C. B. S. Dangi¹, Manpreet Kaur¹ and Madhulika Singh*²

¹Human Genetic Laboratory, C.S.R.D, People’s Group, Bhopal India.

²Sadhu Vaswani P.G. College, Bairagarh, Bhopal India.

Abstract

The plasma copper (Cu) and zinc (Zn) levels act as measure in a various haemoglobinopathies. The role of copper and zinc deficiency in various haemoglobinopathies remains poorly defined. Growth retardation and impaired immune function, suggest a relationship between haemoglobinopathies and level of copper and zinc. Fluctuations in the essential elements levels seem to be related to the different complications associated with the disease. In most of the Haemoglobinopathies there is sever hemolysis of red blood cells that results in release of zinc from red blood cells to blood and then excreted in urine leads to zinc deficiency. Hypercupremia occurs in acute and chronic infections and hemochromatosis, which is a principal complication of haemoglobinopathies.. The zinc supplementation may be helpful in reducing the sufferings of complication in patients of haemoglobinopathies

Keywords

Copper; Haemoglobinopathies; Zinc; Thalasseamia

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Introduction

Haemoglobin is a tetrameric protein with two α and two β chain with four oxygen binding Haem groups. Haemoglobinopathies are the most common single gene inherited disorders in man, which are widespread in world due to immigration [1]. World wide 330,000 affected infants are born annually being 83% sickle cell disorders and 17% thalassemias [1]. The gender discrimination is not observed in Thalassemia as affected men and women are in equal ratio and occur in approximately 4.4 of every 10,000 live births [2] where in case of sickle cell anaemia male ratio is more as compare to female [3]. Haemoglobinopathies may occur due to the production of decreased amount of normal globin chain or structurally abnormal globin chain or persistence of fetal haemoglobin [4, 5]. In Africa and Southeast Asia most of the persons are affected with alpha thalassemia where as in Mediterranean, African, and Southeast Asian descents, the natives are having beta–thalassemia [2]. Thalassemia is due to the defects in the synthesis of one or more of the haemoglobin chains [6]. Alpha-thalassemia is prevalent with defect in α-globin genes at short arm of chromosome 16 [7]. Hb H disease is due to molecular defects of the alpha-globin gene that results in decreased expression of alpha-globin [8]. Hb Bart’s, Hyrops fetalis associated with the absence of all the four α-globin gene. Beta-thalassemia is autosomal recessive disorders, characterized by absent (βº) or reduced (β+])production of β-globin chain of hemoglobin tetramer. Beta-thalassaemia major causes haemolytic anemia, poor growth, and skeletal abnormalities during infancy [2]. β-Thalassemia/Hb E is world’s most common and important mutations [lysine for glutamic acid at position 26 of the β-globin chain]. The combination of Hb E and Hb S [Hb SE] results in a sickle cell disease syndrome similar to sickle beta [+] Thalassemia. Hb Lepore is a structural   β variant resulting from fusion of the δ and β globin genes [9,10] . Haemoglobin S disorder is due to substitution of valine from glutamic acid at position 6 of the β-globin chain with unending complication resulting in organ failure [11].

Common Complications in Haemoglobinopathies

The patients with various haemoglobinopathies suffer from  various  complications such as  growth retardation [12,13,14] , impaired immune status, severe anemia, pubertal delay[15], endocrine complications[16, 15], rickets, scoliosis, spinal deformities, nerve compression, fractures, severe osteoporosis and painful vas-occlusive episode [17] . The most of the cases of haemoglobinopathies are reported to have severe endocrine dysfunction that results in many complications in organs. The increased pathophysiology in sickle cell disease and thalassemia is due to endothelial damage, inflammation and oxidative stress. The cumulative effects of various factors like trace elements, vitamins and growth hormones are involved in various haemoglobinopathies.  Trace elements like copper and zinc play a vital role in preventing the oxidative stresses in human [18].

Role of Copper and Zinc

Copper

It is trace element which exhibits the ubiquitous property. Copper deficiency is quite rare in humans because it is a nutrient that is readily absorbed and has a very low daily requirement [19]. Cu is an important component of proteins essential for neural function. Copper plays an important role in development of neural tube, it is possible because of its participation in oxidative stress [20, 21,22]. Copper plays an integral role in many of our physiologic processes as it acts ligand in many proteins and enzymes. Copper plays essential role in the absorption, storage and metabolism of iron. Copper acts as Co-factor in various enzymes such as:-
Cytochrome oxidase [EC 1.9.3.1], terminal oxidase of the electron –transport chain.
Ceruloplasmin or ferroxidase I [EC 1.16.3.1], oxidation of the ferrous iron of body to ferric form and  thus iron is  incorporated into apotransferrin which is  transported to bone marrow.
Ferroxidase II [EC 1.16.3.1], copper containing enzyme of high relative molecular mass, it oxidises  iron  thus allowing it to be mobilized and transported from liver  to bone marrow  to be used in  erythropoieses [23].
Dopamine β3-hydroxylase [Ec.1.14.17.1], Dopamine–hydroxylase helps in conversion of dopamine to norepinephrine which helps in mediating many neurological functions [24].

Copper Metabolism

Absorption is mainly through the mucosa of the stomach and proximal duodenum, most of it is absorbed in small intestine. A critical component of copper gastrointestinal balance involves enterohepatic circulation. At least one-half of the amount of copper absorbed from small intestine reappears in the bile as strongly bound compounds [25]. Copper half-life is 13-33 days. In biological systems bilary excretion is major route of elimination [26]. Urinary route of excretion plays trivial role in copper clearance, principal route of excretion includes saliva, sweat and through stool [27]. The steps of copper metabolism are depicted in figure 1.

Figure 1: Copper (Cu) Metabolisms  Click here to View figure

Zinc

Zinc an essential trace element for the growth, development and normal enzymatic function in multiple metabolic pathways [28]. Zinc is second most prominent trace metal in human body after iron [26]. Zinc, belongs to first row of transition metals and contains   partially filled d orbital [d10] therefore acts as Lewis acid [it will accept a pair of electron] in all catalytic sites [29]. Redox activity makes  Zn²⁺ a stable ion in biological medium. Normal human body contains 2.3 gm of zinc [29]. High concentrations have been found in brain hippocampus, many medical researchers believe that zinc is a neurotransmitter [30].  It plays vital role in closure of the human neural tube [31]. It plays an essential role in syntheses of RNA, DNA and cell division [32, 33, 34, 35]. Zinc is important for maintaining the DNA integrity [35, 36].  Zinc remains an vital component of all DNA and RNA polymerases [32]. Zinc plays an in key role in immunity by activating the gene of lymphocytes and plays role in function of cell mediated immunity [34, 37]. Zinc is crucial for normal salt-taste perception, wound healing, general growth and development [32, 38]. Zinc finger proteins are implicated in the genetic expression of steroid hormone receptors [39, 40]. Zinc also has anti-apoptotic [41] and antioxidant properties [42]. Zinc can counteract the oxidation by binding sulphydryl groups in proteins and by occupying binding sites for iron and copper in lipids, proteins and DNA [43, 42]. Zinc plays an important role in preventing osteoporosis as it help in normal collagen synthesis and mineralization of bones [44]. In human body, zinc has vital role in metabolic regulation of thyroid [45]. Reticulate Binding Capacity [RBC] of Zn acts as imperative indicator of mean thyroid hormone of patient who is under strict medication [46]. Less amount of zinc interferes with the deiodinase enzyme conversion of T4 to T3[47]. Zinc is a cofactor in 300 enzymes [48, 29,35], involved in a large number of enzymatic functions, fulfilling both structural [maintaining protein structure and stability] and catalytic roles [chemical catalysis] [28,29].

Zinc Metabolism

Zinc is released from food as free ions during digestion. These liberated ions may then bind to endogenously secreted ligands before their transport into the enterocytes in the duodenum and jejunum [49]. Gastrointestinal loss of zinc is half of the total, which is from unabsorbed dietary zinc, a small contribution from intestinal cell shedding, and 1-2 mg from the pancreatic and biliary secretions [49, 50]. The steps of zinc metabolism are depicted in figure 2.

Figure 2 :  Zinc (Zn) Metabolism Click here to View figure

 

The determination   of Copper and zinc ratio

The  copper and zinc are determined by the help of atomic absorption spectrophotometer  (AAS).  The plasma  sample is used for determination of respective  elements[58,68].

Role of Copper and Zinc [Cu:Zn]ratio in deficiency diseases

Trace elements play an important role in numerous biological systems through their action as activators or inhibitors, thus competing with other elements and protein for binding site, influencing the permeability of membrane [51]. Past reports indicate that serum levels of Cu: Zn is abnormal in patients with diseases like Cancer [52] and various haemoglobinopathies. So Cu: Zn has received substantial consideration in thalassemia, sickle cell anemia and various other hemoglobinopathies. Persons having disease related to hemoglobin have poor immune status [53]. Major effect is observed due to micronutrients which are essential to the body but are required in trace amount. The plasma Cu:Zn ratio is  more valuable indicator  of state of  disease in affected persons . The serum zinc level of thalassemia patients was less as compared to serum copper level [54]. The marked zinc deficiency in thalassemia subjects was due to hyperzincuria [loss of zinc in urine] [32]. Deficient linear growth in beta-thalassemia is more prominent in children having low plasma zinc level [55, 56,57]. The improvement in growth was observed in patients treated with zinc supplementation [55].

Thalassemia patients when treated with intravenous desferrioxamine [an iron chelator] [58] results in zinc deficiency [due to chelation of zinc also] results in retinal abnormalities.

Level of calcium, copper and zinc was assessed in patients of beta-thalassemia/hemoglobin E, It was found to be less in both red cells and plasmas compare to control [59]. Zinc deficiency was studied in thalassemic natives of Tehran [60]. Zinc deficiency increases of inability of pancreas to secrete insulin in response to glucose stimulus in Beta Thalassemia subjects [61].Study conducted  in Thalassemia  patients of Mosul, Iraq showed low  level of  serum zinc  compared to normal subject on contrary  serum copper level  was high [62]. Zinc deficiency is also considered a causative factor of osteoporosis and endocrinopathies in Thalassemic subjects [63]. Osteoporosis is common even in well–treated thalassemia patients [64] thus making subjects more prone to fractures. The bone mineral density shows strong correlation with serum zinc [60,65]. The results were supported by study carried on thalassemia adolescents and outcome showed low zinc level as compare to control ones, affecting bone mineral density [66]. Serum Zinc has positive effect on height/ age of thalassemic major patients [67].

The comparative study on Cu: Zn in Hemoglobin H, Beta –thallasemia/ Hemoglobin E disease indicates the lower level of zinc to copper in affected individuals. The zinc insufficiency was observed due to hymolysis causing hyperzincuria[loss of zinc in urine ]resulting in  undergrowth in these patients [68]. Cu: Zn status of Hemoglobin H disease, Beta–thallasemia/HbE and homozygous beta-thallasemia was evaluated, Zinc level in plasma and hair was lower as compare to erthrocytes where as copper level was higher in plasma and erythrocytes [69]. As serum zinc level is decreased, serum Zinc binding capacity [ZnBC] is increased in nutritional zinc deficiency but in thalassemia patient’s serum zinc level is decreased and ZnBC does not increase in chorus [70], this result is confirmed by improvement of anemia with high serum zinc level [71].

In sickle cell subject the zinc level was analyzed in children [72] and marked zinc deficiency was found due the loss of zinc in urine [hyperzincuria] [73, 72, 74].  Homozygous sickle cell anemic subjects plasma zinc levels were significantly decreased [75]. The many complication in sickle cell disease like poor ulcer healing, growth retardation, delay in sexual development, immune deficiencies, and high irreversible sickle cell [ISC] counts are related to low level of the zinc [76].  Zinc-dependent proteins alkaline phosphatase [AP] and retinol-binding protein [RBP] were present in lower amount in serum of sickle patients. The serum zinc was low due loss in urine, zinc malabsorption and chronic intravascular hemolysis [77]. Zinc supplementation in case of homozygous sickle cell anemia reduces irreversible sickled cells [78]. The zinc loss in excretion was more as compare to copper where as plasma concentration of there trace elements were contrary in case sickle cell anaemic subjects [79]. The Zinc deficiency in sickle cell anaemic patients was compared with control and found that even the dietary intake was similar in both cases but marked retardation in growth and low level of red cell zinc and other vitamins were present in former [80]. In the comparative study of homozygous and heterozygous Sickle cell anemia in  Eutrophic children, zinc level in plasma of homozygous Sickle cell anemia was less in comparison to heterozygous Sickle cell anemia and control subjects, reverse condition was observed in the case of plasma level of copper in same subjects [81]. Decrease level of zinc in plasma of sickle cell anemic patients results in decrease in linear growth, skeleton growth, muscle mass and skeleton maturation [82]. The Sickle cell patients when treated with zinc the improvement was observed both in growth and level of zinc in plasma [83, 84]. In the case of haemoglobinopathies subjects are more prone to oxidative damage due to chronic redox imbalance in Red blood cell. Uninhibited production of ROS [Reactive oxygen species] often leads to damage of DNA, protein and lipids [85]. In sickle cell patients copper level is inversely proportional to zinc in plasma that result in fabrication of reactive oxygen thus enhancing the pathopysiological condition in the patients [17]. Zinc supplementation facilitates in improving the immune status thus preventing the nosocomial as well other infections [86].

Some contradicting reports state that copper and zinc was normal in Sickle cell anemic patients of eastern Province of Saudi Arabia but opposite condition was observed in sickle cell anemic subjects of North American Black [87]. In case of the comparative study carried on Serum  copper and zinc levels in sickle cell anaemia and beta-thalassaemia in North Jordan, copper levels were significantly increased in beta-thalassaemia and sickle cell anaemia where as zinc levels were significantly increased in beta-thalassemia but significantly decreased in Sickle cell anaemia [SCA] [88]. Only 3 of the 68 thalassemic patients had zinc deficiency in population study [89]. Zinc status was found normal in Beta-thalassemia subjects who are getting regular blood transfusion and chelators [90].

Conclusion

Wide discrepancy seen by various workers and mentioned in different repots, the cause in variation endorsed due to person to person variation, natural factors and protocol of treatment, blood transfusion and chelators.  Anemia parameters showed significant positive correlation indicating that anemia improves in patients having high serum Zn level.   Patients of Haemoglobinopathies   with complications showed higher plasma Cu:Zn ratio than the patients with normal development. These results indicate the usefulness of using this ratio more efficiently then using each one alone. This conclusion based on decreased level of serum Zn and   increase Cu:Zn ratio hence  Zn supplementation is recommended for patients having different hemoglobinipathies with complications and delayed milestones of development.

Reference

1. Modella B. & Darlison M. [2008] Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 86:480-7.
2. Muncie HL Jr, Campbell J. [2009] Alpha and beta Thalassemia. Am Fam Physician. 80:339-44.
3. Dangi C.B.S, Sajid M., Sawke G.K. and Ambhore J. [2010] Sickle cell haemoglobinopathies in district Bhopal. Indian J. Human genetics.16:2:100-102.
4. Kutlar F. [2007] Diagnostic approach to hemoglobinopathies. Hemoglobin. 31:243-50.
5. Manca L., Masala B. [2008] Disorders of the synthesis of human fetal hemoglobin. IUBMB Life. 60:94-111.
6. Chen W, Zhang X, Shang X, Cai R, Li L, Zhou T, Sun M, Xiong F, Xu X.[2010] The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity. BMC Med Genet. 25;11:31.
7. Cunningham M.J.[ 2010 ] Update on thalassemia: clinical care and complications. Hematol Oncol Clin North Am. 24:215-27
8. Fucharoen S., Viprakasit V. [2009] Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program. 26-34.
9. Harteveld C.L., Wijermans P.W., Arkesteijn S.G., Van Delft P., Kerkhoffs J.L., Giordano PC.[ 2008] Hb Lepore-Leiden: a new delta/beta rearrangement associated with a beta-thalassemia minor phenotype Hemoglobin.32:446-53.
10. McKeown S.M., Carmichael H., Markowitz R.B., Kutlar A., Holley L., Kutlar F.[ 2009] Rare occurrence of Hb Lepore-Baltimore in African Americans: molecular characteristics and variations of Hb Lepores. Ann Hematol. 88:545-8.
11. Wang W.C. [2008] The pharmacotherapy of sickle cell disease. Expert Opin Pharmacother. 9:3069-82.
12. De Sanctis V. [2002] Growth and puberty and its management in thalassaemia. Horm 58:72-9.
13. Moayeri H., Oloomi Z.[ 2006] Prevalence of growth and puberty failure with respect to growth hormone and gonadotropins secretion in beta-thalassemia major. Arch Iran Med. 9:329-34.
14. Zemel B.S., Kawchak D.A, Ohene-Frempong K., Schall J.I., Stallings V.A.[ 2007] Effects of delayed pubertal development, nutritional status, and disease severity on longitudinal patterns of growth failure in children with sickle cell disease. Pediatr Res. 61:607-13.
15. Abdelrazik N., Ghanem H. [2007] Failure of puberty in Egyptian beta thalassemic patients: experience in north east region – Dakahlia province. Hematology. 12:449-56.
16. Rund  D., Rachmilewitz  E. [2005] Beta-thalassemia.  N Engl J Med.  353:1135–1146
17. Hasanato R.M. [2006] Zinc and antioxidant vitamin deficiency in patients with severe sickle cell anemia. Ann Saudi Med. 26:17-21.
18. Hennig B, Meerarani P, Toborek M, McClain CJ. [1999]Antioxidant-like properties of zinc in activated endothelial cells. J Am Coll Nutr.18:152-8.
19. Williams D.M.[ 1983] Copper deficiency in humans. Semin Hematol. 20:118 –28.
20. Morton M.S., Elwood P.C., Abernethy M.[ 1976] Trace elements in water and congenital malformations of the central nervous system in South Wales. Br J Prev Soc Med. 30: 36-39.
21. Burkitt M.J. [2001] A critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: roles of lipid hydroperoxides, alphatocopherol, thiols and ceruloplasmin. Arch Biochem Biophys.394: 117-135.
22. Cengiz B., Soylemez F., Ozturk E, Cavdar AO. [2004] Serum zinc, selenium, copper, and lead levels in women with second-trimester induced abortion resulting from neural tube defects: a preliminary study. Biol Trace Elem Res. 97:225-235.
23. Turnlund J.[ 1998] Copper. In: Shils M, Olson J, Shike M, editors. Modern nutrition in health and disease. Philadelphia: Lippincott. 241.
24. Wu J., Ricker M., Muench J. [2006] Copper deficiency as cause of unexplained hematologic and neurologic deficits in patient with prior gastrointestinal surgery. J Am Board Fam Med. 19:191-4.
25. Raul A Wapnir.[ 1998] Copper absorption and bioavailability. Am J Clin Nutr. 67:1054–60.
26. Barceloux D.G.[ 1999] Copper. J Toxicol Clin Toxicol.37[2]:217-30.
27. Davis, G.K. and Mertz, W. [1987] Copper. In: Trace elements in human and animal nutrition. Vol. 1. 5th edition. W. Mertz [ed.]. Academic Press, New York, NY.
28. Vallee B.L. and Auld D.S.[ 1995] Zinc metallochemistry in biochemistry 73:259-77.
29. McCall K.A., Huang C., Fierke A.[ 2000] Function and mechanism of zinc metalloenzymes, J Nutr. 130:1437-46.
30. Holly M. Lehmann, Barbara B. Brothwell, Laurie P. Volak and Dennis J. Bobilya. [2002] Zinc Status Influences Zinc Transport by Porcine Brain Capillary Endothelial Cells. J. Nutr. 132:2763-2768.
31. Zeyrek D., Soran M., Cakmak A., Kocyigit A., Iscan A.[2009] Serum Copper and Zinc Levels in Mothers and Cord Blood of their Newborn Infants with Neural Tube Defects: A Case-control Study. Indian Pediatr. 46:675-80.
32. Prasad A.S.[ 1983] Zinc deficiency in human subjects. Prog Clin Biol Res.129:1-33.
33. Prasad A.S. [1985] Clinical, endocrinologic, and biochemical effects of zinc deficiency. Spec Top Endocrinol Metab.7:45-76.
34. Shankar A.H., Prasad A.S. [1998] Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 68:447-463.
35. Ho E. [2004] Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem. 15:572-8.
36. Song Y., Chung C.S., Bruno R.S., Traber M.G., Brown K.H., King J.C., Ho E. [2009] Dietary zinc restriction and repletion affects DNA integrity in healthy men. Am J Clin Nutr. 90:321-8.
37. Prasad A.S.[ 2008 ] Zinc in human health: effect of zinc on immune cells. Mol Med. 14:353-7.
38. Prasad A.S., et al.[ 2007] Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation. of cytokines and oxidative stress. Am J Clin Nutr. 85:837-44.
39. Favier A.E.[ 1992] The role of zinc in reproduction. Hormonal mechanisms. Biol Trace Elem Res. 32:363–382.
40. Freedman L.P. [1992] Anatomy of the steroid receptor zinc finger region. Endocr Rev. 13:129–145.
41. Chimienti F., Aouffen M., Favier A. and Seve M. [2003] Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate. Curr Drug Targets. 4,323–338.
42. Zago M.P. and Oteiza P.I. [2001] The antioxidant properties of zinc: interactions with iron and antioxidants. Free Radic Biol Med. 31:266–274.
43. Bray T.M. and Bettger W.J. [1990] The physiological role of zinc as an antioxidant. Free Radic Biol Med. 8:281–291.
44. Hyun T.H., Barrett-Connor E., Milne D.B. [2004] Zinc intakes and plasma concentrations in men with osteoporosis: the Rancho Bernardo Study. Am J Clin Nutr. 80:715-21.
45. Kandhro G., Kazi T., Afridi H., Kazi N., Baig J., Arain M., Sirajuddin, Shah A., Sarfraz R., Jamali M.[ 2009] Effect of zinc supplementation on the zinc level in serum and urine and their relation to thyroid hormone profile in male and female goitrous patients. Clinical Nutrition. 28:162-168.
46. Yoshida K., Kiso Y., Watanabe T.K., Kaise K., Kaise N., Itagaki Y., Yamamoto M., Sakurada T.,Yoshinaga K.[ 1990] Erythrocyte zinc in hyperthyroidism: reflection of integrated thyroid hormone levels over the previous few months. Metabolism. 39:182-6
47. Kaloyanova F., Ivanova-Chemishanska L.,[ 1989] Dose effect relationship for some specific effects of dithiocarbamates . J Hyg Epidemiol Microbiol Immunol. 33:11-7
48. Prasad A.S. [1995] Zinc: an overview. Nutrition. 11:93-9.
49. Krebs N.F. [2000] Overview of zinc absorption and excretion in the human gastrointestinal tract. J Nutrition. 130:1374-1377.
50. Lonnerdal B. [2000] Dietary factors influencing zinc absorption. J Nutrition. 130:1378-1385,.
51. Cavallo E., Gerber M., Marubini E., Richardoson S., Barbieri A., Costa A., Pecarli A., Pujol H.[ 1991] Zinc and copper in breast cancer, a joint study in nothern Italy and southern France. Cancer. 67: 738-745.
52. Yoshida D., Ikeda Y. and Nakazawa S. [1993] Quantitative analysis of copper, zinc and copper/zinc ratio in selected human brain tumors. Journal of Neuro-Oncology. 16: 115.
53. Farmakis D., Giakoumis A., Polymeropoulos E., Aessopos A.[ 2003] Pathogenetic aspects of immune deficiency associated with beta-thalassemia. Med Sci Monit. 9
54. Arcasoy A, Cavdar AO. [1975]Changes of trace minerals [serum iron, zinc, copper and magnesium] in thalassemia. Acta Haematol.53:341-6.
55. Arcasoy A., Cavdar A., Cin S., Erten J., Babacan E., Gözdasoglu S., Akar N.[ 1987 ] Effects of zinc supplementation on linear growth in beta-thalassemia [a new approach]. Am J Hematol. 24:127-36.
56. Theodoridis C., Ladis V., Papatheodorou A., Berdousi H., Palamidou F., Evagelopoulou C., Athanassaki K., Konstantoura O., Kattamis C. [1998] Growth and management of short stature in thalassaemia major. J Pediatr Endocrinol Metab.11:835-44.
57. Fuchs G.J., Tienboon P., Linpisarn S., Nimsakul S., Leelapat P., Tovanabutra S., Tubtong V, DeWier M, Suskind [ 1996 ] Nutritional factors and thalassaemia major. Arch Dis Child. 74:224-7.
58. De Virgiliis S., Congia M., Turco M.P., Frau F., Dessi C., Argiolu F., Sorcinelli R., Sitzia A., Cao A.[ 1988] Depletion of trace elements and acute ocular toxicity induced by desferrioxamine in patients with thalassaemia. Arch Dis Child. 63:250-5.
59. Suthipark K.U., Likidlilid A., Fucharoen S., Pootrakul P., Shumnumsirivath D., Ong-ajyooth S., Plaskett D., Webb J.[ 1991 ] Red cell and plasma calcium, copper and zinc in beta-thalassemia/hemoglobin E. Southeast Asian J Trop Med Public Health. 22:171-5.
60. Shamshirsaz A.A., Bekheirnia M.R., Kamgar M., Pourzahedgilani N., Bouzari N., Habibzadeh M., Hashemi R., Shamshirsaz A.A., Aghakhani S., Homayoun H., Larijani B. [ 2003] Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran. BMC Endocr Disord. 3:4.
61. Dehshal M.H., Hooghooghi A.H., Kebryaeezadeh A., Kheirabadi M., Kazemi S., Nasseh A., Shariftabrizi A., Pasalar P.[ 2007 ]Zinc deficiency aggravates abnormal glucose metabolism in thalassemia major patients. Med Sci Monit. 13:235-9.
62. Al-Samarrai A.H., Adaay M.H., Al-Tikriti K.A., Al-Anzy M.M. [2008] Evaluation of some essential element levels in thalassemia major patients in Mosul district, Iraq. Med J. 29:94-7.
63. De Sanctis V., Wonke B.[ 1994] Aetiology of growth retardation in Thalassemia In Growth in thalassemia, Roma. Mediprint.39.
64. Soliman A.T., El Banna N., Abdel Fattah M., ElZalabani M.M., Ansari BM.[ 1998] Bone mineral density in prepubertal children with α-thalassemia: correlation with growth and hormonal data. Metabolism. 47:541-8.
65. Shamshirsaz A.A., Bekheirnia M.R., Kamgar M., Pakbaz Z., Tabatabaie S.M., Bouzari N., Pourzahedgilani N., Azarkeivan A., Hashemi S.R., Moosavi F., Alebouyeh M., Vosough P., Kimiagar M., Shamshirsaz A.A., Moradi M., Habibzadeh M.R., Nobakhthaghighi N., Larijani B.[ 2007] Bone mineral density in Iranian adolescents and young adults with beta-thalassemia major. Pediatr Hematol Oncol. 24:469-79.
66. Bekheirnia M.R., Shamshirsaz A.A., Kamgar M., Bouzari N., Erfanzadeh G., Pourzahedgilani N., Tabatabaie S.M., Abdollah Shamshirsaz A., Kimiagar M., Ezzati F, Larijani B. [2004] Serum zinc and its relation to bone mineral density in beta-thalassemic adolescents. Biol Trace Elem Res. 97:215-24.
67. Fikry S.I., Saleh S.A., Sarkis N.N., Mangoud H.[ 2003] Study of serum zinc in relation to nutritional status among thalassemia patients in Damanhour Medical National Institute. J Egypt Public Health Assoc. 78:73-93.
68. Vatanavicharn S., Pringsulka P., Kritalugsana S., Phuapairoj P., Wasi P.[ 1982] Zinc and copper status in hemoglobin H disease and beta-thalassemia/hemoglobin E disease. Acta Haematol. 68:317-20.
69. Kajanachumpol S., Tatu T., Sasanakul W., Chuansumrit A., Hathirat P.[ 1997] Zinc and copper status of thalassemic children. Southeast Asian J Trop Med Public Health. 28:877-80.
70. Arcasoy A., Canata D., Sinav B., Kutlay L., Oguz N., Sen M. [2001]Serum zinc levels and zinc binding capacity in Thalassemia. J Trace Elem Med Biol. 15:85-7.
71. Fukushima Tatsuo, Horike, Hideyuki; Fujiki, Shigeatsu; Kitada, Shingo, Sasaki Tamaki, Kashihara, Naoki. [2009]Zinc Deficiency Anemia and Effects of Zinc Therapy in Maintenance Hemodialysis Patients. Therapeutic Apheresis and Dialysis.13: 213-219.
72. Karayalcin G., Lanzkowsky P., Kazi A.B. [1979] Zinc deficiency in children with sickle cell disease. Am J Pediatr Hematol Oncol. 1:283-4.
73. Prasad A.S., Schoomaker E.B., Ortega J., Brewer G.J., Oberleas D., Oelshlegel F.J. [1975] Zinc deficiency in sickle cell disease. Clin Chem. 21:582-7.
74. Niell H.B., Leach B.E, Kraus A.P. [1979] Zinc metabolism in sickle cell anemia. JAMA. 242[24]:2686-7.
75. Muskiet F.D., Muskiet F.A. [1984]Lipids, fatty acids and trace elements in plasma and erythrocytes of pediatric patients with homozygous sickle cell disease. Clin Chim Acta. 15:142:1-10.
76. Reed J.D., Redding-Lallinger R., Orringer E.P. [1987] Nutrition and sickle cell disease. Am J Hematol. 24:441-55.
77. Phebus C.K., Maciak B.J., Gloninger M.F., Paul H.S.[ 1988] Zinc status of children with sickle cell disease: relationship to poor growth. Am J Hematol. 29:67-73.
78. Muskiet F.A., Muskiet F.D., Meiborg G., Schermer JG.[ 1991] Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil. Am J Clin Nutr. 54:736-44.
79. Kilinç Y., Kümi M., Yilmaz B., Tanyeli A.[1991]. A comparative study of zinc and copper values in serum, erythrocytes and urine in sickle cell homozygotes and heterozygotes. Acta Paediatr Scand. 80[8-9]:873-4.
80. Gray N.T., Bartlett J.M., Kolasa K.M., Marcuard S.P., Holbrook C.T., Horner R.D.[1992] Nutritional status and dietary intake of children with sickle cell anemia. Am J Pediatr Hematol Oncol.14:57-61.
81. Pellegrini Braga J.A., Kerbauy J., Fisberg M.[ 1995] Zinc, copper and iron and their interrelations in the growth of sickle cell patients. Arch Latinoam Nutr. 45:198-203.
82. Leonard M.B., Zemel B.S., Kawchak D.A., Ohene-Frempong K., Stallings V.A. [1998]Plasma zinc status, growth, and maturation in children with sickle cell disease. J Pediatr. 132:467-71.
83. Fung E.B., Kawchak D.A., Zemel B.S., Ohene-Frempong K., Stallings V.A.[ 2002] Plasma zinc is an insensitive predictor of zinc status: use of plasma zinc in children with sickle cell disease. Nutr Clin Pract. 17:365-72.
84. Zemel B.S., Kawchak D.A., Fung E.B., Ohene-Frempong K., Stallings V.A.[ 2002] Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr. 75:300-7.
85. Chan AC, Chow CK, Chiu D.[1999]. Interaction of antioxidants and their implication in genetic anemia. Proc Soc Exp Biol Med. 222:274-82.
86. Bao B., Prasad A.S., Beck F.W., Snell D., Suneja A., Sarkar F.H., Doshi N., Fitzgerald J.T., Swerdlow P.[2008]. Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Transl Res. 152[2]:67-80.
87. Alayash A.I., Dafallah A., Al-Quorain A.A., Omer A.H.S., Wilson M.T. [1987] Zinc and Copper Status in Patients with Sickle Cell Anemia. Acta Haematol. 77:2
88. Bashir N.A.[ 1995] Serum zinc and copper levels in sickle cell anaemia and beta-thalassaemia in North Jordan. Ann Trop Paediatr. 15[4]:291-3.
89. Kwan E.Y., Lee A.C., Li A.M., Tam S.C., Chan C.F., Lau Y.L, Low LC.[ 1995]A cross-sectional study of growth, puberty and endocrine function in patients with thalassaemia major in Hong Kong. J Paediatr Child Health. 31:83-7.
90. Mehdizadeh M., Zamani G., Tabatabaee S. [2008] Zinc status in patients with major beta-thalassemia. Pediatr Hematol Oncol.25:49-54.

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