The body cannot actively excrete excess iron, which is normally balanced through minimal daily losses. However, patients receiving frequent blood transfusions for conditions like thalassemia major, sickle cell disease, and other chronic anemias are at risk of iron overload. Each transfused unit contains 200–250 mg of iron, which accumulates in organs such as the liver, heart, and endocrine glands, potentially leading to serious complications.
Iron chelation therapy is essential to prevent toxic buildup, and improvements in iron metabolism management have significantly increased survival in transfusion-dependent patients. Liver disease is the most common complication, while heart damage from iron overload is a leading cause of death in thalassemia major. Regular monitoring with blood tests and MRI helps assess iron levels, and early initiation of chelation therapy is crucial for preventing life-threatening outcomes.
Epidemiology
In the U.S., around 15,000 individuals with sickle cell disease and 4,500 with myelodysplastic syndromes or other refractory anemias rely on regular blood transfusions. Globally, nearly 100,000 patients require ongoing transfusions. Transfusions typically begin at age 4 in children with thalassemia and around age 12 in those with sickle cell disease. Among adults, transfusion therapy usually starts at about age 40 for aplastic anemia and age 60 for myelodysplastic syndromes.
The occurrence of iron overload from transfusions differs worldwide, influenced by the availability of early screening and preventive strategies. Studies show that delayed puberty affects roughly half of males and females with thalassemia. In one cohort, only a third of patients with thalassemia major received regular iron chelation therapy, while the remainder were on intermittent or no treatment—leading to iron overload in over 85% of cases.
Regional differences also exist in organ-specific iron deposition. Patients in Western countries and the Far East exhibit greater iron buildup in the heart compared to those in the Middle East. In Japan, a review of 1,109 iron overload cases found that over 93% were related to transfusions. Similarly, a study from Greece reported that more than half of patients with transfusion-dependent thalassemia major had moderate to severe iron overload, with serum ferritin levels exceeding 2,000 mcg/L and 4,000 mcg/L, respectively.
Anatomy
Pathophysiology
Iron toxicity often remains asymptomatic for years. In transfusion-related cases, the body’s iron regulation becomes disrupted, leading to accumulation that can harm various organs. Long-term iron overload can result in cardiomyopathy, liver cirrhosis, hormonal imbalances, and joint damage.
The liver acts as the main storage site for excess iron, storing it as ferritin and hemosiderin. Unlike ferritin, which circulates in the blood and can be accessed when needed, hemosiderin is an insoluble storage form trapped in tissues and unavailable for immediate use. When transferrin—the main iron transporter—is saturated, levels of labile plasma iron (LPI) increase.
LPI is highly reactive and harmful, capable of generating free radicals that damage DNA, proteins, and cell membranes. Ferritin helps buffer this toxicity, but once overwhelmed, reactive oxygen species (ROS) can cause cellular damage and trigger apoptosis in affected organs. Elevated ROS also reduce nitric oxide availability, contributing to blood vessel injury.
In some conditions like beta-thalassemia, iron overload is worsened by increased intestinal absorption. In thalassemia intermedia, ineffective red blood cell production stimulates erythropoietin, suppresses hepcidin, and promotes excessive dietary iron uptake. In contrast, thalassemia major patients—who mainly receive iron through transfusions—tend to have elevated hepcidin due to the high iron load, despite a lower erythropoietic drive.
Etiology
Iron overload from transfusions is directly linked to the number of transfused blood units. Conditions like β-thalassemia major, myelodysplastic syndromes, sickle cell disease, aplastic anemia, and hemolytic anemia often require repeated transfusions, inevitably leading to iron buildup. Each unit of transfused blood adds about 200–250 mg of iron, and receiving more than 10–20 units significantly increases the risk of overload. Since the human body lacks a natural mechanism to eliminate excess iron, its absorption and recycling must be tightly regulated.
Hepcidin, a key hormone, controls iron balance by inhibiting ferroportin, the iron exporter on macrophages and intestinal cells. Daily red blood cell breakdown by macrophages reclaims about 25 mg of iron, mainly in the reactive ferrous (Fe²⁺) form. This form induces ferritin production to convert it into the less reactive ferric (Fe³⁺) form, which binds to transferrin for safe transport.
When transferrin is saturated, excess iron circulates as non-transferrin-bound iron (NTBI), also known as labile plasma iron (LPI). This form of iron is highly toxic and is taken up by tissues like the heart, liver, pancreas, and endocrine glands, which normally do not store iron unless exposed to pathological conditions.
Hepcidin also influences how much iron is released into the bloodstream. It rises during inflammation or iron excess and drops during anemia, hypoxia, or increased red blood cell production. In diseases like thalassemia and aplastic anemia, ineffective erythropoiesis lowers hepcidin, worsening iron overload even in patients receiving regular transfusions.
Genetics
Prognostic Factors
The introduction of iron chelation therapy, particularly with deferoxamine in the 1980s, has significantly reduced complications associated with iron overload. In Italy, among patients with thalassemia major who began subcutaneous deferoxamine treatment, cardiac-related deaths by age 20 dropped from 5% to 1%. The prevalence of endocrine issues such as hypogonadism, diabetes, and hypothyroidism also declined.
Despite these advances, a retrospective Italian study of 912 transfusion-dependent β-thalassemia patients over a 10-year period showed that those with average serum ferritin levels above 2145 ng/mL had a 7.1 times higher risk of death from any cause compared to those with lower levels. Similarly, liver iron concentrations above 8 mg/g were linked to a 20.2-fold increased risk of mortality.
Survival outcomes have improved over time, especially among individuals born in more recent decades and among female patients. In one long-term study, 68% of thalassemia patients were still alive at age 35, though heart disease accounted for 67% of the deaths.
However, in patients who start chelation therapy late or do not adhere to treatment, dangerously high liver iron levels (over 15 mg/g dry weight) can persist, greatly increasing the risk of cardiac complications and premature death. Prolonged periods of elevated serum ferritin are similarly linked to a higher incidence of heart-related mortality.
Clinical History
Age Group:
Children and adolescents: May present with stunted growth, delayed puberty, or delayed menarche.
Adults: Typically show cardiac, hepatic, and endocrine complications.
Physical Examination
On physical examination, patients with transfusion-induced iron overload may present with several systemic findings. General features can include bronze or gray discoloration of the skin, easy bruising, cachexia, and in children, delayed growth and puberty. Cardiac signs may involve jugular venous distention, an S3 gallop rhythm, pleural effusion, and peripheral edema—indicating possible heart failure. Pulmonary examination may reveal lung crepitations and a loud second heart sound (P2). Abdominal findings often include ascites, tenderness, hepatomegaly, splenomegaly, caput medusae, and umbilical hernia, which suggest advanced liver involvement such as cirrhosis and portal hypertension. Neurologically, signs of hepatic decompensation may be evident through the presence of asterixis and hepatic encephalopathy.
Age group
Associated comorbidity
Chronic transfusion-dependent anemias such as β-thalassemia major, sickle cell disease, myelodysplastic syndromes, aplastic anemia, and hemolytic anemia.
History of multiple transfusions and possible poor chelation therapy compliance.
Associated activity
Acuity of presentation
Chronic and progressive in nature.
Symptoms develop gradually over time but can become acute if complications (e.g., heart failure or cirrhosis) decompensate.
Differential Diagnoses
Alcoholic cirrhosis
Arthritis
Cardiomyopathy
Hemochromatosis
Type 1 Diabetes Mellitus
Hepatitis C
Type 2 Diabetes Mellitus
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Management of TIO involves both non-pharmacological and pharmacological strategies, along with procedural and phased approaches. Non-drug measures include minimizing unnecessary transfusions and promoting erythropoiesis to reduce iron accumulation. Pharmacologic treatment centers on iron chelators: subcutaneous Deferoxamine, and oral agents like Deferasirox and Deferiprone, tailored based on iron burden and patient profile. Therapeutic phlebotomy is occasionally used in stable patients but is limited due to anemia in most cases. Management follows distinct phases—initiation (starting chelation once ferritin >1000 mcg/L), intensification (dose adjustment based on iron burden), and maintenance (long-term iron control and organ protection).
While iron chelation remains the cornerstone of therapy, non-drug strategies can help minimize iron accumulation. These include:
Avoiding unnecessary transfusions
Using the minimum effective transfusion dose
Encouraging erythropoiesis through supportive therapies where applicable
Such measures can reduce the rate of iron loading and help delay the need for chelation or enhance its effectiveness.
Role of Chelating agents
Deferoxamine (Desferal mesylate): It is a siderophore-derived iron chelator obtained from Streptomyces pilosus, primarily used for managing transfusion-induced iron overload. Administered typically as a slow subcutaneous infusion via a portable pump, it forms a 1:1 hexadentate complex with iron, binding approximately 8 mg of iron per 100 mg of drug. Its short half-life (20–30 minutes) necessitates continuous infusion to maximize efficacy, particularly for chelating iron from ferritin and hemosiderin, though it does not affect iron bound to transferrin or within hemoglobin and cytochromes. The drug promotes iron excretion via urine and feces, causing a characteristic red discoloration of urine. The initial dosing is 30 mg/kg/day infused over 8–12 hours, five days a week, with adjustments based on iron status. It is supplied as 500 mg lyophilized vials requiring reconstitution before administration, suitable for intramuscular or slow intravenous infusion.
Deferasirox (Exjade): It is an oral iron chelator available as tablets for suspension, binds iron in a 2:1 tridentate complex and is approved for chronic transfusional iron overload. It is initiated when patients receive about 100 mL/kg of packed red cells and have serum ferritin levels persistently above 1000 mcg/L. The typical dose is 20 mg/kg/day, titrated based on iron burden.
Deferiprone (Ferriprox): It is another oral agent, a hydroxypyridine-4-one derivative that forms bidentate chelates with iron using three molecules per iron ion. With a short half-life of about 2 hours, it is approved for patients aged 3 years and above with transfusion-related iron overload, including in thalassemia and sickle cell disease.
In select cases of transfusion-induced iron overload, especially when the underlying condition (e.g., leukemia or aplastic anemia) is curable and the patient’s hematologic status allows, therapeutic phlebotomy may be used to reduce iron stores. However, unlike in hereditary hemochromatosis, phlebotomy is generally not feasible in anemic patients, which is common in TIO. In such scenarios, phlebotomy is typically reserved for patients in remission or post-transplant recovery with stable hemoglobin levels, making it a supportive but limited procedural intervention in TIO management.
Management of TIO typically follows a phased approach—beginning with the initiation phase, where iron chelation therapy starts once serum ferritin consistently exceeds 1000 mcg/L or after approximately 20 transfusions. This is followed by the intensification phase, during which therapy is adjusted based on iron burden and organ involvement to prevent complications. Finally, the maintenance phase aims to sustain safe iron levels, minimize toxicity, and tailor treatment to transfusion needs and patient response, ensuring long-term organ protection.
The body cannot actively excrete excess iron, which is normally balanced through minimal daily losses. However, patients receiving frequent blood transfusions for conditions like thalassemia major, sickle cell disease, and other chronic anemias are at risk of iron overload. Each transfused unit contains 200–250 mg of iron, which accumulates in organs such as the liver, heart, and endocrine glands, potentially leading to serious complications.
Iron chelation therapy is essential to prevent toxic buildup, and improvements in iron metabolism management have significantly increased survival in transfusion-dependent patients. Liver disease is the most common complication, while heart damage from iron overload is a leading cause of death in thalassemia major. Regular monitoring with blood tests and MRI helps assess iron levels, and early initiation of chelation therapy is crucial for preventing life-threatening outcomes.
In the U.S., around 15,000 individuals with sickle cell disease and 4,500 with myelodysplastic syndromes or other refractory anemias rely on regular blood transfusions. Globally, nearly 100,000 patients require ongoing transfusions. Transfusions typically begin at age 4 in children with thalassemia and around age 12 in those with sickle cell disease. Among adults, transfusion therapy usually starts at about age 40 for aplastic anemia and age 60 for myelodysplastic syndromes.
The occurrence of iron overload from transfusions differs worldwide, influenced by the availability of early screening and preventive strategies. Studies show that delayed puberty affects roughly half of males and females with thalassemia. In one cohort, only a third of patients with thalassemia major received regular iron chelation therapy, while the remainder were on intermittent or no treatment—leading to iron overload in over 85% of cases.
Regional differences also exist in organ-specific iron deposition. Patients in Western countries and the Far East exhibit greater iron buildup in the heart compared to those in the Middle East. In Japan, a review of 1,109 iron overload cases found that over 93% were related to transfusions. Similarly, a study from Greece reported that more than half of patients with transfusion-dependent thalassemia major had moderate to severe iron overload, with serum ferritin levels exceeding 2,000 mcg/L and 4,000 mcg/L, respectively.
Iron toxicity often remains asymptomatic for years. In transfusion-related cases, the body’s iron regulation becomes disrupted, leading to accumulation that can harm various organs. Long-term iron overload can result in cardiomyopathy, liver cirrhosis, hormonal imbalances, and joint damage.
The liver acts as the main storage site for excess iron, storing it as ferritin and hemosiderin. Unlike ferritin, which circulates in the blood and can be accessed when needed, hemosiderin is an insoluble storage form trapped in tissues and unavailable for immediate use. When transferrin—the main iron transporter—is saturated, levels of labile plasma iron (LPI) increase.
LPI is highly reactive and harmful, capable of generating free radicals that damage DNA, proteins, and cell membranes. Ferritin helps buffer this toxicity, but once overwhelmed, reactive oxygen species (ROS) can cause cellular damage and trigger apoptosis in affected organs. Elevated ROS also reduce nitric oxide availability, contributing to blood vessel injury.
In some conditions like beta-thalassemia, iron overload is worsened by increased intestinal absorption. In thalassemia intermedia, ineffective red blood cell production stimulates erythropoietin, suppresses hepcidin, and promotes excessive dietary iron uptake. In contrast, thalassemia major patients—who mainly receive iron through transfusions—tend to have elevated hepcidin due to the high iron load, despite a lower erythropoietic drive.
Iron overload from transfusions is directly linked to the number of transfused blood units. Conditions like β-thalassemia major, myelodysplastic syndromes, sickle cell disease, aplastic anemia, and hemolytic anemia often require repeated transfusions, inevitably leading to iron buildup. Each unit of transfused blood adds about 200–250 mg of iron, and receiving more than 10–20 units significantly increases the risk of overload. Since the human body lacks a natural mechanism to eliminate excess iron, its absorption and recycling must be tightly regulated.
Hepcidin, a key hormone, controls iron balance by inhibiting ferroportin, the iron exporter on macrophages and intestinal cells. Daily red blood cell breakdown by macrophages reclaims about 25 mg of iron, mainly in the reactive ferrous (Fe²⁺) form. This form induces ferritin production to convert it into the less reactive ferric (Fe³⁺) form, which binds to transferrin for safe transport.
When transferrin is saturated, excess iron circulates as non-transferrin-bound iron (NTBI), also known as labile plasma iron (LPI). This form of iron is highly toxic and is taken up by tissues like the heart, liver, pancreas, and endocrine glands, which normally do not store iron unless exposed to pathological conditions.
Hepcidin also influences how much iron is released into the bloodstream. It rises during inflammation or iron excess and drops during anemia, hypoxia, or increased red blood cell production. In diseases like thalassemia and aplastic anemia, ineffective erythropoiesis lowers hepcidin, worsening iron overload even in patients receiving regular transfusions.
The introduction of iron chelation therapy, particularly with deferoxamine in the 1980s, has significantly reduced complications associated with iron overload. In Italy, among patients with thalassemia major who began subcutaneous deferoxamine treatment, cardiac-related deaths by age 20 dropped from 5% to 1%. The prevalence of endocrine issues such as hypogonadism, diabetes, and hypothyroidism also declined.
Despite these advances, a retrospective Italian study of 912 transfusion-dependent β-thalassemia patients over a 10-year period showed that those with average serum ferritin levels above 2145 ng/mL had a 7.1 times higher risk of death from any cause compared to those with lower levels. Similarly, liver iron concentrations above 8 mg/g were linked to a 20.2-fold increased risk of mortality.
Survival outcomes have improved over time, especially among individuals born in more recent decades and among female patients. In one long-term study, 68% of thalassemia patients were still alive at age 35, though heart disease accounted for 67% of the deaths.
However, in patients who start chelation therapy late or do not adhere to treatment, dangerously high liver iron levels (over 15 mg/g dry weight) can persist, greatly increasing the risk of cardiac complications and premature death. Prolonged periods of elevated serum ferritin are similarly linked to a higher incidence of heart-related mortality.
Age Group:
Children and adolescents: May present with stunted growth, delayed puberty, or delayed menarche.
Adults: Typically show cardiac, hepatic, and endocrine complications.
On physical examination, patients with transfusion-induced iron overload may present with several systemic findings. General features can include bronze or gray discoloration of the skin, easy bruising, cachexia, and in children, delayed growth and puberty. Cardiac signs may involve jugular venous distention, an S3 gallop rhythm, pleural effusion, and peripheral edema—indicating possible heart failure. Pulmonary examination may reveal lung crepitations and a loud second heart sound (P2). Abdominal findings often include ascites, tenderness, hepatomegaly, splenomegaly, caput medusae, and umbilical hernia, which suggest advanced liver involvement such as cirrhosis and portal hypertension. Neurologically, signs of hepatic decompensation may be evident through the presence of asterixis and hepatic encephalopathy.
Chronic transfusion-dependent anemias such as β-thalassemia major, sickle cell disease, myelodysplastic syndromes, aplastic anemia, and hemolytic anemia.
History of multiple transfusions and possible poor chelation therapy compliance.
Chronic and progressive in nature.
Symptoms develop gradually over time but can become acute if complications (e.g., heart failure or cirrhosis) decompensate.
Alcoholic cirrhosis
Arthritis
Cardiomyopathy
Hemochromatosis
Type 1 Diabetes Mellitus
Hepatitis C
Type 2 Diabetes Mellitus
Management of TIO involves both non-pharmacological and pharmacological strategies, along with procedural and phased approaches. Non-drug measures include minimizing unnecessary transfusions and promoting erythropoiesis to reduce iron accumulation. Pharmacologic treatment centers on iron chelators: subcutaneous Deferoxamine, and oral agents like Deferasirox and Deferiprone, tailored based on iron burden and patient profile. Therapeutic phlebotomy is occasionally used in stable patients but is limited due to anemia in most cases. Management follows distinct phases—initiation (starting chelation once ferritin >1000 mcg/L), intensification (dose adjustment based on iron burden), and maintenance (long-term iron control and organ protection).
Hematology
While iron chelation remains the cornerstone of therapy, non-drug strategies can help minimize iron accumulation. These include:
Avoiding unnecessary transfusions
Using the minimum effective transfusion dose
Encouraging erythropoiesis through supportive therapies where applicable
Such measures can reduce the rate of iron loading and help delay the need for chelation or enhance its effectiveness.
Hematology
Deferoxamine (Desferal mesylate): It is a siderophore-derived iron chelator obtained from Streptomyces pilosus, primarily used for managing transfusion-induced iron overload. Administered typically as a slow subcutaneous infusion via a portable pump, it forms a 1:1 hexadentate complex with iron, binding approximately 8 mg of iron per 100 mg of drug. Its short half-life (20–30 minutes) necessitates continuous infusion to maximize efficacy, particularly for chelating iron from ferritin and hemosiderin, though it does not affect iron bound to transferrin or within hemoglobin and cytochromes. The drug promotes iron excretion via urine and feces, causing a characteristic red discoloration of urine. The initial dosing is 30 mg/kg/day infused over 8–12 hours, five days a week, with adjustments based on iron status. It is supplied as 500 mg lyophilized vials requiring reconstitution before administration, suitable for intramuscular or slow intravenous infusion.
Deferasirox (Exjade): It is an oral iron chelator available as tablets for suspension, binds iron in a 2:1 tridentate complex and is approved for chronic transfusional iron overload. It is initiated when patients receive about 100 mL/kg of packed red cells and have serum ferritin levels persistently above 1000 mcg/L. The typical dose is 20 mg/kg/day, titrated based on iron burden.
Deferiprone (Ferriprox): It is another oral agent, a hydroxypyridine-4-one derivative that forms bidentate chelates with iron using three molecules per iron ion. With a short half-life of about 2 hours, it is approved for patients aged 3 years and above with transfusion-related iron overload, including in thalassemia and sickle cell disease.
Hematology
In select cases of transfusion-induced iron overload, especially when the underlying condition (e.g., leukemia or aplastic anemia) is curable and the patient’s hematologic status allows, therapeutic phlebotomy may be used to reduce iron stores. However, unlike in hereditary hemochromatosis, phlebotomy is generally not feasible in anemic patients, which is common in TIO. In such scenarios, phlebotomy is typically reserved for patients in remission or post-transplant recovery with stable hemoglobin levels, making it a supportive but limited procedural intervention in TIO management.
Hematology
Management of TIO typically follows a phased approach—beginning with the initiation phase, where iron chelation therapy starts once serum ferritin consistently exceeds 1000 mcg/L or after approximately 20 transfusions. This is followed by the intensification phase, during which therapy is adjusted based on iron burden and organ involvement to prevent complications. Finally, the maintenance phase aims to sustain safe iron levels, minimize toxicity, and tailor treatment to transfusion needs and patient response, ensuring long-term organ protection.
The body cannot actively excrete excess iron, which is normally balanced through minimal daily losses. However, patients receiving frequent blood transfusions for conditions like thalassemia major, sickle cell disease, and other chronic anemias are at risk of iron overload. Each transfused unit contains 200–250 mg of iron, which accumulates in organs such as the liver, heart, and endocrine glands, potentially leading to serious complications.
Iron chelation therapy is essential to prevent toxic buildup, and improvements in iron metabolism management have significantly increased survival in transfusion-dependent patients. Liver disease is the most common complication, while heart damage from iron overload is a leading cause of death in thalassemia major. Regular monitoring with blood tests and MRI helps assess iron levels, and early initiation of chelation therapy is crucial for preventing life-threatening outcomes.
In the U.S., around 15,000 individuals with sickle cell disease and 4,500 with myelodysplastic syndromes or other refractory anemias rely on regular blood transfusions. Globally, nearly 100,000 patients require ongoing transfusions. Transfusions typically begin at age 4 in children with thalassemia and around age 12 in those with sickle cell disease. Among adults, transfusion therapy usually starts at about age 40 for aplastic anemia and age 60 for myelodysplastic syndromes.
The occurrence of iron overload from transfusions differs worldwide, influenced by the availability of early screening and preventive strategies. Studies show that delayed puberty affects roughly half of males and females with thalassemia. In one cohort, only a third of patients with thalassemia major received regular iron chelation therapy, while the remainder were on intermittent or no treatment—leading to iron overload in over 85% of cases.
Regional differences also exist in organ-specific iron deposition. Patients in Western countries and the Far East exhibit greater iron buildup in the heart compared to those in the Middle East. In Japan, a review of 1,109 iron overload cases found that over 93% were related to transfusions. Similarly, a study from Greece reported that more than half of patients with transfusion-dependent thalassemia major had moderate to severe iron overload, with serum ferritin levels exceeding 2,000 mcg/L and 4,000 mcg/L, respectively.
Iron toxicity often remains asymptomatic for years. In transfusion-related cases, the body’s iron regulation becomes disrupted, leading to accumulation that can harm various organs. Long-term iron overload can result in cardiomyopathy, liver cirrhosis, hormonal imbalances, and joint damage.
The liver acts as the main storage site for excess iron, storing it as ferritin and hemosiderin. Unlike ferritin, which circulates in the blood and can be accessed when needed, hemosiderin is an insoluble storage form trapped in tissues and unavailable for immediate use. When transferrin—the main iron transporter—is saturated, levels of labile plasma iron (LPI) increase.
LPI is highly reactive and harmful, capable of generating free radicals that damage DNA, proteins, and cell membranes. Ferritin helps buffer this toxicity, but once overwhelmed, reactive oxygen species (ROS) can cause cellular damage and trigger apoptosis in affected organs. Elevated ROS also reduce nitric oxide availability, contributing to blood vessel injury.
In some conditions like beta-thalassemia, iron overload is worsened by increased intestinal absorption. In thalassemia intermedia, ineffective red blood cell production stimulates erythropoietin, suppresses hepcidin, and promotes excessive dietary iron uptake. In contrast, thalassemia major patients—who mainly receive iron through transfusions—tend to have elevated hepcidin due to the high iron load, despite a lower erythropoietic drive.
Iron overload from transfusions is directly linked to the number of transfused blood units. Conditions like β-thalassemia major, myelodysplastic syndromes, sickle cell disease, aplastic anemia, and hemolytic anemia often require repeated transfusions, inevitably leading to iron buildup. Each unit of transfused blood adds about 200–250 mg of iron, and receiving more than 10–20 units significantly increases the risk of overload. Since the human body lacks a natural mechanism to eliminate excess iron, its absorption and recycling must be tightly regulated.
Hepcidin, a key hormone, controls iron balance by inhibiting ferroportin, the iron exporter on macrophages and intestinal cells. Daily red blood cell breakdown by macrophages reclaims about 25 mg of iron, mainly in the reactive ferrous (Fe²⁺) form. This form induces ferritin production to convert it into the less reactive ferric (Fe³⁺) form, which binds to transferrin for safe transport.
When transferrin is saturated, excess iron circulates as non-transferrin-bound iron (NTBI), also known as labile plasma iron (LPI). This form of iron is highly toxic and is taken up by tissues like the heart, liver, pancreas, and endocrine glands, which normally do not store iron unless exposed to pathological conditions.
Hepcidin also influences how much iron is released into the bloodstream. It rises during inflammation or iron excess and drops during anemia, hypoxia, or increased red blood cell production. In diseases like thalassemia and aplastic anemia, ineffective erythropoiesis lowers hepcidin, worsening iron overload even in patients receiving regular transfusions.
The introduction of iron chelation therapy, particularly with deferoxamine in the 1980s, has significantly reduced complications associated with iron overload. In Italy, among patients with thalassemia major who began subcutaneous deferoxamine treatment, cardiac-related deaths by age 20 dropped from 5% to 1%. The prevalence of endocrine issues such as hypogonadism, diabetes, and hypothyroidism also declined.
Despite these advances, a retrospective Italian study of 912 transfusion-dependent β-thalassemia patients over a 10-year period showed that those with average serum ferritin levels above 2145 ng/mL had a 7.1 times higher risk of death from any cause compared to those with lower levels. Similarly, liver iron concentrations above 8 mg/g were linked to a 20.2-fold increased risk of mortality.
Survival outcomes have improved over time, especially among individuals born in more recent decades and among female patients. In one long-term study, 68% of thalassemia patients were still alive at age 35, though heart disease accounted for 67% of the deaths.
However, in patients who start chelation therapy late or do not adhere to treatment, dangerously high liver iron levels (over 15 mg/g dry weight) can persist, greatly increasing the risk of cardiac complications and premature death. Prolonged periods of elevated serum ferritin are similarly linked to a higher incidence of heart-related mortality.
Age Group:
Children and adolescents: May present with stunted growth, delayed puberty, or delayed menarche.
Adults: Typically show cardiac, hepatic, and endocrine complications.
On physical examination, patients with transfusion-induced iron overload may present with several systemic findings. General features can include bronze or gray discoloration of the skin, easy bruising, cachexia, and in children, delayed growth and puberty. Cardiac signs may involve jugular venous distention, an S3 gallop rhythm, pleural effusion, and peripheral edema—indicating possible heart failure. Pulmonary examination may reveal lung crepitations and a loud second heart sound (P2). Abdominal findings often include ascites, tenderness, hepatomegaly, splenomegaly, caput medusae, and umbilical hernia, which suggest advanced liver involvement such as cirrhosis and portal hypertension. Neurologically, signs of hepatic decompensation may be evident through the presence of asterixis and hepatic encephalopathy.
Chronic transfusion-dependent anemias such as β-thalassemia major, sickle cell disease, myelodysplastic syndromes, aplastic anemia, and hemolytic anemia.
History of multiple transfusions and possible poor chelation therapy compliance.
Chronic and progressive in nature.
Symptoms develop gradually over time but can become acute if complications (e.g., heart failure or cirrhosis) decompensate.
Alcoholic cirrhosis
Arthritis
Cardiomyopathy
Hemochromatosis
Type 1 Diabetes Mellitus
Hepatitis C
Type 2 Diabetes Mellitus
Management of TIO involves both non-pharmacological and pharmacological strategies, along with procedural and phased approaches. Non-drug measures include minimizing unnecessary transfusions and promoting erythropoiesis to reduce iron accumulation. Pharmacologic treatment centers on iron chelators: subcutaneous Deferoxamine, and oral agents like Deferasirox and Deferiprone, tailored based on iron burden and patient profile. Therapeutic phlebotomy is occasionally used in stable patients but is limited due to anemia in most cases. Management follows distinct phases—initiation (starting chelation once ferritin >1000 mcg/L), intensification (dose adjustment based on iron burden), and maintenance (long-term iron control and organ protection).
Hematology
While iron chelation remains the cornerstone of therapy, non-drug strategies can help minimize iron accumulation. These include:
Avoiding unnecessary transfusions
Using the minimum effective transfusion dose
Encouraging erythropoiesis through supportive therapies where applicable
Such measures can reduce the rate of iron loading and help delay the need for chelation or enhance its effectiveness.
Hematology
Deferoxamine (Desferal mesylate): It is a siderophore-derived iron chelator obtained from Streptomyces pilosus, primarily used for managing transfusion-induced iron overload. Administered typically as a slow subcutaneous infusion via a portable pump, it forms a 1:1 hexadentate complex with iron, binding approximately 8 mg of iron per 100 mg of drug. Its short half-life (20–30 minutes) necessitates continuous infusion to maximize efficacy, particularly for chelating iron from ferritin and hemosiderin, though it does not affect iron bound to transferrin or within hemoglobin and cytochromes. The drug promotes iron excretion via urine and feces, causing a characteristic red discoloration of urine. The initial dosing is 30 mg/kg/day infused over 8–12 hours, five days a week, with adjustments based on iron status. It is supplied as 500 mg lyophilized vials requiring reconstitution before administration, suitable for intramuscular or slow intravenous infusion.
Deferasirox (Exjade): It is an oral iron chelator available as tablets for suspension, binds iron in a 2:1 tridentate complex and is approved for chronic transfusional iron overload. It is initiated when patients receive about 100 mL/kg of packed red cells and have serum ferritin levels persistently above 1000 mcg/L. The typical dose is 20 mg/kg/day, titrated based on iron burden.
Deferiprone (Ferriprox): It is another oral agent, a hydroxypyridine-4-one derivative that forms bidentate chelates with iron using three molecules per iron ion. With a short half-life of about 2 hours, it is approved for patients aged 3 years and above with transfusion-related iron overload, including in thalassemia and sickle cell disease.
Hematology
In select cases of transfusion-induced iron overload, especially when the underlying condition (e.g., leukemia or aplastic anemia) is curable and the patient’s hematologic status allows, therapeutic phlebotomy may be used to reduce iron stores. However, unlike in hereditary hemochromatosis, phlebotomy is generally not feasible in anemic patients, which is common in TIO. In such scenarios, phlebotomy is typically reserved for patients in remission or post-transplant recovery with stable hemoglobin levels, making it a supportive but limited procedural intervention in TIO management.
Hematology
Management of TIO typically follows a phased approach—beginning with the initiation phase, where iron chelation therapy starts once serum ferritin consistently exceeds 1000 mcg/L or after approximately 20 transfusions. This is followed by the intensification phase, during which therapy is adjusted based on iron burden and organ involvement to prevent complications. Finally, the maintenance phase aims to sustain safe iron levels, minimize toxicity, and tailor treatment to transfusion needs and patient response, ensuring long-term organ protection.
Both our subscription plans include Free CME/CPD AMA PRA Category 1 credits.
Digital Certificate PDF
On course completion, you will receive a full-sized presentation quality digital certificate.
medtigo Simulation
A dynamic medical simulation platform designed to train healthcare professionals and students to effectively run code situations through an immersive hands-on experience in a live, interactive 3D environment.
medtigo Points
medtigo points is our unique point redemption system created to award users for interacting on our site. These points can be redeemed for special discounts on the medtigo marketplace as well as towards the membership cost itself.
Community Forum post/reply = 5 points
*Redemption of points can occur only through the medtigo marketplace, courses, or simulation system. Money will not be credited to your bank account. 10 points = $1.
All Your Certificates in One Place
When you have your licenses, certificates and CMEs in one place, it's easier to track your career growth. You can easily share these with hospitals as well, using your medtigo app.
