Download to read offline
More Related Content
Similar to Iron Overload Diagnosis, Manifestations, and Treatment
Iron Overload Diagnosis, Manifestations, and Treatment
- 1. IRON OVERLOAD Don JayricV. Depalobos, MD Level II Internal Medicine Resident Hematology Rotator Department of Internal Medicine Ospital ng Palawan July 03, 2025 ONP IM Conference Room
- 2. Objectives: ■ To presenta case presented with jaundice and splenomegaly ■ To discuss Iron Overload, its causes, pathophysiology, available treatments and complications of therapy ■ To discuss the medications available to treat Iron Overload
- 3. CASE Ragnar 31/M CC: Jaundice HPI: 2years pta noted jaundice and splenomegaly, generalized body weakness, and easy fatigability. (+) 2-3x BT every year since then FMHx: (+) Thalassemia both Sister and Brother (both expired) Hgb 72 Hct 23.7 WBC 8.8 Plt 253 Ferritin >1,000ng/mL
- 4.
- 5. CASE Ragnar 31/M CC: Jaundice HPI: 2years pta noted jaundice and splenomegaly, generalized body weakness, and easy fatigability. (+) 2-3x BT every year since then FMHx: (+) Thalassemia both Sister and Brother (both expired) Hgb 72 Hct 23.7 WBC 8.8 Plt 253 Ferritin >1,000ng/mL Final Diagnosis: Hemoglobin E with alpha and beta thalassemia; Iron Overload Treatment: BT 1U PRBC Deferiprone 500mg/tab, 1 tablet PO TID
- 6. Iron Overload ■ Increasediron intake over a sustained period – RBC transfusions (TDT) – increased iron absorption(NTDT) ■ Iron overload is inevitable – lack mechanisms to excrete excess iron. ■ Iron accumulation can damage many tissues, causing: – heart failure, cirrhosis, liver cancer, growth retardation and multiple endocrine abnormalities Taher, A. et al. Guidelines For The Management Of Transfusion-dependent Β-thalassaemia 5th Ediiton Chapter 3 p70 Tubagus, D. et al. “The Correlation between Iron Overload and Endocrine Function in Adult Transfusion-Dependent Beta- Thalassemia Patients with Growth Retardation” doi: 10.2147/JBM.S325096 https://sheehannaturalhealth.com/another-functional-medicine-success-story-iron-overload-digestion-and-immune-system/
- 7. Shash, H. Non-Transfusion-DependentThalassemia: A Panoramic Review; https://doi.org/10.3390/medicina58101496 Pinto, V. et al. ”Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series” Figure 1
- 8. Target of ironoverload (IOL) in transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) Iron Load Rate Non-Transfused: approximately 2–5 g/year Transfused: 7.5–15.1 g/year Shash, H. Non-Transfusion-Dependent Thalassemia: A Panoramic Review; https://doi.org/10.3390/medicina58101496 Pinto, V. et al. ”Management of Iron Overload in Beta-Thalassemia Patients: Clinical Practice Update Based on Case Series” Figure 1
- 9. Rate of IronLoading ■ 420 mL of donor blood contains approximately 200 mg of iron (0.48 mg/mL of whole donor blood) ■ Iron in mg/mL of blood can be estimated from 1.08 x the haematocrit of donated product ■ The equivalent of 100-200 mL of pure RBC per kg body weight per year are transfused, equivalent to 108-216 mg of iron/kg body weight, or 0.3-0.6 mg/kg/day. ■ Normal intestinal iron absorption is about 1-2 mg/day. ■ Increased iron absorption becomes significant when bone marrow expansion exceeds five times that of healthy individuals – Prevented by pretransfusion Hgb above 9g/dL (threshold of 9.5g/dL) – If not achieved, absorption can rise to 3-5mg/day
- 10. Toxicity From IronOverload Iron Toxicity Mechanisms ■ Iron is ‘kept safe’ by binding to molecules such as transferrin, ferritin, and chelators ■ Results from repeated blood transfusions or long-term increased iron absorption, generates a variety of ROS, most notably hydroxyl radicals.
- 11. Toxicity From IronOverload Distribution and Consequences of Transfusional Iron Overload
- 12. Toxicity From IronOverload Distribution and Consequences of Transfusional Iron Overload
- 13. Monitoring Of IronOverload Serum Ferritin - generally reflect body iron stores and are relatively easy and inexpensive to determine sequentially
- 14. Monitoring Of IronOverload Liver Iron Concentration - Inadequate control of LIC is linked to the risk of hepatic as well as extrahepatic damage. - Normal: 1.8 mg/g dry weight - >7 mg/g dw were associated with poor outcomes - Sustained high LIC values (above 15-20 mg/g dw) have been linked to liver fibrosis progression, liver function abnormalities, as well as increased risk of myocardial iron and cardiovascular disease. - LIC is the most reliable indicator of body iron load, which can be derived from the following formula: Total body iron stores in mg iron/kg body weight = 10.6 x LIC (in mg/g dw) - Methods of measuring Liver Iron Concentration: - Biopsy - Superconducting quantum interference device (SQUID) - MRI
- 15. Monitoring Of IronOverload Liver Iron Concentration (MRI and Biopsy)
- 16. Monitoring Of IronOverload Other Modalities: • Myocardial iron estimation: T2* and other tools • Cardiac Function • Monitoring of other organ function and iron-mediated damage • 24-hour urinary iron estimation • Plasma non-transferrin-bound iron and labile plasma iron
- 17. AIMS of IronChelation Therapy 1. Prevention Therapy The primary goal of chelation therapy is to prevent toxicity from iron The secondary goal is to maintain safe levels of body iron at all times, by balancing iron intake from blood transfusions with iron excretion by chelation (iron balance).
- 18. AIMS of IronChelation Therapy 2. Rescue Therapy Chelation therapy should therefore be initiated before toxic levels of iron have accumulated. Constant exposure to chelator can protect and reverse organ dysfunction.
- 19. AIMS of IronChelation Therapy 3. Emergency Therapy If clinical heart failure develops, urgent action is required, which usually requires changing and/or intensifying the treatment.
- 20. AIMS of IronChelation Therapy 4. Dose Adjustment of Therapy Regimens require adjustment to changing circumstances. Monitoring is important to avoid: a) under-chelation with increased iron toxicity b) over-chelation and increased chelator toxicity
- 21. AIMS of IronChelation Therapy 5. Adherence to Therapy Chelation must be taken regularly for it to work. Poor adherence can result from practical issues such as difficulty with DFO infusions, intolerance of a particular chelator, psychological/psychosocial issues, or limited accessibility.
- 22. AIMS of IronChelation Therapy 1. Prevention Therapy 2. Rescue Therapy 3. Emergency Therapy 4. Dose Adjustment of Therapy 5. Adherence to Therapy
- 23. Mechanism of Actionof Licensed Chelators
- 24. Mechanism of Actionof Licensed Chelators Deferoxamine (DFO): binds to nontransferrin bound iron (NTBI) or to iron found in ferritin forming a molecule which is later excreted via the kidneys. Deferiprone (DFP): orally bioavailable iron chelator that binds to ferric iron (Fe3+) to form a stable 1:3 iron-chelator complex which is then excreted from the body through the urine. Deferasirox (DFR): same with DFP and it also increase hepcidin levels, which can lead to the degradation of ferroportin. DFR-Iron Complexes are excreted mainly in feces.
- 25. Practical Prescribing OfIndividual Chelators
- 26. Practical Prescribing OfIndividual Chelators
- 27. Key Unwanted AdverseEffects And Monitoring Requirements
- 28. Key Unwanted AdverseEffects And Monitoring Requirements
- 29. Key Unwanted AdverseEffects And Monitoring Requirements
- 30. Key Unwanted AdverseEffects And Monitoring Requirements
- 31. Key Unwanted AdverseEffects And Monitoring Requirements
- 32. DEFEROXAMINE MONOTHERAPY DFOreduced the complications of iron overload. Age of commencing chelation is a key factor affecting. Chronic treatment is costly and inconvenient, requiring subcutaneous or intravenous infusion over at least 8 hours a day at least 5 days a week in regularly transfused patients. Adherence to therapy has been the main limiting factor to successful outcomes. Generally recommendation that therapy not be started until SF levels reach 1000 ng/mL, and with downward adjustment of dosing over chelation below this SF value.
- 33. DEFEROXAMINE MONOTHERAPY Effects onSerum Ferritin DFO has been linked to protection from heart disease and to improved survival if levels are consistently less than 2500 ng/mL with even better outcomes at levels <1000 ng/mL. Effects on Liver Iron Recommended dose of 50 mg/kg at least 5 days a week to decrease LIC to optimal levels Effects on Cardiac Iron Myocardial Iron can improve provided that treatment is given at adequate doses, frequency, and duration Continuous intravenous doses of 50-60 mg/kg/day can normalize LVEF over three months
- 34.
- 35. DEFEROXAMINE MONOTHERAPY StartingDFO Therapy: Provided that treatment is (1) begun within 2-3 years of beginning transfusion therapy, (2) administered regularly (at least 5 times a week, preferably 7 days a week), and (3) administered in adequate doses. Standard dosing and frequency: Slow subcutaneous infusion of a 10% DFO solution over 8-12 hours is recommended, a minimum of 5 days per week. Dose adjustment to avoid DFO toxicity: Therapeutic Index: <0.025. Computed at mean daily dose (mg/kg)/SF ng/mL Use of Vitamin C: 2-3mg/kg/day taken at the time of infusion
- 36.
- 37. CASE E. Amal et.Al., “Management of transfusion-dependent β-thalassemia (TDT): Expert insights and practical overview from the Middle East”
- 38. CASE E. Amal et.Al., “Management of transfusion-dependent β-thalassemia (TDT): Expert insights and practical overview from the Middle East”
- 39. Key Points: • SerialSF measurement is indicated in all TDT patients, to be conducted regularly at least every 3 months or at shorter/longer frequencies as needed based on iron overload level and iron chelation modification needs. • Chelation therapy is an effective treatment modality in improving survival, decreasing the risk of heart failure, and decreasing morbidities from transfusion-induced iron overload. • Prevention of iron accumulation using chelation therapy is preferable to rescue treatment because iron-mediated damage is often irreversible, and removal of storage iron by chelation is slow - particularly after it has escaped the liver. • Chelation therapy will not be effective if it is not taken regularly – a key aspect of chelation management is to work with patients and their families to optimize adherence.
- 40. Key Points: • GuidelinesFor The Management Of Transfusion- dependent Β-thalassaemia (Tdt) 5th Edition • Entezari, S. “Iron Chelators in Treatment of Iron Overload” • Nemeth, E. “Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis” • Pinto, V. “Management of Iron Overload in Beta- Thalassemia Patients: Clinical Practice Update Based on Case Series” • Tandara, L. “Iron metabolism: current facts and future directions”
- 41.
Editor's Notes
- #3 Hemoglobin Electrophoresis Result: The current hemoglobin electrophoresis pattern when correlated with the Complete Blood Count (done on March 03, 2025 at Adventist Hospital-Palawan) is suspicious for the presence of Hemoglobin E. However, the presence of other hemoglobin variants/hemoglobinopathies cannot be entirely ruled out. Correlation with clinical and pertinent ancillary findings as well as alpha and beta globin genotyping and gene sequencing for confirmation. Beta thalassemia is generally more severe than alpha thalassemia because it disrupts the production of beta-globin chains, which are essential for forming normal adult hemoglobin (HbA). In contrast, alpha thalassemia affects the production of alpha-globin chains, but the body can compensate to some extent by producing other types of hemoglobin like HbF (fetal hemoglobin) and HbH. This difference in compensation leads to more profound and widespread consequences in beta thalassemia, often requiring lifelong blood transfusions and leading to more severe complications.
- #4 Hemoglobin Electrophoresis Result: The current hemoglobin electrophoresis pattern when correlated with the Complete Blood Count (done on March 03, 2025 at Adventist Hospital-Palawan) is suspicious for the presence of Hemoglobin E. However, the presence of other hemoglobin variants/hemoglobinopathies cannot be entirely ruled out. Correlation with clinical and pertinent ancillary findings as well as alpha and beta globin genotyping and gene sequencing for confirmation.
- #5 Hemoglobin Electrophoresis Result: The current hemoglobin electrophoresis pattern when correlated with the Complete Blood Count (done on March 03, 2025 at Adventist Hospital-Palawan) is suspicious for the presence of Hemoglobin E. However, the presence of other hemoglobin variants/hemoglobinopathies cannot be entirely ruled out. Correlation with clinical and pertinent ancillary findings as well as alpha and beta globin genotyping and gene sequencing for confirmation.
- #6 Hemoglobin Electrophoresis Result: The current hemoglobin electrophoresis pattern when correlated with the Complete Blood Count (done on March 03, 2025 at Adventist Hospital-Palawan) is suspicious for the presence of Hemoglobin E. However, the presence of other hemoglobin variants/hemoglobinopathies cannot be entirely ruled out. Correlation with clinical and pertinent ancillary findings as well as alpha and beta globin genotyping and gene sequencing for confirmation.
- #7 Iron overload occurs when iron intake is increased over a sustained period, either as a result of red blood cell (RBC) transfusions or from increased iron absorption through the gastrointestinal tract. Both occur in β-thalassaemia syndromes, with blood transfusion being the major cause in transfusion-dependent β-thalassaemia (TDT) whereas increased gastrointestinal absorption is more important in non-transfusion dependent β-thalassaemia (NTDT) Iron overload is inevitable with repeated transfusions because humans lack mechanisms to excrete excess iron. Iron accumulation can damage many tissues, causing heart failure, cirrhosis, liver cancer, growth retardation and multiple endocrine abnormalities like hypogonadism, growth hormone deficiency, hypothyroidism, and diabetes mellitus.
- #9 Labile cellular iron (LCI), released after phagocytosis of transfused red blood cells by the reticuloendothelial system, binds to circulating plasma transferrin (two Fe3+ molecules). When the transferrin iron-binding ability is exceeded (transferrin saturation 60–80%), the non-transferrin-bound iron (NTBI) appears in the plasma and accumulates in different types of cells: hepatocytes, cardiomyocytes, and pituitary and pancreatic cells. In particular, a highly reactive Fe2+ subspecies of NTBI, labile plasma iron (LPI), can enter cells through calcium channels that are not regulated by intracellular iron concentration. Reactive oxygen species (ROS) produced by NTBI/LPI and LCI contribute to oxidant damage, cellular dysfunction, apoptosis, fibrosis, and necrosis in target organs, including the myocardium, liver, and endocrine glands. Iron transport through these channels is organ-specific and may explain the different loading rates observed by MRI [33]. Likewise, the rate of iron unloading in the liver is much faster than in the heart and endocrine organs [33]. Each unit of transfused packed RBCs (PRBCs) contains 200–250 mg of iron; therefore, 4800–12,000 mg of iron per year (2–4 PRBCs/month) is introduced in a usual transfusion regimen for a TDT patient, compared to 400–700 mg of iron absorbed from the diet per year, which is lost through cell sloughing and bleeding. In TDT, the predominant mechanism of IOL is secondary to transfusion therapy (Figure 1). In NTDT, IOL is a process that accumulates iron with advancing age, and it develops even in the absence of regular RBC transfusions. Secondary hepcidin suppression and enhanced intestinal absorption lead to preferential portal and subsequent hepatocyte iron loading and relatively lower levels of serum ferritin compared to TDT patients [31] (Figure 1). In NTDT, iron accumulation preferentially occurs in the liver rather than the myocardium
- #10 In transfused patients, a unit processed from 420 mL of donor blood contains approximately 200 mg of iron (0.48 mg/mL of whole donor blood). For RBC preparations with variable haematocrits, the iron in mg/mL of blood can be estimated from 1.08 x the haematocrit of donated product The iron content is the same for units that are packed, semi-packed, or diluted in additive solution. In TDT patients receiving transfusions as per these Guidelines, the equivalent of 100-200 mL of pure RBC per kg body weight per year are transfused, equivalent to 108-216 mg of iron/kg body weight, or 0.3-0.6 mg/kg/day. This increases body iron stores to many times the norm, unless chelation treatment is provided. In TDT patients, the rate of dietary iron absorption is small relative to iron accumulated from blood transfusion. Normal intestinal iron absorption is about 1-2 mg/day, this increases in β-thalassaemia secondary to expansion of red cell precursors and consequent inhibition of hepcidin synthesis in the liver. Increased iron absorption becomes significant when bone marrow expansion exceeds five times that of healthy individuals. Such expansion can be prevented by using transfusion regimens that keep the pretransfusion haemoglobin above 9 g/dL (a threshold of ≥9.5 g/dL is recommended in the Guidelines, see Chapter 2). When such haemoglobin values are not achieved, absorption can rise to 3-5 mg/day, representing an additional 1-2 g of iron loading per year.
- #11 In health, iron is ‘kept safe’ by binding to molecules such as transferrin, but in iron overload the capacity to bind iron is exceeded both within cells and in plasma. The iron not bound to transferrin is iron is highly reactive, alternating between two states, Fe3+ and Fe2+, with the latter leading to generation of harmful free radicals (atoms or molecules with unpaired electrons) damaging many tissues unless eliminated or buffered by chelator. In iron overload resulting from repeated blood transfusions or long-term increased iron absorption, iron that is not bound to naturally occurring molecules, such as transferrin or ferritin, or to therapeutic iron chelators, generates a variety of ROS, most notably hydroxyl radicals. *Hydroxyl Radicals contribute to cellular damage by attacking DNA, proteins, and lipids, potentially leading to mutations, protein misfolding, and lipid peroxidation, which can disrupt cellular function and contribute to various diseases. This occurs in cells where labile plasma iron is taken up and accumulates as storage iron (ferritin and haemosiderin). ROS generate lipid peroxidation and organelle and DNA damage and dysregulate mechanisms involved in apoptotic cell death, increasing the risk of neoplasia such as hepatoma. These free radicals can damage lipid membranes, organelles and DNA, causing cell death and the generation of fibrosis. Free iron also increases the risk of infections and neoplasia. Labile iron is also more available to microorganisms than iron bound to transferrin or ferritin, thereby increasing the risk of infection. Labile cellular iron (LCI), released after phagocytosis of transfused red blood cells by the reticuloendothelial system, binds to circulating plasma transferrin (two Fe3+ molecules). When the transferrin iron-binding ability is exceeded (transferrin saturation 60–80%), the non-transferrin-bound iron (NTBI) appears in the plasma and accumulates in different types of cells: hepatocytes, cardiomyocytes, and pituitary and pancreatic cells. In particular, a highly reactive Fe2+ subspecies of NTBI, labile plasma iron (LPI), can enter cells through calcium channels that are not regulated by intracellular iron concentration. Reactive oxygen species (ROS) produced by NTBI/LPI and LCI contribute to oxidant damage, cellular dysfunction, apoptosis, fibrosis, and necrosis in target organs, including the myocardium, liver, and endocrine glands. Iron transport through these channels is organ-specific and may explain the different loading rates observed by MRI [33]. Likewise, the rate of iron unloading in the liver is much faster than in the heart and endocrine organs [33]. Each unit of transfused packed RBCs (PRBCs) contains 200–250 mg of iron; therefore, 4800–12,000 mg of iron per year (2–4 PRBCs/month) is introduced in a usual transfusion regimen for a TDT patient, compared to 400–700 mg of iron absorbed from the diet per year, which is lost through cell sloughing and bleeding. In TDT, the predominant mechanism of IOL is secondary to transfusion therapy (Figure 1). In NTDT, IOL is a process that accumulates iron with advancing age, and it develops even in the absence of regular RBC transfusions. Secondary hepcidin suppression and enhanced intestinal absorption lead to preferential portal and subsequent hepatocyte iron loading and relatively lower levels of serum ferritin compared to TDT patients [31] (Figure 1). In NTDT, iron accumulation preferentially occurs in the liver rather than the myocardium
- #12 Most of the body iron is incorporated in hemoglobin of circulating erythrocytes (60-70%) . Approximately 20-30% of iron in the body is in the form of ferritin and hemosiderin in hepatocytes and RES macrophages as a spare iron . The amount of iron bounded to trans- ferrin is about 3 mg but plasma transferrin compartment functions as transit compartment through which flows about 20 mg of iron each day . Under circumstances of iron overload NTBI can appear in plasma . The bone marrow is the main consumer of circulating iron . 18-20 mg of iron, mostly recycled, is used for hemoglobin synthesis in 200 billion new erythrocytes every day . Healthy people absorb 1-2 mg of iron per day which compensates for iron loss . NTBI - non-transferin bound iron; RBCs - red blood cells; Tf - transferrin .
- #13 In the absence of iron overload, iron uptake into cells is controlled by the interaction of transferrin with its receptors – mainly on red cell precursors, hepatocytes and dividing cells. In iron overload, transferrin iron binding becomes saturated, and iron species appear in plasma that are not bound to transferrin (plasma NTBI). The distribution and mechanisms of NTBI uptake into cells is fundamentally different from transferrin-mediated uptake (Figure 2). The main routes of iron turnover and uptake are shown by solid red arrows on the right panel: 20 mg of iron is delivered daily to the erythron in health. This increases several fold in untransfused β- thalassaemias but can be inhibited by transfusion. NTBI is generated when transferrin (which is about 30% saturated in healthy adults) becomes saturated. Transferrin saturation occurs following iron overload of the macrophage system, but also as a result of decreased clearance of transferrin iron in transfused patients. The organs in which NTBI is taken up and retained as storage iron are shown on the left, with >80% cleared by hepatocytes. Despite variable and lower quantities of iron taken into other tissues, serious and often irreversible iron-mediated damage may occur. Iron excretion by chelation therapy acts mainly at sites (1) the interception of iron released from macrophages after red cell catabolism, and (2) iron released by the catabolism of ferritin within hepatocytes. Macrophages in the liver (Kupffer cells) also load with iron by phagocytosis of senescent autologous or transfused RBCs. Breakdown of the resulting haemoglobin in the hepatic reticuloendothelial macrophages produces intracellular reactive Fe2+ which stimulates production of ferritin. Ferritin internalises reactive Fe2+ and converts it to non-toxic Fe3+ for storage. The stored Fe3+ is converted back to Fe2+ for release from liver macrophages, so there is toxic exposure on the way into and out of storage but the stored Fe3+ is not reactive. Liver iron concentration (LIC) reflects total body iron and increases linearly with number of transfusions in the absence of effective chelation [12]. Organ damage in transfusional iron overload reflects the pattern of NTBI uptake into tissues. Some tissues are spared, while others such as myocardial muscle, endocrine tissue, and hepatocytes take up NTBI rapidly. This iron is then stored as ferritin or haemosiderin which are visible by magnetic resonance imaging (MRI), often at different rates [13]. Without chelation therapy, myocardial iron overload can induce heart failure, as early as the second decade (see Chapter 4). Iron overload also damages the anterior pituitary leading to hypogonadism, growth retardation, and delayed puberty. Endocrine complications, namely diabetes mellitus, hypothyroidism and hypoparathyroidism also occur (see Chapter 6). Liver disease with fibrosis and eventually cirrhosis are also serious complications. Hepatocellular carcinoma, particularly if concomitant chronic viral hepatitis is present can also occur (See Chapter 5) [14].
- #15 Inadequate control of LIC is linked to the risk of hepatic as well as extrahepatic damage. Normal LIC values of up to 1.8 mg/g dry weight (dw) and LIC values of up to 7 mg/g dw can be seen without apparent adverse effects on the liver, while levels >7 mg/g dw were associated with poor outcomes [20]. Sustained high LIC values (above 15-20 mg/g dw) have been linked to liver fibrosis progression [33], liver function abnormalities [34], as well as increased risk of myocardial iron and cardiovascular disease [18]. With inadequate LIC control, iron accumulates initially in the liver and later in the heart, so that high LIC can predict the risk of myocardial iron accumulation. Conversely, a falling LIC with chelation usually precedes improvement in myocardial iron [6, 35]. Thus, with chelation therapy, whilst high LIC increases the risk of cardiac iron overload, the measurement of LIC will not reliably predict concomitant myocardial iron and hence cardiac risk. Secondly, myocardial iron is removed more slowly by chelation than liver iron and so iron may be found in some patients despite currently well controlled LIC. LIC is the most reliable indicator of body iron load, which can be derived from the following formula: Total body iron stores in mg iron/kg body weight = 10.6 x LIC (in mg/g dw) [12]. Sequential measurement of LIC is the best way to determine whether body iron is increasing or decreasing with time (iron balance). While SF measurement is simple, relatively inexpensive, and can be repeated frequently, LIC determination should be considered for those patients whose SF levels deviate from expected trends (i.e., those with suspected co-existing hepatitis or patients on chelation regimens with variable or uncertain responses), as this may reduce the risk of giving either inadequate or excessive doses of chelation therapy. Since the relationship of SF to iron overload and iron balance has not yet been established, assessment of LIC may be particularly useful when new chelating regimes are being used. As mentioned earlier, at high levels of SF (>4000 ng/mL), the relationship to LIC is not linear and patients may show a fall in LIC (negative iron balance) without a clear trend in SF in the first 6-12 months. When a patient fails to show a fall in SF over several months the change in LIC can identify whether the current regimen is adequate or need to be modified. Missing the equivalent of one or two days of chelation a week with attendant return of NTBI can affect SF and extrahepatic iron loading, so close attention to adherence is critical [4].
- #17 Myocardial iron estimation: T2* and other tools The physical principles of heart iron measurement by MRI are the same as for the liver, with the additional challenge of measuring a moving object – the myocardium. Cardiac Function Sequential monitoring of LVEF can identify patients at high risk of developing heart failure [15]. When LVEF fell below reference values, there was a 35-fold increased risk of clinical heart failure and death, with a median interval to progression of 3.5 years, allowing time for intensification of chelation therapy. This approach required a reproducible method for determination of LVEF such as multigated acquisition (MUGA) scan or MRI, while echocardiography was generally too operator- dependent for this purpose. Other Organ Function In general, by the time diabetes, hypothyroidism, hypoparathyroidism, or hypogonadotropic hypogonadism have been identified, irreversible damage has set in, and the focus then becomes replacing hormones. Individuals with significant iron loading can also have partial adrenal insufficiency [56, 57] and empiric stress dosing of corticosteroids should be considered in the face of clinical decompensation of any kind. 24-hour Urinary Iron Estimation This was initially used when assessing iron excretion by DFO (about half of total iron excreted in urine) [65] or deferiprone (DFP) (over 80% of iron excreted in urine), but is not useful with DFX, as nearly all the iron is excreted in faeces. The inherent variability in daily iron excretion necessitates repeated determinations and this is not widely used in routine monitoring. Urine iron has also been used in comparing combination or monotherapy regimes containing DFP [66-68]. Plasma NTBI and LPI Assay Assays may estimate NTBI directly using a chelation capture method followed by high performance liquid chromatography (HPLC) [69] or by colorimetric analysis [70], or indirectly by exploiting the impact of labile iron species to oxidised fluorochrome, such as in the labile plasma iron (LPI) assay [71, 72]. A potential advantage of the LPI assay is that it is better suited to measurements when iron chelators are present in the plasma .
- #18 Prevention therapy: the primary goal of chelation therapy is to prevent toxicity from iron. This means that adequate levels of chelator must be present to keep reactive Fe2+ species near zero all the time. The toxicity from iron is related to sum of toxic Fe2+ exposure and the duration of time of the exposure. The secondary goal is to maintain safe levels of body iron at all times, by balancing iron intake from blood transfusions with iron excretion by chelation (iron balance).
- #19 Rescue therapy: once iron overload has occurred, iron excretion rate with chelation must exceed that accumulated from transfusion. Removal of storage iron is slow and inefficient, because only a small proportion of body iron is available for chelation at any moment. Once iron has been deposited in some tissues, damage is often irreversible. Prevention is therefore preferable to rescue. Chelation therapy should therefore be initiated before toxic levels of iron have accumulated. Constant exposure to chelator can protect and reverse organ dysfunction by buffering reactive iron even though non-reactive iron is visible by MRI [6], although functional reversal is not guaranteed, especially with endocrine organs [77].
- #20 Emergency therapy: if clinical heart failure develops, urgent action is required, which usually requires changing and/or intensifying the treatment.
- #21 Dose adjustment of therapy: regimens require adjustment to changing circumstances. Reports that refer only to whether a patient is ‘on’ or ‘off’ a particular chelation regimen miss the critical importance of tailoring dosing and frequency to the patient needs. These can be identified by careful monitoring of body iron and its distribution. Monitoring is important to avoid a) under-chelation with increased iron toxicity or b) over-chelation and increased chelator toxicity. The dosing and regimen must be adjusted periodically to take these factors into account.
- #22 Adherence to therapy: chelation must be taken regularly for it to work. This requires good adherence. Intermittent high dose chelation can induce negative iron balance but does not provide continuous protection from labile iron and also risks increased toxicity from the chelator. Poor adherence can result from practical issues such as difficulty with DFO infusions, intolerance of a particular chelator, psychological/psychosocial issues (see Chapter 12), or limited accessibility. A key role of the treating centre is the monitoring and encouragement of adherence, alongside support from the patient’s family. Regular interaction with experienced thalassaemia centre providers to review the treatment plan and provide encouragement that good adherence to chelation can bring about excellent outcomes is critical.
- #23 Prevention therapy: the primary goal of chelation therapy is to prevent toxicity from iron. This means that adequate levels of chelator must me present all the to time keep reactive Fe2+ species near zero all the time. The toxicity from iron is related to sum of toxic Fe2+ exposure and the duration of time of the exposure. The secondary goal is to maintain safe levels of body iron at all times, by balancing iron intake from blood transfusions with iron excretion by chelation (iron balance).
- #24 Figure 3. Maintenance of systemic iron homeostasis by action of hepatic hormone hepcidin . Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of iron regulatory hormone hepcidin . Hepcidin is negative regulator of iron metabolism that represses iron efflux from sites of main iron flow: macrophages, he- patocytes and enterocytes decreasing thus transferrin saturation and reducing iron availability . Iron deficiency, hypoxia/anemia and increased erythropoietic activity decrease hepcidin expression while iron overload (except HH) and inflammation increase it .
- #25 Ferroportin plays a crucial role in iron absorption by acting as the primary iron exporter on the basolateral membrane of intestinal cells (enterocytes). It transports iron from inside the enterocyte into the bloodstream, making it available for the rest of the body. This process is tightly regulated by the hormone hepcidin, which controls ferroportin's activity and thus systemic iron levels. Central role of hepcidin in iron metabolism. Hepcidin produced by hepatocytes down-regulates iron export to circulating transferrin from iron ‘donor’ cells (hepatocytes, macrophages and duodenal enterocytes) by promoting the internalization and lysosomal degradation of ferroportin. Hepatocytes take up iron in a number of forms, whereas enterocytes obtain their iron predominantly from the gut lumen (see Fig. 11.4) and macrophages are specialized to deal with the high throughput of iron from senescent red cells. Figure 3. Maintenance of systemic iron homeostasis by action of hepatic hormone hepcidin . Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of iron regulatory hormone hepcidin . Hepcidin is negative regulator of iron metabolism that represses iron efflux from sites of main iron flow: macrophages, he- patocytes and enterocytes decreasing thus transferrin saturation and reducing iron availability . Iron deficiency, hypoxia/anemia and increased erythropoietic activity decrease hepcidin expression while iron overload (except HH) and inflammation increase it .
- #26 Figure 1: Deferoxamine, deferiprone, and deferasirox mechanism of action in the management of iron overload. Deferoxamine binds to nontransferrin bound iron (NTBI) or to iron found in ferritin forming a molecule which is later excreted via the kidneys. Deferoxamine also promotes ferritin degradation in lysosomes. To determine how ferritin gains entry into the lysosome, we focused on autophagy. Autophagy is one of the few mechanisms known by which cytosolic proteins gain access to the lysosomal lumen. Deferiprone and deferasirox chelate cytosolic labile iron. Besides, deferasirox can increase the levels of hepcidin that results in the degradation of ferroportin. Deferiprone (DFP): Mechanism: DFP is an orally bioavailable iron chelator that binds to ferric iron (Fe3+) to form a stable 1:3 iron-chelator complex. Cellular Entry: DFP can readily enter cells and access intracellular iron pools, including the cytosol. Chelation: Once inside the cell, DFP binds to cytosolic labile iron, effectively removing it from the cellular environment. Excretion: The DFP-iron complex is then excreted from the body, primarily through the urine. Deferasirox (DFR): Mechanism: Deferasirox is also an orally active iron chelator that preferentially binds to ferric iron (Fe3+). Cellular Entry: Similar to DFP, deferasirox can also penetrate cells and access intracellular iron, including the cytosol. Chelation: Deferasirox effectively chelates cytosolic labile iron, reducing its concentration within the cell. Excretion: The deferasirox-iron complex is mainly eliminated through the feces. Hepcidin Modulation: Deferasirox can also increase hepcidin levels, which can lead to the degradation of ferroportin, a protein involved in iron export, further impacting iron homeostasis. Key Differences: Binding Ratio: DFP forms a 1:3 complex with iron, while deferasirox primarily binds to ferric iron. Excretion Pathway: DFP-iron complexes are excreted primarily in the urine, while deferasirox-iron complexes are excreted mainly in the feces. In summary: Both deferiprone and deferasirox are effective in chelating cytosolic labile iron, but they differ in their precise mechanisms of action and excretion pathways.
- #34 DFO was first introduced in the late 1960s and gradually reduced the complications of iron overload and, when taken sufficiently regularly and at sufficient doses, improved survival progressively. Age of commencing chelation is a key factor affecting survival [17, 21, 23] as well as comorbidities such as hypogonadism [118] and other endocrine disturbances, including diabetes mellitus [16, 17, 23]. However, chronic treatment is costly and inconvenient, requiring subcutaneous or intravenous infusion over at least 8 hours a day at least 5 days a week in regularly transfused patients. Adherence to therapy has been the main limiting factor to successful outcomes [7]. Over-chelation can also be a problem, particularly in children or when doses are not modified for age or level of iron overload. Because of such concerns, guidelines have been conservative, generally recommending that therapy not be started until SF levels reach 1000 ng/mL, and with downward adjustment of dosing over chelation below this SF value.
- #35 8.1.2. Effects on serum ferritin Long-term control of SF with DFO has been linked to protection from heart disease and to improved survival if levels are consistently less than 2500 ng/mL [16] with even better outcomes at levels <1000 ng/mL [17]. Control of SF is dependent on dose and frequency of use compared with transfusional iron loading rate [8]. For example, a mean daily dose of 42 mg/kg resulted in a small mean decrease in SF over one year, whereas 51 mg/kg resulted in a decrease of approximately 1000 ng/mL [106]. 8.1.3. Effects on liver iron A mean dose of 37 mg/kg stabilised LIC for baseline LIC values of between 3 and 7 mg/g dw [106]. At LIC values >14 mg/g dw, a mean dose of 51 mg/kg resulted in LIC decreases of 6.4 mg/g dw. Thus, a dose of 50 mg/kg at least 5 days a week is recommended, if a decrease to optimal LIC levels is required once growth has ceased. It should be emphasised that these are average changes and that the dose required varies with the transfusional iron rate [8]. 8.1.4. Effects on cardiac iron Myocardial iron, as estimated by mT2*, can improve with either subcutaneous or intravenous DFO, provided that treatment is given at adequate doses, frequency, and duration. Improvement in mild to moderate cardiac iron, even at low intermittent doses (5 days a week), has been confirmed [119, 120].
- #37 Starting DFO therapy: provided that treatment is (1) begun within 2-3 years of beginning transfusion therapy, (2) administered regularly (at least 5 times a week, preferably 7 days a week), and (3) administered in adequate doses, DFO has a well-established impact on survival and on cardiac and other complications of iron overload. In TDT, this should start before transfusions have deposited enough iron to cause tissue damage. Current practice is to start after the first 10-20 transfusions, or when SF level approaches 1000 ng/mL. If chelation therapy begins before 3 years of age, particularly careful monitoring of growth and bone development is advised, along with reduced dosage. Standard dosing and frequency: slow subcutaneous infusion of a 10% DFO solution over 8-12 hours is recommended, a minimum of 5 days per week (see Table 7) for practical details on DFO infusion). In countries where pre-filled balloon infusers are available, this eases adherence to DFO. In general, average daily doses should not exceed 40 mg/kg until skeletal growth has been completed: 20-40 mg/kg for children and up to 50-60 mg/kg for adults, as an 8-12-hour subcutaneous infusion. To achieve negative iron balance in patients with average transfusion rates, 50 mg/kg/day at least 5 days a week is required. However, daily administration is preferable to maximise reduction in NTBI and thus reactive iron exposure. It is important that patients with high iron loading and those at increased risk of cardiac complications, receive adequate doses and frequency, are advised about compliance, or are considered for alternative chelator regimens. Dose adjustment to avoid DFO toxicity: at low SF levels (500-1000 ng/mL), the DFO dose needs to be reduced, and DFO-related toxicities monitored particularly carefully. Dose reductions can be guided using the therapeutic index calculated as: mean daily dose (mg/kg)/SF ng/mL, and kept at <0.025 [95]. This index is not a substitute for careful clinical monitoring. LIC may be a more reliable alternative to SF in monitoring response. Use with vitamin C: vitamin C increases iron excretion by increasing the availability of chelatable iron but if given in excessive doses, may increase the toxicity of iron. It is recommended not to give more than 2-3 mg/kg/day as a supplement, taken at the time of the DFO infusion, so that the liberated iron is rapidly chelated.