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Year : 2019  |  Volume : 10  |  Issue : 1  |  Page : 40-46

Trace elements as a diagnostic biomarker for premalignant lesions and malignant conditions

1 Department of Periodontology and Implantology, VSPM Dental College and Research Centre, Nagpur, Maharashtra, India
2 Department of ENT, NKP Salve Institute of Medical Sciences, Nagpur, Maharashtra, India

Date of Web Publication15-Mar-2019

Correspondence Address:
Surekha Rathod
Department of Periodontics and Implantology, VSPM Dental College and Research Centre, Digdoh Hills, Hingna Road, Nagpur - 440 017, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/srmjrds.srmjrds_52_18

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The aim of this paper was to study and compare the levels of copper (Cu), iron (Fe), and zinc (Zn) in patients with premalignant lesions or malignant conditions. A schematic search was conducted according to population, intervention, comparison, outcome in order to obtain appropriate articles for critical appraisal. The review incorporated a total of 16 articles, including in vivo human studies published in English language. Studies with premalignant and malignant conditions and trace elements including Cu as an essential element and Fe and Zn as other elements were considered. No limit was placed on a number of patients and studies involving blood investigations were included in this review. The exclusion criteria were in vitro nonhuman non-English studies. Case series, case reports, retrospective studies, and studies involving only saliva/tissue investigations were also excluded and studies not having any of the above-mentioned trace elements were also excluded from the study. Results of the studies suggested that serum Cu and Zn as well as the Cu to Zn ratio can be used as biomarkers for oral precancer and cancer. Thus, a comprehensive understanding of these trace elements can be used as a reliable biomarker for development and progression of oral cancer.

Keywords: Copper, iron, malignant conditions, premalignant lesions, trace elements, zinc

How to cite this article:
Rathod S, Rathi P, Harkare V. Trace elements as a diagnostic biomarker for premalignant lesions and malignant conditions. SRM J Res Dent Sci 2019;10:40-6

How to cite this URL:
Rathod S, Rathi P, Harkare V. Trace elements as a diagnostic biomarker for premalignant lesions and malignant conditions. SRM J Res Dent Sci [serial online] 2019 [cited 2023 Mar 31];10:40-6. Available from:

  Introduction Top

The human body contains various elements which can be classified as abundant elements and trace elements.[1] The normal function of the human body is reliant on a number of complex physiologic processes,[2] and this function of the living body is through the maintenance of osmotic pressure and membrane potential.[3] Growth and development of human body is influenced by his/her daily nutritional intake. The nutrients important for the healthy growth, development, and maintenance are micronutrients and macronutrients or trace elements.[2] Trace elements are chemical elements required in minute amounts, usually as part of a vital element.[1]

Nineteen trace elements have been divided into three groups [Table 1].[4]
Table 1: World Health Organization classification, 1973

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Functions of trace elements


Apart from being significant for a lot of other enzymes, copper (Cu) in its numerous forms is the third plentiful element in the body. Cu is concerned with the release process of energy inside the cell and contributes to the performance of many antioxidants. The regulation and formation of hormones such as melatonin are restricted by Cu, through a broad variety of neurotransmitters and other neuroactive compounds including the absorption of catecholamines. Furthermore, collagen production, configuration of red blood cells, and the oxidation of fats are reliant on the concentration of Cu. It is also necessary for the appropriate performance of Vitamin C and iron (Fe) absorption.[5],[6],[7],[8],[9] Cu has varied roles in biological electron transport and oxygen transportation. Cu is an important component of other proteins associated with the processing of oxygen. Cu and Fe cooperate in the reduction of oxygen, in cytochrome c oxidase, which is necessary for aerobic respiration.[10]


Zinc (Zn) is an element with extensive application in health of humans. It is obligatory for a healthy immune system. It is also considered necessary for the cell division, hair, tissue, nails, skin and muscle growth, synthesis of protein, and collagen which are essential for wound healing.[5],[6],[7],[8],[9] Zn is found in nearly 100 specific enzymes, and it serves in transcription factors as structural ions. It is “characteristically the second most plentiful transiting metal in organisms” after Fe, and it is the only metal which appears in all enzyme classes.[11] In blood plasma, Zn bounds to and is transported by albumin and transferrin. As transferrin also transports Fe, too much of Fe reduces Zn absorption and vice versa.[10] The amount of Zn in blood plasma stays comparatively constant in spite of Zn intake. Zn is used as a signaling molecule to communicate between cells of the salivary gland, prostate, immune system, and intestine with other cells.[12]


Fe is an important trace element found in almost all living organisms. The role of Fe in the maintenance, development, and defensive abilities of the oral mucosa has been well documented in the literature.[10] Enzymes and proteins which contain Fe, often the heme prosthetic groups, take part in many biological oxidations and in transport. Hemoglobin, cytochrome, and catalase are the examples of proteins found in higher organisms.[13] In the oral mucosa, Fe plays a part in the maturation of epithelium through the action of cytochrome oxidase and is also thought to have a role in the maintenance of the permeability barrier.[14] The role of Fe in collagen synthesis is well established. Fe is a cofactor along with molecular oxygen alpha-ketoglutarate and ascorbic acid that is required for collagen synthesis by enzymes proline hydroxylase and peptidyl lysine.[10]

The development of oral cancer is a multistep process arising from preexisting potentially malignant lesions. Leukoplakia is the most common precancer representing 85% of such lesions.[15] It has been suggested that a vast majority of oral squamous cell carcinomas (SCCs) in India arise from preexisting leukoplakia.[16] Similarly, the incidence of oral submucous fibrosis (OSMF) is increasing such as an epidemic targeting the younger generation.[17] Among all the risk factors, the disease is mainly associated with the use of tobacco in its various forms such as pan masala, gutkha, and kharra (areca nut and tobacco).[18],[19] OSMF is now recognized as an Indian disease worldwide and has the highest potential of malignancy among all other premalignant lesions.[20] The malignant transformation rate of OSMF has been reported as 2.3%–7.6% in the Indian context.[21],[22]

Currently, the primary focus has shifted to early detection of oral premalignant and malignant conditions rather than diagnosing it at advanced stages. If such lesions are timely detected and treated, it may not progress to worse conditions. There are various techniques such as comet assay test, nick test, and colposcopy[23] that investigate the changes in oral tissues but are invasive or expensive.

Trace elements have been extensively studied in recent years to assess whether they have any modifying effects in the etiology of precancer or cancer. Immunological and biochemical alterations in the serum of such patients can help not only in the early diagnosis, appropriate treatment but also as indicators of prognosis, as the disease progresses.[24]

Therefore, our review attempts to compare the biochemical investigations (serum levels of Cu, Fe, and Zn) in premalignant lesions or malignant conditions and to relate the importance of evaluated parameters. Hence, the aim of this paper was to study and compare the levels of Cu, Fe, and Zn in patients with premalignant lesions or malignant conditions.

  Materials and Methods Top

A schematic search was conducted to obtain appropriate articles for critical appraisal. Population, intervention, comparison, outcome was determined to appropriately decide the parameters to check\compare the levels of Cu, Fe, and Zn in patients with premalignant or malignant conditions for the search methodology, and relevant articles were searched from various databases such as PubMed and Google Scholar. Then, the searches from the various databases were combined, and duplicate articles were subsequently removed. By examining the bibliographies of retrieved articles, additional articles were identified and using the inclusion and exclusion, the titles of the retrieved articles were read independently by three authors. Articles were eliminated if two out of the three authors deemed it was inappropriate for inclusion. Finally, at the full-text stage, two investigators read and assessed each of the articles based on the criteria used in previous stages [Table 2].
Table 2: Search methodology (population, intervention, comparison, outcome)

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The review included in vivo human studies published in English language. Studies with premalignant and malignant conditions and trace elements including Cu as an essential element, and Fe and Zn as other elements were considered. No limit was placed on a number of patients and studies involving blood investigations were included in this review. The exclusion criteria were in vitro nonhuman non-English studies. Case series, case reports, and retrospective studies were also excluded and studies not having any of the above-mentioned trace elements were also excluded from the study [Chart 1].

Trace elements in the pathogenesis of premalignant and malignant lesions


Areca nut has high Cu content (302 nmol/g), the substantial amount of which is released in saliva,[25] 15–30 min after chewing areca nut.[26] Cu is the nutrient essential to carry out enzymatic functions important for human metabolism, including cytochrome-c oxidase, superoxide dismutase (SOD), metallothionein, and lysyl oxidase. In vitro, raised Cu concentrations show increase proliferation of fibroblasts. High Cu and ceruloplasmin levels were observed in patients with premalignant and malignant and oral lesions.[20] Some studies have shown that high Cu is responsible for severity of OSMF.[25] The damage caused by Cu ions is due to superoxide radicals, these complexes react with hydrogen peroxide to form hydroxyl radicals that cause the destruction of RNA, DNA, and protein ultimately resulting in the malignancy.[24] The reason behind increase serum Cu might be the release of Cu containing the ceruloplasmin due to the inflammatory response of liver or reduced degeneration of serum ceruloplasmin. Cytological study confirmed the important role of Cu in the pathogenesis of OSMF showing intense staining in smears of OSMF as compared to smears from nonchewers. Thus, it can prove an efficient marker of early diagnosis of malignant transformation [Figure 1].[27]
Figure 1: Mechanism of pathogenesis of oral submucous fibrosis

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Zn is an important part of biomembranes that manage membrane stability and lipid peroxidation-related injury. The role of Zn in carcinogenesis can be suggested by its role in DNA and RNA polymerase, inhibitory effect on phosphodiesterase, and activation of membrane-bound adenylyl cyclase. Deficiency of Zn also contributes to cancer initiation by the activation of nuclear factor-kappa B expression and consequent induction of tumorigenic signaling.[28] The role of Zn as a trace element in OSMF has been evaluated in many studies. Reduced levels of Zn were found in most studies and were attributed to the decreased immunity status of individuals.[29],[30],[31] Zn is a constituent of SOD, an enzyme that removes free radicals, Zn has the reverse effect and protects against carcinogenesis.[32] Second, Zn decreases the activity of Cu-containing lysyl oxidase enzyme, and thus causes the inhibition of cross-linkage of collagen peptides. It also plays a noteworthy role in promoting collagen degradation through collagenase and matrix metalloproteinase. Zn thus bears an inverse relationship with Cu and interferes with the mucosal absorption of Cu.[33]


OSMF can be a sign of chronic Fe deficiency and a counterpart of Plummer–Vinson syndrome.[34] The reason of Fe deficiency in OSMF patients can be multifactorial. It may be due to the utilization in collagen formation by the process of hydroxylation of proline and lysine, altered epithelial cell turnover rate, or depletion of nutrients due to pronounced difficulty in mastication.[35] Sarcomas and skin cancers have been reported, where intramuscular injections with Fe dextran were used. Different malignant neoplasms of various organs are seen in idiopathic hemochromatosis, but liver cancer is a common complication. The mechanisms of carcinogenesis are thought to be that Fe bound to liver generates hydroxyl radicals through the Fenton reaction that further damages the DNA.[1]

  Results of the Included Studies Top

Anuradha and Sityamala Devi[36] studied the hematological status and trace elements in various stages of OSMF and found a significant decrease in the levels of hemoglobin, Fe, ceruloplasmin, Cu, and Zn and they correlated well with the progression of the disease. Some studies[24],[37] evaluated the levels of circulating immune complexes, trace elements (copper, iron, and selenium) in the serum of patients with OSMF, oral leukoplakia (L), and oral SCC (OSCC), and showed that these immunological and biological markers may be associated with the pathogenesis of oral premalignant and malignant lesions and their progressions. A study was done to estimate the serum levels of Zn, Cu, and Cu/Zn ratio in patients with OSMF and found that the mean serum levels of Zn showed no change through clinical and histological stages of OSMF. The mean serum levels of Cu and Cu/Zn ratio showed a gradual increase from clinical and histological Grade I–IV in OSMF patients. Some similar studies estimated these levels in oral leukoplakia, submucous fibrosis, and SCC and suggested that serum Cu and Zn as well as the Cu to Zn ratio can be used as a biomarker for oral precancer and cancer.[38],[39],[40]

A study evaluated the levels of circulating trace elements (Cu, Fe, magnesium [Mg], Zn, and calcium) in the serum of patients with OSMF and OSCC, and the results showed that among all the trace elements, the best predictor for occurrence of both the lesions was Cu, and they have a role to play in the pathogenetic mechanisms of OSMF.[6],[28] Kode and Karjodkar[41] compared the levels of the trace elements (Cu, Zn, Fe, and Mg) in patients with gutkha eating habits with or without OSMF and in healthy patients and found that there was a significant difference in the serum Mg, Zn, and Fe levels between the patients with habits and the normal healthy individuals and concluded that these biological markers may be associated with pathogenesis of OSMF, therefore, may help in early detection, management, and prognosis of the disease.[42],[43]

Controversial to above-mentioned studies, Srilekha[44] concluded that Cu and Zn deficiencies develop in OSMF, serum Cu and Zn levels are sensitive, but not specific, whereas serum Cu Zn ratio is the most reliable indicator in assessing progression of malignancy. Some recent studies[45],[46],[47],[48] also estimated and compared the levels of serum Cu and Fe among participants with OSMF of different clinical stages and healthy controls and found that Cu level increased as clinical stage of OSMF increased, and Fe level decreased in OSMF group in comparison to healthy controls. It was also evident that the serum values of Cu and Zn in patients with oral cancer were high and Fe levels were low when compared with the control group [Table 3], [Table 4], [Table 5], [Table 6].
Table 3: Characteristics of the included studies - number of patients, age range, comparison groups, intervention, intervention test, and parameters

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Table 4: Characteristics of the included studies - Serum copper levels

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Table 5: Characteristics of the included studies - Serum zinc levels

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Table 6: Characteristics of the included studies - Serum iron levels

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  Conclusion Top

Trace elements such as Cu, Zn, and Fe are required in minimal quantities for normal functioning of the body. Trace elements have been extensively studied in recent years to assess if they have any modulating effects in the predisposition of premalignant and malignant conditions. Trace elements are also known to act as anticancer agents through control of a number of biological mechanisms. Thus, a comprehensive understanding of these trace elements can be used as a reliable biomarker for development and progression of oral cancer.

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Conflicts of interest

There are no conflicts of interest.

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[PUBMED]  [Full text]  


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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