Though the disease was known to be centered around the Southeast Asian and Middle Eastern regions, a recent review has highlighted the increasing prevalence of β-thalassemia in North America and Western Europe. ¹ Approximately 1.5% of the world’s population are carriers of β-thalassemia, where the number varied across regions, including in specific countries. ² For example, among Southeast Asian countries the number of β-thalassemia carriers ranged between 0.5% and 12.8% as reported in Myanmar and Malaysia, respectively. ³ In Indonesia, it is estimated that 3.0–10.0% of the population have the β-thalassemia trait depending on the population. ⁴ In 2019, data from Indonesian Pediatric Association indicated at least there were 10,500 registered thalassemia patients but this figure is far below the estimation. ⁴

People with β-thalassemia require a lifelong blood transfusion due to their inability to produce sufficient normal hemoglobin A. Ineffective erythropoiesis in β-thalassemia patients occurs because of the inherited genetic mutations causing impaired β-globin protein and consequently the imbalance in α- and β-globin chains production. ⁵ The condition leads to the inevitable hyperabsorption of irons deriving from either dietary irons or those from blood transfusion. ⁶ Excessive iron and its deposition could cause cardiac complications, which currently affects 25% of total 26,893 β-thalassemia major patients according to a meta-analysis. ⁷ To prevent the toxicity of iron overload, the patients should receive iron chelating therapy. The life expectancy of people with β-thalassemia major could be improved, even to be similar to those with β-thalassemia intermedia if managed with an iron chelating agent. ⁸

Based on a systematic literature review, a person with transfusion-dependent thalassemia should pay $128,062 for blood transfusion and iron chelating therapy. ⁹ In Indonesia itself, the access to iron chelation therapy is still a challenge, especially in rural areas. ¹⁰ It is worth mentioning that Indonesia lies in a thalassemia belt area owing to the high prevalence and carrier rate. ¹¹ Therefore, it is of importance to focus the research on the Indonesian population to improve the clinical management and monitoring of iron overload among patients with β-thalassemia major. There are two oral iron chelating drugs usually used in Indonesia deferiprone and deferasirox. Deferiprone has two ligands which could coordinate with Fe forming a complex with three chelator molecules. ¹² Meanwhile, deferasirox has three ligands that could coordinately bind one Fe atom to form a complex with two chelator molecules. ¹² Understanding the performance of these two drugs in reducing the iron level could provide an insight into more effective and cost-efficient management. Although these drugs are the main oral iron chelating drugs in Indonesia, ⁴ studies comparing their effects on liver function are limited and focused in Java. ^{13 , 14} In addition, the iron storage protein, ferritin, has been suggested as an indicator of iron overload and has been used to monitor iron chelation therapy efficacy. ^{15 , 16} Its correlation with liver enzymes could be an indicator for liver damage monitoring. ^{17 , 18}

The objective of the study was to compare the performance and adverse effects of two oral iron chelating drugs (i.e., deferiprone (Ferriprox) and deferasirox (Exjade)) on the liver in β-thalassemia major patients with chronic transfusion. The effect on the liver were assessed by measuring the levels of serum ferritin, transaminase (ALT), aspartate transaminase (AST), total bilirubin, indirect bilirubin and direct bilirubin among patients with β-thalassemia major and chronic transfusion. In addition, we performed a correlation test between serum ferritin with ALT, AST, and total bilirubin.

Increased ferritin levels in the sera of thalassemic patients are expected since they have ineffective erythropoiesis conditions, allowing hyperabsorption of dietary irons in the intestines. Multiple reports have suggested the effect of iron overload-associated liver abnormalities, indicated by the raised level of liver enzymes. Egyptian patients with β-thalassemia, aged 1.1 to 17 years old, had a mean serum ferritin level of 1367.52 ± 856.22 ng/mL, which exceeded the normal range in children (7–140 ng/mL). ¹⁹ Following the blood transfusion, irons are retained in the macrophages due to the increased hepcidin, hence elevation in serum ferritin. ²⁰ Hepcidin production is suppressed due to erythropoietic activity which allows increased absorption of dietary iron in addition to the iron obtained from blood transfusion. Elevated ferritin as an iron storage marker was reported to have a strong correlation with iron overload condition. ²¹ Among 291 thalassemic children in Cipto Mangunkusumo Hospital, Indonesia, there was a predominance of mild, moderate, and severe degrees of iron overload (28.2%, 34.7%, and 27.8%, respectively). ²²

Overaccumulation of iron in the liver could damage the organ following reactive oxygen species (ROS) formation through Haber-Weiss and Fenton reactions. ²³ Ferric iron could be reduced to ferrous iron resulting in the formation of hydroxyl radicals which promotes DNA and protein damages, oxidation of amino acid side chains, and peroxidation of phospholipid. ²⁴ In this present study, we found the abnormally high averaged values of serum AST and ALT (51.57±32.77 and 49.19±48.32, respectively), suggesting the presence of hepatic injury. The correlation tests revealed that serum AST and ALT levels are strongly influenced by ferritin, hence hepatoxicity of iron overload. Similarly, a study on 100 patients with β-thalassemia major reported the strong positive correlation between serum ferritin and AST or ALT. ¹⁹ Based on the study with a slightly higher number of transfusion-dependent thalassemic patients (n=138), ferritin was also found to be positively correlated with liver enzymes (AST and ALT). ¹⁷ Among patients with acute dengue fever, similar relationships among serum ferritin, AST, and ALT were also reported, where serum ferritin was proposed as an indicator for liver damage. ¹⁸ In the light of this iron toxicity, it is of importance for thalassemic patients undergoing blood transfusion to receive iron chelating therapies.

Herein, we observed differences of total, indirect, and direct bilirubin and ALT levels between deferiprone and deferasirox groups. All the aforementioned biomarkers were statistically higher in the latter group. In the correlation test, we did not find a correlation between ferritin and bilirubin, indicating that increased bilirubin was not associated with the efficacy of the iron chelator. In previous studies, hepatoxicity of deferasirox has been reported. ^{25 – 27} In drug-induced hepatic injury, the drugs induce the detrimental immune modulations after attaching to the enzyme molecules. ²⁸ The neo-antigens eventually initiate the immune response cascade which could result in cytotoxicity and apoptosis. ²⁸ Nonetheless, the reactions are delayed and required multiple exposures. Another proposed mechanism of the deferasirox-induced hepatic injury is the blockage of salt transport proteins (cholestatic injury), ^{25 , 26} which is supported by the findings of higher bilirubin levels in this present study. However, a case report suggested mitochondrial injury as the most explaining mechanism of deferasirox-induced liver injury which is consistent with elevations of transaminases. ²⁷

Our data indicated that the levels of serum total, indirect bilirubin, and direct bilirubin were significantly higher in patients treated with deferasirox than deferiprone. Deferasirox has three ligands that could bind one Fe atom to form a complex with two chelator molecules while deferiprone only has two ligands. ¹² The hepatoxicity effect of deferasirox was found to be more potent in patients with long-term transfusion as compared to those with short-term transfusion. However, interestingly, deferasirox could maintain its iron chelating efficacy even though the patients have undergone blood transfusion for more than 7 years. In the case of deferiprone, serum ferritin was produced at a higher level in patients with long-term blood transfusion. This is an indication that deferiprone lost its efficacy as an iron chelating agent as the patient received more blood transfusion. Our findings are in agreement with a study that continually monitored the long-term efficacy of deferasirox, which appeared to be sustained for 3.5 years. ²⁹ Deferasirox uniquely has a longer half-life and bioavailability in the plasma (lasting for 24 hours) than other iron chelating therapies. ³⁰ It is worth noting that, among patients receiving short-term blood transfusion herein, lower ferritin was observed in the deferiprone group than in the deferasirox group. In previous studies, deferasirox had a lower rate of effectiveness. ^{16 , 31}

Our study had some limitations. For example, we did not simultaneously assess the effects of deferasirox or deferiprone in the thalassemic patients. The number of patients recruited in the study was too few, limiting the results in terms of being clinically meaningful. Moreover, we did not measure iron overload in specific organs, which could give an important insight since the drugs’ efficacies are dependent on the targeted organ. Diagnosis using magnetic resonance imaging (MRI) or other definitive tools should be carried out to conclude the hepatic injury in the patients.

Patients with β-thalassemia major have a higher level of serum ferritin, which is strongly correlated with the elevations of serum ALT and AST levels, respectively. Deferasirox poses a higher risk of developing liver dysfunction than deferiprone, as suggested by increased levels of bilirubin and ALT. While deferiprone has reduced efficacy among patients managed with long-term blood transfusion, deferasirox could yield a similar efficacy regardless of the length of the chronic transfusion. These findings could be used as guidance for medical practitioners in determining the oral chelating therapies for iron-overload conditions among β-thalassemia major patients, by considering the net clinical benefits of each drug. Although a higher number of participants is required to obtain meaningful clinical conclusions, medical practitioners should be aware of the net clinical benefit of prescribing the oral chelators to transfusion-dependent β-thalassemia major patients.