Introduction:
Thalassemia is a hereditary disease. There is a range of clinical phenotypes, consequences, and therapeutic approaches for thalassemic disorder. Chronic hemolytic anemia (reduced number of blood cells with increased destruction of blood cells) without significant reticulocytosis (increase in reticulocytes, which is an immature red blood cell) and a variety of secondary pathophysiologic mechanisms result from an imbalance in the relative amounts of α-globin and β-globin chains (two polypeptide chains of hemoglobin), which causes early apoptosis of maturing nucleated red blood cells with formation of new blood cells in an attempt for potential compensation. Blood transfusions are frequently necessary for more severe cases of thalassemia, potentially every several weeks. Iron builds up in the blood due to blood transfusions over time, which can harm the heart, liver, and other organs. Iron chelation therapy helps to reduce the amount of iron in the blood. Regular transfusions might cause an accumulation of iron. Excess iron can also develop in some thalassemia patients who don't receive frequent transfusions. For the sake of health, extra iron must be eliminated. One might need to take an oral medicine like deferasirox (Exjade, Jadenu) or deferiprone (Ferriprox) to assist the body in getting rid of the excess iron. Deferoxamine (Desferal), another medication, is injected for the same purpose. This article discusses the complications of this iron overload and preventive measures.
What Are Thalassemia-Related Iron Overloads and Its Complications?
A recent categorization of thalassemic disorder takes the degree of transfusion dependency into account, classifying it into transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Iron overload can result through routine transfusions, which have traditionally been used to treat severe forms of the condition, as well as increased intestinal iron absorption signaled by inadequate erythropoiesis (inadequate formation of new red blood cells). A physiological process in the human body does not support the elimination of the extra iron burden caused by a blood transfusion. The amount of elemental iron in each unit of transfused packed red blood cells ranges from 200 to 250 mg. With an anticipated monthly transfusion rate of 2 to 4 U-packed red blood cells, transfusional iron in TDT typically ranges from 0.3 to 0.6 mg/kg per day. Reticuloendothelial macrophages phagocytize senescent (old) transfused red blood cells. To bind transferrin, labile cellular iron is therefore released into the plasma. Transferrin delivers iron through the blood to several tissues, including the liver, spleen, and bone marrow.
Non-transferrin-bound iron is easily transferred into the liver (hepatocytes), heart (cardiac myocytes), and endocrine glands through calcium channels after transferrin binding is saturated. Different clinical complications of iron overload are caused by the buildup of iron in various organs. Target organ cellular dysfunction, apoptosis (natural cell death), and necrosis (cell/tissue death) are caused by reactive oxygen species generated by the metabolism of non-transferrin-bound iron.
In the past, cardiac siderosis—the source of arrhythmias and heart failure and a significant factor in TDT mortality—has been the most significant clinical complication of iron overload. A typical finding in TDT patients is iron overload-related hepatic and endocrine abnormalities.
Over the past few decades, NTDT has been explored and analyzed more often, and it has become clear that iron overload affects various organs differently.
Complications due to iron overload in TDT thalassemic patients are enlisted below:
- Cardiovascular Complications
- Cardiac siderosis (iron overload in heart tissues).
- Left ventricular heart failure.
- Endocrinal Complications
- Diabetes mellitus.
- Osteoporosis.
- Hypothyroidism.
- Hypoparathyroidism.
- Hypoparathyroidism.
- Hypogonadism.
- Growth retardation.
- Liver Complications
- Liver cirrhosis.
- Liver fibrosis.
- Viral hepatitis.
Complications due to iron overload in NTD thalassemic patients are enlisted below:
- Cardiovascular Complications
- Pulmonary hypertension.
- Right ventricular heart failure.
- Venous thrombosis.
- Hepatocellular carcinoma.
- Endocrine Complications
- Osteoporosis.
Other Complications
- Gallstones.
- Extramedullary hematopoietic tumors.
- Leg ulcers.
- Silent cerebral ischemia.
How Are Thalassemia-Related Iron Overload and Its Complications Diagnosed?
Serum Ferritin Test:
Cutoffs have been proposed for NTDT of 300 ng/mL for the absence of iron overload and >800 ng/mL for the presence of clinically significant iron excess. Ferritin is a protein present inside the cells that store iron. When serum ferritin is above 2500 ng/mL, it accurately predicts cardiac siderosis and endocrine disorders but has little potential to predict cardiac iron overload in TDT. In TDT, it is frequently utilized that a serum ferritin threshold of >1000 ng/mL is a sign that iron chelation therapy should be started. On the other hand, the acute phase reactant serum ferritin changes in response to inflammatory, viral, and other stress conditions.
MRI:
Given its safety and reproducibility, magnetic resonance imaging (MRI) employing R2 or T2* methods have replaced liver biopsy as the gold standard for LIC (large immature cells) measurement. Using the T2* approach, MRI is also utilized to measure the myocardial iron content in milliseconds. As myocardial iron content rises, T2* becomes shorter.
How Can Thalassemia-Related Iron Overload and Its Complications Be Prevented?
Gene Therapy:
One tactic that could assist in preventing iron overload is to hit a step sooner. The potential of gene therapy is actively being investigated. Patients are enrolled in a few current clinical trial studies. Regular long-term blood transfusions won't be necessary because of the potential improvement in normal hematopoiesis, which will also lessen the risk of transfusional iron overload and accompanying consequences. Using enzymes like clustered, regularly interspaced short palindromic repeats/Cas9, genome editing entails introducing DNA breaks into specific genome regions. In treating thalassemia, whether transfusion dependent or not, targeted disruption of proteins like BCL11A that quiet the globin genes may allow for speedier and safer outcomes.
Modified Activin Receptor II Fusion Proteins:
It is assumed that it will improve late-stage erythropoiesis by serving as ligand traps for TGF- TGF-superfamily members (control the development, differentiation, and function of diverse cell types). Treatment with such medicines aims to raise hemoglobin levels in both NTDT and TDT while lowering the need for transfusions in TDT, and preliminary results from phase 2 trials are positive.
Long-Acting Hepcidin:
To inhibit iron absorption, long-acting hepcidin analogs (minihepcidins) have been created and are now being researched. Minihepcidins can be employed alone or in conjunction with ICT to manage iron overload if and when made available for clinical use.
Conclusion:
In conclusion, thalassemia-related iron overload must be effectively prevented and managed to reduce complications and enhance patient outcomes. Regular monitoring, chelation therapy, and adherence to treatment plans achieve reduced iron load and appropriate iron levels. Successful preventative techniques emphasize the value of education, early intervention, and comprehensive care in the management of thalassemia and the necessity of collaborative efforts between healthcare professionals, patients, and families.