Serum Heavy Metal Levels in Patients with Ineffective Erythropoiesis and the Effect of Chelation on Heavy Metal Levels
Authors: Bayhan Turan , Unal Sule , Cirak Eyup , Erdem Onur , Akay Cemal , Eker Ibrahim , Tuncer A. Murat , Cetin Mualla , Gumruk Fatma 
Published: October 2019

Abstract
Aim: In disorders with ineffective erythropoiesis like thalassemia major (TM) iron absorption from gastrointestinal tract increases regardless of iron store. Iron is taken into enterocytes at duodenum via apical divalent metallo protein 1 (DMT-1) protein. Besides iron DMT-1 also transports other divalent metals like cadmium (Cd) , cobalt (Co), copper (Cu), lead (Pb), manganese, nickel, and zinc (Zn). In our study we hypothesized that absorption of heavy metals via DMT-1 protein may be elevated in particularly TM and other disorders with ineffective erythropoiesis, and we aimed to investigate blood heavy metal levels in these patients and compare with control group.
Methods: Study was performed between December 2014 and April 2015 in Hacettepe University Children Hospital Pediatric Hematology Clinic and Gulhane Military Medical Academy Pediatric Hematology Clinic. Blood samples were taken from patients with TM, thalassemia intermedia (TI), congenital dyserythropoietic anemia (CDA), and age and sex matched healthy control group. Heavy metal exposure was searched via questionnaire for each participant. Serum heavy metals including aluminium (Al), Cd, Co, crom (Cr), Cu, Pb, selenyum (Se), and Zn were measured.
Results: Blood samples were obtained from 51 patients with TM, 8 with TI, 9 with CDA, and control group included 65 healthy volunteers. General characteristics of patients and control group were showed on Table 1. There wasn't statistical difference between patients and control group in terms of age and heavy metal exposure. Plasma or serum heavy metal levels of patients and control group were shown in Table 2. Patients with TM were found to have lower Al, Pb, Se, and Zn, and higher Cd levels compared to control group. In patients with TM, Cd level was higher than control group, however median value of Cd was still in normal range. In TI group only Se level was lower (p; 0.003), in CDA group both Se (p; 0.008) and Zn (p; 0.02) levels were lower compared to control group. When we looked for patients with TM, TI, and CDA who were treated with deferasirox; Al, Pb, Se, and Zn levels were lower, and Cd level was higher than control group.
Discussion: Opposite to our hypothesis Al, Pb, Se. and Zn levels were lower in TM group and in group of patients who were on deferasirox. Se and Zn levels in patients with TM have been studied before but contradictory results have been reported. Generally they were reported to be lower in patients with TM. These results have been explained with micronutrient deficiency, and chelator treatment. Deferasirox has been reported to bind to Al and Zn, as well. The lower Al and Zn levels in our study may be explained with deferasirox therapy. Deferasirox may also have capacity to bind Pb, related to the lower levels found in our study in deferasirox group. In addition to iron chelation, chelator treatment with deferasirox might have protective effects in patients with ineffective erythtopoiesis against heavy metal toxicity.
Table 1. General characteristics of patient and control groups TM TI CDA Control Number 51 8 9 65 Age* (year) 20.2 (4.5-39) 8.8 (3.4-37) 9 (2.5-14.6) 16.8 (3-39) Male/female 23/28 3/5 6/3 33/32 Heavy metal exposure YesNo 2130 62 81 3134 Chelator usage NoDeferasiroxDeferoxamineDeferoxamine+ deferriprone 04641 2600 4500 TM: thalassemia major, TI: thalassemia intermedia, CDA: congenital dyserythropoietic anemia *Median and range
Table 2. Heavy metal levels in patient and control groups TM TI CDA Control pa Aluminium (mcg/L) (0-50) 27.,6 (10.1-82.1)* 50.1 (18.2-91.3) 41.1 (11.3-48.5) 43.8 (2.4-175.6) 0.01 Copper (mcg/dL) (70-150) 71.7 (22.3-175.5) 90.5 (27.9-165.2) 59.9 (35.1-110.3) 78.5 (20.5-189) 0.1 Zinc (mcg/dL) (70-120) 56 (21.8-126.2) 63.8 (34.4-130.2) 59.3 (23.6-76.9) 70.8 (36-166.8) 0.001 Cadmium (mcg/L) (0.3-1.2) 0.75 (0.34-2.82) 0.77 (0.36-1.37) 0.59 (0.38-0.78) 0.58 (0.23-3.54) 0.002 Cobalt (mcg/L) (0.5-3.9) 0 (0-6.73) 0.19 (0-1.94) 0.08 (0-2.49) 0.39 (0-6.59) 0.23 Crom (mcg/L) (2.8-45) 45.08 (39.4-63.8) 45.1 (41.7-47.5) 45.7 (35.5-53.7) 46.9 (28.5-96.1) 0.49 Lead (mcg/L) (0-150) 3.83 (0-22.7) 6.71 (0-11.1) 5.18 (0-16.3) 9.31 (0-45.2) 0.01 Selenium (mcg/L) (0-150) 24.6 (11.8-42.5) 21.7 (8.7-35.3) 25.6 (20.3-31.8) 33.,3 (15.1-71.5) <0.001 TM: thalassemia major, TI: thalassemia intermedia, CDA: congenital dyserythropoietic anemia * Median and range aComparison of control group and patients with thalassemia major

Disclosures
No relevant conflicts of interest to declare.