Progression of Liver Fibrosis Can be Controlled Under Adequate Chelation in Transfusion-Dependent Thalassemia (TDT).
Authors: Maira Diletta , Cassinerio Elena , Marcon Alessia , Mancarella Marta , Fraquelli Mirella , Cappellini Maria Domenica 
Published: October 2019

Abstract
BACKGROUND. A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection have been implicated in the development of liver fibrosis. The objective of iron chelation is to avoid the complications of siderosis, such as hepatocellular injury. As a matter of fact, adequate chelation therapy is mandatory in order to prevent liver disease progression. In the last few years the availability of different chelating agents (coupled with anti-HCV therapy) allowed control of liver disease due to secondary iron overload. Transient elastography (TE, Fibroscan®) is a non-invasive and rapid diagnostic tool that enables accurate prediction of hepatic fibrosis by measuring liver stiffness (LSM). Patients with TDT could benefit from regular non-invasive assessment of liver fibrosis as an indirect indicator of treatment adequacy and therapeutic compliance.
AIM. We investigated the efficacy of adequate iron chelation to prevent the progression of liver fibrosis in TDT patients over a time period of approximately 4 years.
MATERIALS AND METHODS. We analysed data in a retrospective cohort study over a 4±1.5-year time period. Ninety-nine patients with beta-thalassemia major (41 M, 58 F, aged 36±6 years), followed at Rare Disease Center, Ca' Granda Hospital in Milan, were enrolled in the study. All patients received regular transfusions every 2-4 weeks. Chelation therapy was registered using deferasirox (DFX), deferoxamine (DFO), deferiprone (DFP) or a combination of the three. All the participants underwent TE and T2-weighted magnetic resonance imaging (T2*MRI) twice (at baseline,T0 and after approximately 4 years, T1). Liver iron concentration (LIC) was assessed by T2*MRI using the appropriate formula at T0 and T1. LSM was measured according to the following cut-off: <5.0 kPa no fibrosis (F0), 5.1-7.9 kPa mild fibrosis (F1), >7.9 kPa moderate fibrosis (F2), >10.3 advanced fibrosis (F3), >11.9 kPa cirrhosis (F4). We divided our cohort into groups depending on the administered chelating agent and the presence of iron overload defined by a LIC > 4.23 mg Fe/g dry weight (corresponding to a T2* value > 6.3 ms).
RESULTS. At baseline the mean pre-transfusion Hb levels was 9.74 ± 1.17 g/dL, the mean iron intake 0.33 ± 0.07 mg Fe/kg/d and median serum ferritin 669.5 ng/ml (range 113-5912). HCV-RNA positivity was found in 33 patients (33%) at T0: 20 patients were treated for hepatitis C during the observation period. The overall mean LSM was 7.4±3.2 kPa, the mean hepatic T2* was 9.92±7.01 ms and the mean LIC was 4.81±3.82 mg/g dw (n=99). Data available at 4±1.5 years showed a significant reduction in liver stiffness (6.6±3.2 kPa, p 0.017), iron overload measured by hepatic T2* (12.84±7.28 ms, p < 0.001) and LIC (3.65±3.45 mg/g dw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurment (n=41). The number of patients with moderate to advanced fibrosis (LSM ≥ F2) decreased, yet not significantly (30% vs 19%, p 0.07). Subjects treated with a stable dose of DFX over the entire period of observation (n=39) showed a reduction of LSM (6.9±2.3 vs 6.06±2.4, p 0.04) and a concomitant improvement of hepatic T2* and LIC values (respectively 11.02±6.57 vs 15.04±6.42 and 3.84±2.81 vs 2.49±1.89, p < 0.001). In this group we observed a substantial decrease in the number of patients with LIC > 4.23 mg Fe/g dw (33% vs 13%, p 0.01). A reduction of LSM, yet not statistically significant due to the limited size of the cohort, was achieved in patients on combined DFO+DFP at T0 and T1 (n=6, 8.6±5.5 vs 7.3±3.8). The group of patients on DFO (n=11) remained stable over time. Patients who underwent anti-HCV therapy showed an even more evident reduction in LSM (9±3 vs 7±3.1, p 0.016).
CONCLUSION. These data support evidence on the efficacy of adequate iron chelation therapy and, if necessary, anti-HCV treatment in decreasing or at least controlling the progression of liver fibrosis measured by TE in transfusion-dependent BTM patients. Therapeutic compliance and tailoring of drugs is essential to prevent hepatic injury resulting from siderosis. Moreover, proper chelation and treatment of HCV infection act sinergistically to limit progression of liver disease in TDT patients with active hepatitis C, so that development of cirrhosis could be either prevented or greatly delayed.

Disclosures
Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme-Sanofi: Membership on an entity's Board of Directors or advisory committees.