is very cytotoxic. It is noteworthy here that majority of the cellular Cu is found in the binding form to the proteins e.g. Cu chaperons (hCOX17, HAH1/Atox1 and hCCS), which distribute the Cu to specific cellular compartments for its incorporation into Cu requiring proteins. Additionally Cu is also bound to glutathione, metallothionine and ceruloplasmin [7]. The oxidative stress due to production of excessive free radicals has been implicated to skin inflammation and pathogenesis of psoriasis [3], which may lead to psoriatic lesions and important antioxidant barrier in the skin resulting in elevation of free oxygen radical in psoriatic plaques. The PASI score was used to assess the severity of psoriasis which revealed two forms of the psoriasis; mild form of the psoriasis (n = 48) and severe form of the psoriasis (n = 24). The mild form of the psoriasis had maximum number of cases since it includes both mild and moderate form of the psoriasis because of cut off value of PASI score < 10.
The present study exhibited a good correlation between serum Cu and severity of the psoriasis, indicating an augmented level of the Cu which play a role in the pathogenesis of the psoriasis. The free Cu can cause cellular damage by producing free hydroxyl radicals like: superoxide radicals (SODs), hydrogen peroxide (H2O2) and hydroxyl (OH) via “Fenton’s reaction” which has been implicated in various pathological conditions e.g. Indian childhood cirrhosis, Wilson disease and Alzheimer’s disease [8]. The increased Cu/Zn ratio is due to no alteration in zinc levels between psoriatic group and controls.
However, zinc is very important essential trace elements. Deficiency of Zn may lead to skin lesion as it was observed in acrodermatitis enteropathica [5]. Notably, few studies have shown the reduced levels of serum zinc in both mild and severe form of the psoriasis and elevated levels of Cu in both mild and severe psoriasis [9]. There are some reports which have shown that augmented levels of copper where zinc levels are low, could be a contributing factor in many pathological conditions viz schizophrenia, hypertension, autism childhood hyperactivity and premenstrual syndrome [10]. Recently, the interactions of copper and zinc with cellular prion proteins had differential effects on the solubility due to degree of Cu/Zn ratio. Strikingly, Cu and Zn act as antagonistic to each other. It is also evident form the studies where there zinc supplementation is used in Cu associated toxicity in the diseases association with the Cu toxicity e.g. Indian childhood cirrhosis, Wilson disease. Here the zinc inhibits the Cu absorption as at intestinal, cellular and metal binding proteins levels. Taken together, all these findings conclude that augmented level of serum copper could be the possible candidate in the genesis and severity of the psoriasis.
Acknowledgements
The authors highly appreciate Mr. Rajesh for his statistical assistance and to the department of Biochemistry as well as department of Dermatology, MMIMSR for providing research facilities.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Footnotes
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