Link between Genotype and Multi-Organ Iron and Complications in Children with Transfusion-Dependent Thalassemia.

Antonella Meloni,Francesco Massei,Maria Rita Gamberini,Riccardo Righi,Maria Caterina Putti,Stefania Renne,Giuseppe Messina,Vincenzo Positano,Giuseppe Peritore,Laura Pistoia,Liana Cuccia,Filippo Cademartiri,Elena Facchini,Paolo Ricchi

doi:10.3390/jpm12030400

Abstract

We evaluated the impact of the genotype on hepatic, pancreatic and myocardial iron content, and on hepatic, cardiac and endocrine complications in children with transfusion-dependent β-thalassemia (β-TDT). We considered 68 β-TDT patients (11.98 ± 3.67 years, 51.5% females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network. Iron overload was quantified by T2* technique and biventricular function by cine images. Replacement myocardial fibrosis was evaluated by late gadolinium enhancement technique. Three groups of patients were identified: homozygous β+ (N = 19), compound heterozygous β0β+ (N = 24), and homozygous β0 (N = 25). The homozygous β0 group showed significantly lower global heart and pancreas T2* values than the homozygous β+ group. Compared to patients with homozygous β+ genotype, β0β+ as well as β0β0 patients were more likely to have pancreatic iron overload (odds ratio = 6.53 and 10.08, respectively). No difference was detected in biventricular function parameters and frequency of replacement fibrosis. No patient had cirrhosis/fibrosis, diabetes or heart failure, and the frequency of endocrinopathies was comparable among the groups. In pediatric β-TDT patients, there is an association between genotype and cardiac and pancreatic iron overload. The knowledge of patients’ genotype can be valuable in predicting some patients’ phenotypic features and in helping the clinical management of β-TDT patients.

Highlights

Beta-thalassemia is a genetic blood disease with a high incidence in the Mediterranean basin, Middle East, Indian subcontinent, Central Asia, and Far East [1]
The aim of the present study was to evaluate the impact of the genotype on hepatic, pancreatic and myocardial iron content, and on hepatic, cardiac and endocrine complications in children with transfusion-dependent β-thalassemia
We found out that, compared to patients with the homozygous β+ genotype, patients with the homozygous β0 genotype and patients with the β0β+ genotype had a risk ten and six times higher, respectively, to develop pancreatic iron overload

Summary

Introduction

Beta-thalassemia is a genetic blood disease with a high incidence in the Mediterranean basin, Middle East, Indian subcontinent, Central Asia, and Far East [1]. Beta-thalassemia is characterized by a wide spectrum of clinical manifestations and laboratory findings, and the disease phenotype largely depends on the underlying mutations of the β-globin gene [2]. In the Mediterranean Region the commonest mutations are CD39, IVS-1,110, IVS-1,1, IVS-1,6, IVS-2,745, IVS-2,1, and CD8, while CD41/42, IVS, 1-5, CD17, -28, COD8/9, IVS,654, and IVS-1,1 are the most prevalent mutations in the Asian Region [1]. These mutations cause a reduced (β+) or absent (β0) production of the β-globin chain, with relative excess of α-chains. The correlation between genotype and phenotype is complex, because other secondary/tertiary modifiers and environmental factors interact with the different allelic variants [2] and modulate the complex pathophysiology of β-thalassemia

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