Beta-thalassemia, also known as β-thalassemia is a genetic disorder marked by reduced or absent beta chain synthesis of hemoglobin, leading to ineffective erythropoiesis and severe anemia. Patients with transfusion-dependent β-thalassemia (TDT) require regular blood transfusions to sustain adequate hemoglobin level. The non-transfusion-dependent thalassemia (NTDT) patients manage anemia without transfusions; however, they still face serious health issues. Both types of patients experience iron overload due to increased intestinal absorption and transfusions, resulting in iron accumulation in vital organs and significant morbidity and mortality. This review explores the mechanisms of iron overload in β-thalassemia, diagnostic techniques, and advances in managing this condition (1^✔ ✔Trusted Source
Exploring the Impact of Iron Overload on Mitochondrial DNA in β-Thalassemia: A Comprehensive Review

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‘Did You Know?
Beta-thalassemia is a hereditary blood condition that restricts the body’s capacity to produce beta-globin, a crucial protein essential for the production of hemoglobin and red blood cells. #betathalassemia #ironoverloading #medindia’
      

How Does Iron Overload Occur? Role of Iron Absorption and Hepcidin

In β-thalassemia, iron overload occurs through two primary mechanisms: transfusional iron overload in TDT patients and increased gastrointestinal iron absorption in NTDT patients due to ineffective erythropoiesis and low hepcidin levels. Hepcidin, a liver-derived hormone, regulates iron homeostasis by inhibiting intestinal iron absorption and iron release from macrophages. In β-thalassemia, hepcidin levels are inappropriately low, leading to excessive iron absorption. This dysregulation results in systemic iron overload. The iron overload leads to the production of reactive oxygen species (ROS) through iron-mediated Fenton reactions, contributing to oxidative stress and tissue damage. Chronic iron overload is particularly detrimental to the liver, heart, and endocrine organs, leading to fibrosis, cardiomyopathy, and endocrine dysfunctions, respectively.

Impact of Iron Overload on Mitochondrial function

Recent studies suggest that an excess of iron could negatively affect mitochondrial function, worsening the pathophysiology of the disease. The buildup of iron in mitochondria may disrupt the electron transport chain, lower adenosine triphosphate production, and raise the production of reactive oxygen species, leading to increased tissue damage and medical issues. New findings propose that certain mutations in mitochondrial DNA (mtDNA) could also play a role in intensifying iron overload in patients with β-thalassemia.

Methods for Detecting and Tracking Iron Overload

Diagnosing iron overload involves several parameters, with serum ferritin levels being a primary indicator. Elevated serum ferritin levels, typically above 300 ng/ml in males and 150–200 ng/ml in females, signal excess iron accumulation. However, inflammation, infection, and liver disorders can affect ferritin levels, necessitating the use of additional markers such as total iron binding capacity, serum transferrin saturation, and non-transferrin-bound iron (NTBI). Magnetic resonance imaging (MRI) has replaced liver biopsy for non-invasive quantification of hepatic iron overload and can also assess iron accumulation in the heart and other organs. T2* MRI is particularly useful for evaluating cardiac iron overload and guiding chelation therapy adjustments. Liver iron concentration (LIC) measurement through R2 and R2* MRI techniques provides a reliable assessment of hepatic iron burden.

Treatment Strategies

The primary treatment for iron overload is chelation therapy, using agents like deferoxamine, deferiprone, and deferasirox to bind and eliminate excess iron. Patient adherence is crucial for the therapy’s effectiveness, along with other factors like side effects and cost. Deferoxamine, administered through infusion, is effective but less compliant to patients, while oral chelators like deferiprone and deferasirox offer more convenience and better compliance. Ongoing research aims to improve chelation therapy by developing new chelators, exploring combination treatments, and using antioxidant-rich plant extracts. Combination therapy, such as deferiprone and deferoxamine, has shown synergistic effects in enhancing iron removal and reducing toxicity.

Way Forward – Research Advancements

Research studies are focused on revealing the molecular mechanisms responsible for iron overload and creating targeted treatments. Progress in genetic and molecular screening has enhanced our knowledge of genotype-phenotype correlations in thalassemia.

Instances that involve mtDNA mutations present further complications, requiring tailored treatment strategies. Progress in gene therapy and mitochondrial replacement techniques provides encouraging possibilities for specific targeted interventions.

Methods like next-generation sequencing (NGS) facilitate the detection of mutations in genes that control iron metabolism. Advances in gene editing technologies, particularly CRISPR-Cas9, show potential for rectifying genetic abnormalities linked to iron overload. Furthermore, nanoparticle-based delivery mechanisms present opportunities for targeted treatment, minimizing systemic toxicity and enhancing therapeutic efficacy. Research is also underway on hepcidin mimetics and modulators to effectively restore hepcidin levels and manage iron absorption.

Summary

Iron overload poses a significant challenge in the management of β-thalassemia. Timely detection and regular monitoring play a crucial role in preventing damage to organs. Although chelation therapy is the foundation of treatment, the need for alternative therapeutic approaches is evident due to its limitations. Progress in molecular genetics and targeted therapies provides optimism for better management of iron overload in patients with β-thalassemia. Tailored treatment strategies, guided by genetic and molecular profiling, are imperative for enhancing patient outcomes. Ongoing research and clinical trials are essential for the development of safer and more efficient treatments, ultimately enhancing the quality of life for individuals with β-thalassemia worldwide.

Reference:

1. Exploring the Impact of Iron Overload on Mitochondrial DNA in β-Thalassemia: A Comprehensive Review – (https://www.xiahepublishing.com/1555-3884/GE-2023-00128)

Source-Medindia