Worldwide the greatest burden of disease related to beta thalassemia resides in Asia and is largely represented by Hemoglobin E beta thalassemia (HbE/thal) [Weatherall DJ, Ann New York Acad Sci 2005, 1054:11-17]. HbE/thal is the most common serious form of beta thalassemia in many Asian populations. In Sri Lanka, over 17 years, we have characterized over 200 affected patients and had proposed [Olivieri, NF, et al., J Pediatr Hematol Oncol, 2000, 22:593-597], as now shown in less common forms of non-transfusion dependent thalassemia [Taher AT, et al., Br J Haematol 2010, 150:486-489], that non-transfusional iron accumulation (NTIA) is a potential complication in non-transfused patients with HbE/thal. In 2009, we implemented R2-MRI [St Pierre, TG, et al., Blood 2005, 105:855-861] in Sri Lanka. Here we report the variation and severity of non-transfusional iron accumulation (NTIA), in parallel with screening tests of organ dysfunction, in a first group of patients with HbE/thal.
Patients aged > 7 years with clinical evidence of iron overload (generally a serum ferritin > normal range in the absence of a history of regular transfusions) were recruited from The National Thalassaemia Centre (NTC), Kurunegala, Sri Lanka. LIC was measured using R2-MRI (FerriScan¨) with facilities situated a 6 hour return bus trip from the NTC. Liver function was evaluated using serum alanine transaminase (ALT). Fasting blood glucose (FBG), thyroid stimulating hormone (TSH), serum calcium and phosphate and serum ferritin (SF) were measured in local laboratories. Cardiac function was measured using echocardiography. Correlations between parameters were assessed using non-parametric (Spearman) analysis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimum cut-off values of LIC and serum ferritin for predicting ALT values above the upper limit of the laboratory reference range.
LIC measurements were successfully acquired for 110 of 112 enrolled subjects (45 male/ 67 female) with median age [range] 22.5 [7.8 – 61.5] years over 3 years. The variation in LIC was considerably, and unexpectedly, broad: median [range] LIC was 8.8 [0.7 – 65.0] mg Fe/g dw. LIC exceeded the threshold of risk established as 7.0 mg Fe/g dw [Olivieri NF, Brittenham GM, Blood 1997, 89:739-761] in a substantial proportion (57%) of patients. In parallel, organ dysfunction was observed: in a substantial group (52%), ALT was increased above normal range, while in 11%, ejection fraction was reduced (less than 56%). FBG and TSH were elevated above normal range in a substantial proportion of patients (6% and 30% respectively). Significant correlations were observed between LIC and serum ferritin concentration (r2=0.69, p<0.0001), LIC and ALT (r2=0.52, p<0.0001), and SF and ALT (r2=0.48, p<0.0001). The distributions of LIC in patients with normal and abnormal ALT readings are shown in Fig 1. Using ALT as an indicator of liver damage, ROC curve analysis suggests that LIC of 6.35 mg Fe/g dw or a serum ferritin of 772 ng/mL is a threshold associated with liver dysfunction developing from NTIA in HbE/thal. Correlations of either LIC or SF with ejection fraction, FBG, TSH, serum calcium or serum phosphate were not observed, as expected given the nature of the evolution of these complications as described in other iron-loaded patients.
This study of Asian patients with HbE/thal using R2-MRI, an FDA-approved non-invasive method of evaluation of LIC, reveals a wide range of NTIA and, in parallel, a significant proportion of patients with evidence of liver dysfunction. Our data suggest that the liver is at direct risk from NTIA in HbE/thal at a threshold of 6.35 mg Fe/g dry liver tissue. More robust correlations with dysfunction occurring in other organs may be expected to emerge during longitudinal studies which will be critical to understanding the evolution of organ damage occurring secondary to NTIA in this disorder. These studies are urgently needed to prevent morbidity and premature death in this most common form of beta thalassemia.
St Pierre:Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Research Funding; Celgene: Consultancy; Shire: Consultancy.
Asterisk with author names denotes non-ASH members.