Thalassemia intermedia (TI) is part of the thalassemia syndromes, which are the commonest genetic disorders worldwide, and is a member of the non-transfusion-dependent thalassemia (NTDT) group. By definition, β-thalassemia intermedia is a hemoglobin disorder characterized by a reduction in the expression of the β-globin gene ^{1, 2} . Iron overload in TI has more than one cause, the most important is increased gut absorption. In addition, ineffective erythropoiesis and hemolysis may increase the need for blood transfusions with the eventual result of iron overload ^{3, 4} . High morbidity rates usually accompany iron accumulation in NTDT and TI and has a significant impact on free radicals and oxidative stress tissue damage. Iron chelators are the best solution to alleviate these pathologies ^{5, 6} .

Deferasirox is the main oral iron chelation therapy according to international guidelines, but it is not free from side effects, leading to issues surrounding compliance, resulting in excessive body iron. Accordingly, recent research aims to assist, improve, or even substitute the use of iron chelating drugs using certain plants ^{7, 8} . The common tea plant Camellia sinensis has been utilized globally as a tea drink in various subtypes based on the manufacturing process: black (fermented), green (non-fermented), and oolong (semi-fermented). Tea belongs to the group of common beverages worldwide and it is considered as the number one beverage (after water) in Iraq and some other parts of the world ^{9, 10} .

Regarding green tea (GT), polyphenols are the main ingredient, representing 24–36% of dry weight. Catechins are the mainstay of these polyphenol compounds, which have inhibitory effects on iron (heme and non-heme) absorption across gut cells. This may lead to extraordinary negative iron balance in humans who consume GT as part of their daily diet ^{11, 12} .

Consequently, this randomized controlled trial aimed to assess the iron accumulation levels in TI patients treated with deferasirox with additional GT intake using serum ferritin (SF) and liver iron concentration (LIC). Also, hemoglobin (Hb) levels were assessed regularly.

Due to non-compliance, the GT group had 29 patients (five patients excluded) and the control group had 28 patients (six patients excluded) at the end of the study ( Figure 1).

The two groups had comparable (non-significant) general demographic data at baseline ( Table 1). Iron overload (measured by SF or LIC) and volume of packed red blood cells (RBC) transfusion during the previous year calculated just before the start of study period showed no significant differences between groups. Deferasirox mean doses for the GT (36.89±7.24 mg/kg/day) and control (37.21±1.13 mg/kg/day) groups were high and near to the maximum approved doses, but were not significantly different between the groups.

LIC was significantly reduced (P<0.05) after 12 months in both the GT group (baseline, 19.4±2.3 Fe/gram/dry weight; 12 months, 12.1±1.3 Fe/gram/dry weight), and control groups (baseline, 19.8±1.7 Fe/gram/dry weight; 12 months, 15.2±1.6 Fe/gram/dry weight) ( Figure 2). Similarly, SF levels were significantly decreased at the end of study period (P<0.05) in the GT (baseline, 2617±549 ng/ml; 12 months, 1328±127 ng/ml) and control (baseline, 2684±164 ng/ml; 12 months, 1813±235 ng/ml) groups.

Deferasirox use was comparable at the start and end of the study period for both the GT (baseline, 36.89±7.24 mg/kg/day; 12 months, 36.24±6.83 mg/kg/day) and control (baseline, 37.21±1.13 mg/kg/day; 12 months, 37.15±3.78 mg/kg/day) groups.

The mean volume of transfused packed RBC during the study period was estimated after 12 months from the baseline and revealed no statistical significance between GT (70.64±7.84 ml/kg) and control (72.14±8.35 ml/kg) patients. The net reduction of LIC (Fe/gram/dry weight) in GT patients was 7.3 (baseline, 19.4; 12 months, 12.1), while for control patients the net result was 4.6 (baseline, 19.8; 12 months, 15.2). A significant reduction (P<0.05) of LIC was found in the GT group in comparison with the control cases. The drop of serum ferritin in GT patients after 12 months [1289 ng/ml (2617-1328)] was significantly (P<0.05) higher than that of the control group [871 ng/ml (2684-1813)] ( Table 2).

Hemoglobin readings gradually increased in both the GT and control groups over the study period. GT patients had higher Hb levels after 12 months than the control group (8.4 versus 8.2), but this was not statistically significant (P=0.37) ( Figure 3).

Iron overload is a major consequence of TI. Physicians have several challenges when using medications that eliminate excessive iron, including type, dose, expected adverse effects, and the best time to start an iron chelator. Therefore, the need for a naturally mediated iron chelator based on plants is increasing along with the increase of thalassemia patients around the world ^{13– 15} . Green tea (GT) seems to be one of the best available options due to its natural properties to counteract iron absorption in addition to other promising advantages ^{16, 17} .

There are several ways to estimate the overload of iron in thalassemia patients, such as the widely available test of SF, and the most accurate non-invasive recent method of LIC using the R2 MRI technique ^{18, 19} .

Patients with TI usually have high iron content loading in their tissues as evidenced by other studies from different areas of the world ^{13, 20, 21} . Our sample of patient had even higher iron content, which is in line with other reports from Middle East ^{3, 14} . This might be due to compliance deterioration, background cultural beliefs, possible side effects of iron chelating drugs, and the frequent use of mimic medications in this part of the world ²² .

GT consumption in our sample was associated with decreased ferritin levels mirroring better iron chelation. This was also noticed by other works done on both humans and animals with transfusion dependent thalassemia ^{23– 25} . SF could be affected by the antioxidant properties of GT ^{26, 27} . However, a recent study that added curcumin to GT for thalassemia patients discovered a slight increase of SF after two months, with the reasons for this unknown to the authors ²⁸ .

A more sophisticated method of iron accumulation assessment in TI is LIC, and in this study, we found a significant drop in the GT group compared to the control group. This has only been previously reported in animal studies, and an online search conducted by the present authors failed to reveal human trials ¹⁵ . It should be noted that iron deficiency has been documented in healthy individuals consuming large amounts of GT ²⁹ .

Surprisingly, in the GT group, TI patients developed slightly higher hemoglobin readings than controls. Again, no previously published data was found to verify this, but it might be related to better iron removal and effects of antioxidant characteristics of GT, which could be associated with improved hematopoiesis and less red blood cells hemolysis. However, GT is historically associated with anemia in a healthy population, especially in high doses ³⁰ .

Although this trial was conducted in the largest thalassemia center within Iraq country borders, its small sample size could be considered as a limitation. We recommend other interested scientists throughout the world to involve more patients with more variables and risk factors to deeply investigate the effects of GT in TI and discover more plant-based iron chelation therapies with better effects.

Thalassemia intermedia patients having usual medical care, including blood transfusion and deferasirox oral iron chelation therapy, have significantly superior levels of iron chelation and slightly better hemoglobin levels when consuming GT regularly compared with a control group.