AnemiaVolume 2012 (2012), Article ID 270923, 7 pagesdoi:10.1155/2012/270923Review ArticleCorrelation of Oxidative Stress with Serum Trace Element Levels and Antioxidant Enzyme Status in Beta Thalassemia Major Patients: A Review of the LiteratureQ. Shazia,1 Z. H. Mohammad,1 Taibur Rahman,2 and Hossain Uddin Shekhar21School of Medicine, Universiti Malaysia Sabah (UMS), Locked Bag 2073, 88999 Kota Kinabalu, Sabah, Malaysia2Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, BangladeshReceived 4 January 2012; Accepted 25 February 2012Academic Editor: Mehran KarimiCopyright © 2012 Q. Shazia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractBeta thalassemia major is an inherited disease resulting from reduction or total lack of beta globin chains. Patients with this disease need repeated blood transfusion for survival. This may cause oxidative stress and tissue injury due to iron overload, altered antioxidant enzymes, and other essential trace element levels. The aim of this review is to scrutinize the relationship between oxidative stress and serum trace elements, degree of damage caused by oxidative stress, and the role of antioxidant enzymes in beta thalassemia major patients. The findings indicate that oxidative stress in patients with beta thalassemia major is mainly caused by tissue injury due to over production of free radical by secondary iron overload, alteration in serum trace elements and antioxidant enzymes level. The role of trace elements like selenium, copper, iron, and zinc in beta thalassemia major patients reveals a significant change of these trace elements. Studies published on the status of antioxidant enzymes like catalase, superoxide dismutase, glutathione, and glutathione S-transferase in beta thalassemia patients also showed variable results. The administration of selective antioxidants along with essential trace elements and minerals to reduce the extent of oxidative damage and related complications in beta thalassemia major still need further evaluation.1. IntroductionBeta thalassemia is one of the most common inherited single gene disorder caused by about 200 mutations in the beta globin genes. In beta thalassemia where there is no or reduced production of beta globin chains, the alpha chain production will continue to occur. This increased synthesis of alpha chains makes the developing erythrocytes more fragile leading to early damage, ineffective erythropoeisis and anemia. Beta thalassemia exists in different forms depending upon the beta globin chains deficit. The most severe form among them is beta thalassemia major which occurs as a result of inheritance of two beta globin chain mutations either in homozygous or compound heterozygous states. Patients with beta thalassemia major need repeated blood transfusions for survival due to severe anemia. The beta globin chain deficit for beta-thalassemia trait (minor) is 50%, while that for beta-thalassemia major is 100% and between 50–80% for beta-thalassemia intermediate [1]. Malaysia has a multiracial population of 27.7 million, consisting of 50.8% Malays, 23.0% Chinese, and 6.9% Indians, indigenous people of Sabah and Sarawak (11.0%), and other minority groups (8.3%) [2]. According to the report of Malaysian Ministry of Health, one (1) out of twenty (20) Malaysians is a carrier of thalassemia. In Malaysia, there are about 600,000–1 (one) million thalassemia carriers. They are common among Malays, Chinese, and Sabahans but rarely among Indians and native Sarawakians. Thalassemia major is considered to be one of the life-threatening genetic disorders in Malaysia with the gene frequency of 3.4–4.5% [3]. Recurrent blood transfusions in beta thalassemia major lead to accumulation of excess iron in the body tissues. This secondary iron overload is responsible for peroxidative damage by increased production of reactive oxygen species within the erythrocytes leading to oxidative stress. This oxidative stress will cause growth failure as well as liver, cardiovascular, endocrine, and neurological complications in beta thalassemia major. It has been evident from previous studies that iron overload is the main causative agent responsible for increased production of free radical and reactive oxygen species and subsequent oxidative stress which is compensated by various antioxidants present in the body. These antioxidants are complex molecules that protect important biological sites from oxidative injury [4] in a retrospective study involving 123 thalassemia major children found that the most common complication among these beta thalassemic children was growth failure (57.8%) which may be due to neurosecretary disturbance and insensitivity of growth hormone. They further concluded that chronic anemia and hemosiderosis may also be the contributing factors to growth failure. The next is the liver problems (21.1%), heart diseases (13.8%), and endocrinopathies (4.2%).2. Oxidative StressOxidative stress is defined as the interruption of balance between oxidants and reductants within the body due to the excess production of peroxides and free radicals. This imbalance will cause damage to cellular components and tissues in the body leading to oxidative stress. In patients with beta thalassemia major where frequent blood transfusions are required due to severe anemia, oxidative stress occurs as a result of increased levels of lipid peroxides and free-radical intermediates, as well as the decrease in total antioxidant capacity. Use of iron chelatory agents in combination with antioxidants can be helpful in the regulation of the antioxidant status in patients with beta thalassemia major. Oxidative stress and disturbance in antioxidant balance in beta thalassemia major has been studied extensively [5, 6]. Seventy-two children with beta thalassemia major on iron chelation therapy and 72 age-matched healthy controls irrespective of sex were included in the study. They found a significant increase in the levels of lipid peroxide and iron and significant decrease in levels of vit E and total antioxidant capacity. Serum zinc was significantly increased while copper levels decreased and there is a nonsignificant increase in erythrocyte superoxide dismutase. The results suggested that the oxidative stress and decreased antioxidant defence mechanism play an important role in the pathogenesis of beta thalassemia major.It is concluded that repeated blood transfusions in beta thalassemia major patients causes secondary iron overload and this makes erythrocytes vulnerable to peroxidative injury [7]. Iron overload leads to peroxidative damage in beta-thalassemia major and antioxidant systems try to reduce tissue damage by lowering lipid peroxidation. They found that the markers of lipid peroxide damage such as melon-dialdehyde, antioxidant enzyme superoxide dismutase, and nitric oxide levels were significantly raised in thalassemia major children while mean glutathione peroxidase (GPx) levels were reduced in patients as compared to controls. These markers significantly correlated with serum ferritin levels. There was no significant difference in Glutathione (GSH) levels but it correlated with serum iron levels.3. Oxidative Stress and Serum Trace ElementsTrace elements and the minerals play a vital role in the body to perform its functions properly. These elements and the minerals should present in the body in appropriate amounts and must be available for reacting with other elements to form critical molecules as well as to participate in various important chemical reactions. A number of trace elements are found in human plasma and here we are interested to discuss the correlation of trace elements like selenium, copper, zinc, and iron with oxidative stress in beta thalassemia major.3.1. SeleniumOne of the essential trace elements in human plasma is selenium. Selenium was first discovered as a byproduct of sulfuric acid production. It is a well-known electrometalloid and is mostly famous due to its anti cancerous properties. It is an essential constituent of the enzyme glutathione peroxidase and also incorporates in various important proteins such as hemoglobin and myoglobin. Selenium is also a component of the unusual amino acids selenocysteine which is essential for the production of various useful enzymes in the body. It helps in preventing free radical damage caused by ferrous chloride, and heme compounds. Its deficiency may affect the iron binding capacity of transferrin which leads to increase iron stores and subsequent tissue damage. An age- and gender-matched case control study has been conducted on patients with beta thalassemia major on iron chelation therapy [8]. The study indicates a significant decrease in plasma concentrations of the essential element selenium as well as decreased plasma activity of selenium-dependent antioxidant enzyme glutathione peroxidase (GPx). They also found significantly increased concentrations of all measures of body iron in beta-thalassemia patients as compared to healthy controls: another study on relationship between iron overload and antioxidant micronutrient status among 64 transfusion-dependent beta thalassemia major children on chelation therapy and 63 age- and sex- matched controls [9]. They measured serum levels of vitamins A and E, zinc, selenium, and copper and found significantly decreased levels of all these elements in beta thalassemia major children as compared to controls. There is a study done to evaluate the in vitro effects of vitamin C and selenium on natural killer cell activity of beta thalassemia major indicates a significant decreased in natural killer cell activity in all thalassemic patients as compared to control. The NK activity is increased by low-dose selenium treatment but no change is observed in control group. High-dose selenium decreased NK activity significantly in splenectomised patients. The result indicates the careful use of selenium dosage in thalassemic major patients [10].3.2. CopperCopper is the other essential trace element present in our bodies. It mostly forms metalloprotiens which act as enzymes. Copper is the major component of hemoglobin which is a protein responsible for oxygen transport in blood cells. Along with vitamin C, it is responsible for the production of protein called elastin thus maintaining the elasticity of the skin, blood vessels, and lungs. It is antibacterial and bears important antioxidant properties. Copper is a central component of the antioxidant superoxide dismutase molecule and also helps in the formation of protein called ceruloplasmin thereby protecting the cells from free-radical injury. Copper is also required for the production of hormones like nor adrenaline and prostaglandins which are hormone-like chemicals involved in the regulation of blood pressure, pulse, and healing. Deficiency of this trace element will lead to anemia, neutropenia, and growth impairment, abnormalities in glucose and cholesterol metabolism, and increased rate of infections. On the other hand, an accumulation of copper in body leads to Wilson’s disease with copper accumulation and cirrhosis of liver. A prospective study was performed to determine the serum levels of zinc and copper in beta thalassemia major children [11]. This cross-sectional study revealed that hypozincemia is common in thalassemic patients, but there is no copper deficiency. Another study was carried out to evaluate the level of some essential elements in one hundred and five thalassemic blood-transfusion-dependent patients and 54 healthy controls [12]. They found lower serum zinc and magnesium levels and higher copper and potassium levels in thalassemic major patients as compared to controls. Zinc deficiency may be due to hyperzincuria resulted from the release of zinc from hemolyzed red cells while hypercupremia occurs in acute and chronic infections and hemochromatosis which is the principal complication of thalassemia. A study done on status of thyroid function and iron overload in patients with beta thalassemia major on Deferoxamine in Jordan concluded that there is significantly high (