The Emerging Role of Liver Stiffness Measurement in Transfusion Dependent Thalassemia

β-thalassemia is a globally distributed hereditary red blood cell disorder whose clinical management still relies on chronic red blood cell transfusions combined with iron chelation therapy. In transfusion-dependent β-thalassemia (TDT), long-term monitoring of liver and cardiac iron overload is essential to prevent severe organ damage. Prolonged iron exposure, particularly when combined with virus-related chronic hepatitis, acts synergistically to promote liver fibrosis and progression to cirrhosis 1. Previous studies have suggested that liver fibrosis may reflect years of sustained oxidative stress related to iron overload affecting multiple organs 2. Consistently, experience in the allogeneic transplant setting shows that iron-related organ damage negatively impacts transplant-related mortality 3. To investigate the relationship between liver iron overload and liver fibrosis in TDT using non-invasive approaches, we analyzed data from a retrospective cohort of 831 TDT patients followed between 2010 and 2019 at four Italian reference centers for hemoglobinopathies using the Webthal computerized medical record system 4. From this cohort, we selected 165 patients, who underwent liver stiffness measurement (LSM) and liver iron concentration (LIC) assessment within the same year (Figure S1). Patients with a diagnosis of hepatocellular carcinoma, HIV or HBV infection were excluded. No intrahepatic mass-like of extramedullar hematopoiesis was present in our cohort. When multiple paired evaluations were available, the most recent concurrent assessment was considered. Concerning HCV Ab positive patients, the evaluation after direct-acting anti-viral drugs treatment was considered (Figure S2) 5. Liver stiffness (LSM) was assessed by transient elastography (FibroScan) according to European Association for the Study of the Liver (EASL) guidelines 6. Based on EASL guidelines, a cutoff of 8 kPa was used since LSM below 8 kPa is associated with a very low probability of advanced liver fibrosis (bridging fibrosis) 6. In our cohort, the median age at evaluation was 38.5 years (Q1–Q3: 30.5–43.0) and 51% were male (Table S1). The median LSM was 5.2 kPa (Q1–Q3: 4.3–6.3). A total of 151 patients (91.5%) had no advanced liver fibrosis (LSM 8 kPa strongly supports the use of LSM into annual follow-up alongside LIC in TDT patients. Study conception: G.L.F., L.D.F. Data collection: G.B.F., F.L., S.B., R.O., R.L., A.P. Statistical analysis: B.G. Writing – original draft: B.G., L.D.F., G.L.F.; Review and interpretation: L.D.F., G.L.F., B.G, G.B.F., F.L., S.B., R.O., R.L., A.P., L.B. The authors would like to thank Antonia Gigante for her support. The authors have nothing to report. The study was approved by the local Ethics Committees of participating centers, and all patients provided written informed consent for data collection and use. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1: Patient selection flow diagram. With concurrent evaluation it is intended evaluation of LSM and LIC in the same year. Figure S2: Longitudinal trend of LSM during the period of observation in HCV Ab negative and positive patients. Table S1: Demographic and clinical characteristics of the study population. Table S2: Demographic, biochemical and histological features in patients with and without spleen. Table S3: Demographic, biochemical and histological features in patients with HCV Ab positive vs. HCV Ab negative. Table S4: Characteristics of patients by LSM category. Table S5: Association of age, sex, and liver iron concentration (LIC) with liver stiffness measurements (LSM), stratified by HCV antibody status. Table S6: Comparison of main characteristics of studies on liver stiffness and iron overload in TDT patients. Means and standard deviations (SD) or their estimation are reported. Supporting Information: is available online and includes additional details on data collection, variable categorization and statistical analysis and supporting tables and figures. Specifically, Figure S1 provides a patient selection flow-diagram, Figure S2 provides the longitudinal trend of LSM during the period of observation in HCV Ab negative and positive patients. Table S1 provides demographic and clinical characteristics of patients, Tables S2–S4 summarize analyses by splenectomy, HCV Ab Status and LSM category; Table S5 reports the association of age, sex, and liver iron concentration (LIC) with LSM, stratified by HCV Ab status; Table S6 reports the comparison of main characteristics of studies on liver stiffness and iron overload in TDT patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.