Relação do dano oxidativo, mutação do gene HFE e fator de necrose tumoral (TNF-α) com a sobrecarga de ferro transfusional em portadores de síndromes mielodisplásticas

Abstract

Introduction: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and dysplasia in one or more cell lines, peripheral cytopenias and a variable risk of progression to acute leukemia. Anemia is present in 80 % of patients. Many develop transfusion dependence and iron overload (IOL), which leads to generation of reactive oxygen species (ROS). Oxidative stress, together with tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis and evolution of MDS. Objective: To evaluate the relationship of iron status with oxidative damage, mutation of the HFE gene and the levels of TNF-α in patients with MDS, followed at the Hematology Unit of the Federal University of Ceará. Methods: 101 patients with MDS, 24 with and 77 without transfusional IOL were analyzed, from May 2010 to September 2011. The control group comprised 87 healthy individuals. The profile of iron was evaluated by classical techniques, oxidative damage by spectrophotometric methods and mutation of the HFE gene study by PCR – RFLP. Results: We observed a significant increase in malonaldehyde (MDA) and nitrite in patients with IOL when compared to the other groups (p< 0.0001). The MDA and nitrite were directly correlated with serum ferritin (FRT) (r = 0.3328, p= 0.0033, r=0.4255, p< 0.0001, respectively). There was a positive correlation between FRT and antioxidant enzymes, superoxide dismutase (SOD) (r =0.5957, p< 0.0001), catalase (CAT) (r =0.4064, p=0.0003) and glutathione peroxidase (GPx) (r=0.7313, p< 0.0001). In patients with IOL a significant increase of TNF-α was observed, which was directly correlated with FRT (r = 0.4165 p=0.0002). At least one mutation in the HFE gene was identified in 30.8 % of patients with MDS and in 5.75% of healthy controls, most heterozygous for H63D. Subjects with mutations in the HFE gene showed ferritin levels significantly higher than those without the mutation in all groups. All markers of oxidative stress were higher in patients with IOL, independent of HFE gene mutations. Conclusions: The disease presented later in males and with more severity criteria for worse outcome in the study population. The oxidative stress observed was related to iron overload and the HFE gene mutation did not constitute an additional factor. These data provide new information about the pathogenesis of this heterogeneous disease and may provide the basis for new therapeutic interventions.