Iron Overload and Chelation Therapy in Hemoglobinopathies

Rayan Bou-Fakhredin,Joseph Elias,Ali T Taher

doi:10.4081/thal.2018.7478

Rayan Bou-Fakhredin, Joseph Elias + Show 1 more

Open Access

https://doi.org/10.4081/thal.2018.7478

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Abstract

Iron overload (IOL) is highly prevalent among patients with hemoglobinopathies; both transfusion dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT). Whether IOL is secondary to regular transfusions like in TDT, or develops from increased intestinal absorption like in NTDT, it can cause significant morbidity and mortality. In TDT patients, iron accumulation in organ tissues is highly evident, and leads to organ toxicity and dysfunction. IOL in NTDT patients is cumulative with advancing age, and concern with secondary morbidity starts beyond the age of 10 years, as shown by the OPTIMAL CARE study. Several modalities are available for the diagnosis and monitoring of IOL. Serum ferritin (SF) assessment is widely available and heavily relied on in resource-poor countries. Non-invasive iron monitoring using MRI has become the gold standard to diagnose IOL. Three iron chelators are currently available for the treatment of IOL: deferoxamine (DFO) in subcutaneous or intravenous injection, oral deferiprone (DFP) in tablet or solution form, and oral deferasirox (DFX) in dispersible tablet (DT) and film-coated tablet (FCT). Today, the goal of ICT is to maintain safe levels of body iron at all times. Appropriate tailoring ICT with chelator choices and dose adjustment must be implemented in a timely manner. Clinical decision to initiate, adjust and stop ICT is based on SF, MRI-LIC and cardiac T2*. In this article, we review the mechanism of IOL in both TDT and NTDT, the pathophysiology behind it, its complications, and the different ways to assess and quantify it. We will also discuss the different ICT modalities available, and the emergence of novel therapies.

Highlights

Iron overload (IOL) is highly prevalent among patients withThalassemia is an inherited disease with multiple genetic hemoglobinopathies; both transfusion dependent thalassemia forms, including alpha-thalassemia, beta-thalassemia, hemoglobin (TDT) and non-transfusion dependent thalassemia (NTDT)
We review the mechae nism of IOL in both transfusion- dependent thalassemia (TDT) and NTDT, the pathophysiology behind it, its complications, and the different ways to assess and quantify m it
Whether IOL is secondary to regular transfusions like in TDT, or develops from increased intestinal absorption like in NTDT, it can cause significant morbidity and mortality

Summary

Introduction

Thalassemia is an inherited disease with multiple genetic hemoglobinopathies; both transfusion dependent thalassemia forms, including alpha-thalassemia, beta-thalassemia, hemoglobin (TDT) and non-transfusion dependent thalassemia (NTDT). Hepcidin synthesis by the liver suppresses the release of m iron from erythroid precursors, hepatocytes, basolateral membranes Non-com of hepatocytes, and macrophages by binding to ferroportin, which toxic NTBI enters mitochondria and leads to the formation of toxic radicals and ROS This in turn leads to gene alterations resulting in cell apoptosis and or fibrosis in different target organs including the myocardium, liver, and endocrine glands [7]. When compared to increased risk for complications related to iron overload, while healthy individuals, patients with NTDT were found to have a LIC values >15 mg/g were predictive of advanced liver fibrosis, higher prevalence of rhythm disorders, pericardial diseases and mortality, and increased risk of cardiac disease in TDT [10, 25]. This relaxation occurs faster (shorter T2* in ms) with increasing tissue (myocardial, liver...) iron concentrations [1, 24]

Iron chelation therapy

Iron chelation therapy in transfusion dependent thalassemia

Recommended dose

Indication to stop ICT

Findings

Conclusions