Non-Transferrin-Bound Iron, Iron Load and Hypoxia May Induce Low-Grade Inflammation in Patients with Thalassemia Intermedia.

Inflammation is known to play an important role in the pathogenesis of thalassemia. Serum levels of pro-inflammatory cytokines such as IL-6 and TNF-a are known to be elevated in thalassemic patients, suggestive a low-grade inflammatory status. These levels are comparable to the ones observed in patients with diabetes, obesity and atherosclerosis. Altered redox status has also been shown in thalassemic erythrocytes. Reactive oxygen species (ROS) are generated in increased amounts after the precipitation of excess unmatched globin chains, the deposition of non-heme iron and hemichromes and the induced inflammation. In this study we assessed the levels and possible causes of inflammatory status in patients with thalassemia intermedia (TI).

Thirty-five patients with TI, 13 men and 22 women, aged 8-63 years were included in the study. None of the patients had received any transfusion therapy for at least 6 months prior of sampling, while 25/35 patients had been splenectomized. We measured the hematologic and biochemical parameters, including Hb, HbF ferritin and soluble transferrin receptors (sTfR) with standard methodology. Serum concentrations of non-transferrin bound iron (NTBI) were estimated using graphite furnace atomic absorption spectrometry. Determination of high-sensitivity CRP (hs-CRP or cardiophase-CRP) was performed using the Siemens Advia 1800 Clinical Chemistry System. Furthermore, we obtained P₅₀ values from oxygen equilibrium curves (OEC) drawn in fresh whole blood. Oxygen delivery and release parameters were calculated using the “Siggaard–Andersen's Oxygen Status Algorithm”.

hs-CRP levels were elevated 2.12±0.55 mg/L compared to lean control values 1.2±0.19 mg/L (p<0.008). Most of the patients (60 %) showed evidence of low-grade inflammation based on the hs-CRP levels. NTBI levels were significantly elevated (2.4±2.2micromol/L), with only 10/30 patients having levels <0.5micromol/L, which is proposed as normal limit. As accepted P₅₀ values were indicative of relative tissue hypoxia (all patients demonstrate increase oxygen affinity). All of the patients showed evidence of increased eryhtropoeitic activity, as indicate by the elevated sTfR levels ranged from 4.0 to 22.9mg/L (3- to 19-fold increase of erythroid marrow activity).

The main results of the evaluated correlations showed that: a) hs-CRP levels correlated positively with NTBI concentrations (r=0.741, p<0.0001), b) hs-CRP levels correlated positively with ferritin levels (r=0.522, p=0.004) and c) hs-CRP levels correlated negatively with P₅₀ values (r=-0.409, p=0.03), while no correlation was found between hs-CRP levels and the degree of ineffective erythropoiesis expressed as sTfR concentrations (p> 0.223).

These findings demonstrate that patients with TI have a chronic low-grade inflammation. Similar inflammatory status has been also shown in patients with atherosclerosis, diabetes and obesity. The level of inflammation correlated with indexes of iron homoestasis, alteration of which is commonly observed in patients with TI. Thus, it seems plausible that the oxidative effects of NTBI and increased iron burden result in chronic inflammation in these patients. The observed negative correlation of inflammation and P₅₀ is of interest, as it indicates possible involvement of tissue hypoxia in inflammation processes.

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