Phenotypic evolution in Haemoglobin E beta-thalassaemia: A three-decade progression to Pulmonary Hypertension, Cardiac Cirrhosis, and Hepatocellular Carcinoma

Haemoglobin E β-thalassaemia exhibits marked phenotypic heterogeneity, with some patients remaining non–transfusion-dependent for prolonged periods despite ongoing ineffective erythropoiesis and progressive iron loading. We report a 51-year-old woman diagnosed at 22 years of age who remained non–transfusion-dependent for over two decades. Despite minimal transfusion exposure, she developed significant iron overload (peak ferritin 3,490 ng/mL), followed by progressive splenomegaly and hypersplenism. Between 2018 and 2023, worsening anaemia and marrow exhaustion led to a transition to transfusion-dependent thalassaemia, with concurrent pulmonary hypertension confirmed by right heart catheterisation in 2024. After defaulting from care and discontinuing chelation therapy, she presented with decompensated chronic liver disease due to combined iron overload and cardiac cirrhosis. In 2025, further deterioration revealed hepatocellular carcinoma in segment VI (4.4 × 5.3 × 4.6 cm). This case highlights late phenotypic evolution in non–transfusion-dependent thalassaemia and the catastrophic consequences of unregulated iron toxicity, culminating in hepatocellular carcinoma and death within two months of diagnosis. It underscores the critical need for sustained monitoring, continuous chelation, and proactive surveillance for extrahepatic complications, including pulmonary hypertension and hepatocellular carcinoma, in un-transfused, iron-loaded patients.