Introduction

Box

Patients with thalassaemia develop iron overload due to increased iron absorption secondary to ineffective erythropoiesis and repeated red cell transfusions. Regardless of the source, excess iron can lead to significant organ damage. The goals of treatment (more...)

Thalassaemia and ineffective erythropoiesis

Thalassaemia is characterized by abnormal globin gene expression resulting in total absence or quantitative reduction of globin chain synthesis [7,8]. Globin chain imbalance causes apoptosis of erythroid precursors, leading to both medullary and intravascular haemolysis [9]. Thalassaemia creates a state of ineffective erythropoiesis (IE), which refers to the inability to produce an adequate number of mature red blood cells (RBC) in the presence of increased immature erythroid precursors driven by anaemia [10]. Intramedullary apoptosis of erythroid precursors results in an erythroid maturation arrest and perturbation of normal iron regulatory mechanisms, leading to increased iron absorption and the release of iron from storage pools that is out of proportion to the degree of iron loading [10].

Normally, the iron regulatory peptide hepcidin increases in the presence of iron overload, blocking export of absorbed iron from enterocytes and stored iron from macrophages to reduce plasma iron [6]. Erythroferrone produced by the increased RBC progenitors seen in thalassaemia lowers hepcidin, increasing circulating iron [11]. As the result, hepcidin levels are lower than expected for the degree of iron loading. The erythroferrone-mediated suppression of hepcidin, coupled with the inability to use the iron to make mature RBC because of IE, results in iron overload [9, 10]. In transfusion-dependent thalassaemia (TDT), the iron input is much higher, and severe hepatic and, more importantly, severe endocrine and cardiac iron loading occurs because the binding capacity of transferrin is exceeded and labile plasma iron (LPI) goes up, leading to unregulated iron loading.

Iron toxicity and role of Fe²⁺

Iron toxicity is related to exposure to reactive ferrous iron (Fe²⁺), also referred to as labile plasma/cellular iron (LPI/LCI). Importantly, pathologic loading of iron into extra-hepatic sites (endocrine organs and heart) only occurs when LPI is elevated. In the absence of transfusion, the amount of iron loading is determined by the degree of IE. With transfusion, hepatic and reticuloendothelial iron loading is much greater and linearly related to the number of RBC transfused [1]. Extra-hepatic distribution of iron occurs because the iron binding capacity of transferrin is exceeded, the marrow cannot use iron to make RBC, and LPI rises. Elevated levels of LPI are pathologic and are seen in conditions with IE, such as thalassaemia [12], in contrast to conditions with effective erythropoiesis like sickle cell disease or hereditary spherocytosis where LPI is low [13, 14].

IE is an important feature of non-transfusion-dependent β-thalassaemia (NTDT-β) [15, 16] and haemoglobin H (HbH) disease (NTDT-α) [10,16], and it also occurs in TDT when the marrow is not well suppressed.

Box

Iron toxicity and subsequent organ dysfunction is related to the amount of exposure to the reactive form of iron (Fe²⁺), the duration of exposure, and the protective effects of antioxidant mechanisms [6]. Ferrous iron (Fe²⁺) reacts with hydrogen peroxide (more...)

As there are many different α- and β-thalassaemia gene mutations and combinations, there are subsequently different degrees of IE and associated exposure to LPI.

The biology of iron transport explains the relation of extra-hepatic iron loading to LPI exposure. The major source of iron in humans is recycling of senescent endogenous or transfused red cells by macrophages in the reticuloendothelial system, where internalized heme is degraded by heme oxygenase and Fe²⁺ is produced [15]. Intracellular Fe²⁺, also called labile cellular iron (LCI), is either stored in ferritin, which converts Fe²⁺ to non-reactive ferric iron (Fe³⁺), or is released into the plasma through the iron export protein, ferroportin [6]. Ferrous iron is then converted to non-toxic Fe³⁺ by plasma ceruloplasmin upon exiting the cell through ferroportin, where it binds to the transport protein transferrin. Ferritin production is driven by high levels of Fe²⁺ in the cytoplasm (LCI), as well as the inflammatory cytokine IL-6 [19].

Transferrin binds two molecules of Fe³⁺ and transferrin-bound iron (TBI) enters the cell through receptor-mediated endocytosis after binding to transferrin receptor-1 (TfR1) [6,10], which is expressed on the surface of nearly every cell type. Normally, in the presence of excess LCI, TfR1 is downregulated, preventing intracellular entry of TBI and protecting cells from iron overload [20]. Liver is one of the few cell types that also possess transferrin receptor-2 (TfR2), which is not downregulated by high LCI, allowing the liver to load via transferrin even when intracellular Fe²⁺ is high and additionally allowing TfR2 to serve as the iron sensor. Since humans have no way to excrete excess iron, and there is substantial iron in transfused RBC (0.8 mg/mL), iron levels achieved by recurrent transfusion are significantly higher than those achieved by the increased iron absorption due to IE alone. Under normal circumstances, this elegant system keeps iron absorption and losses in balance.

Normally, about 20% to 30% of transferrin is bound to Fe³⁺. Non-transferrin-bound iron (NTBI) can be detected in plasma as soon as transferrin saturation reaches 35%, rising significantly when transferrin saturation exceeds 70% to 80% [4, 5], making transferrin saturation a reasonable clinical surrogate for NTBI/LPI. NTBI is mainly ferric-citrate and is in equilibrium with the loosely bound and highly reactive Fe²⁺ subspecies of NTBI, LPI [4]. The heart and endocrine organs are protected from import of transferrin-bound iron through downregulation of TfR1. However, if LPI (Fe²⁺) is present, it can enter these organs non-physiologically through divalent ion transporters for Ca²⁺ and Zn²⁺ that are not regulated by iron. Importantly, pathologic extra-hepatic iron deposition (pancreas, pituitary, heart) only develops when NTBI/LPI is present, making iron loading of extra-hepatic sites an indicator of exposure to toxic LPI [6, 21]. When iron loading occurs due to iron absorption only, as in NTDT, it takes decades for enough iron to load so that transferrin saturation is exceeded and NTBI/LPI appears, and the heart and endocrine organs load. In TDT, this can happen within a much shorter time such that extra-hepatic loading may be seen by a year or two of life with severe IE or no erythropoietic activity [22, 23].

This physiology is very important clinically, because iron chelators immediately drop circulating NTBI (Fe³⁺) near zero [24], and therefore drop reactive LPI, preventing loading through divalent ion transporters and markedly reducing tissue exposure to toxic iron. Thus, for effective protection against iron toxicity, the chelator needs to circulate all the time. This also means that chelators can protect from Fe²⁺ toxicity even if the tissue iron measured by MRI (which is non-reactive Fe³⁺) is still high.

α-Thalassaemia and iron overload

Box

The α-thalassaemia syndromes differ from β-thalassaemias in that excess α-homotetramers in β-thalassaemia are more unstable than excess β-homotetramers in α-thalassaemia, causing earlier damage to red cell (more...)

Because of anaemia and poor oxygen carrying ability of the haemoglobin that is made, infants with four α-gene deletion (haemoglobin Bart’s hydrops foetalis or α-thalassaemia major) require in utero transfusions to survive until delivery [29], providing an in-utero source of iron overload. There was presence of pituitary and pancreatic iron loading by 1.5 years of age as well as increased LIC in a small series of children with α-thalassaemia major but there was no evidence of organ dysfunction in this group [23]. They had moderate to severe iron overload that responded well to chelation, but the more concerning finding was that nearly all patients had pancreatic and pituitary iron deposition prior to four years of age suggesting exposure to toxic Fe2⁺. However, this is not significantly different than other chronically transfused young children [22]. Ferritin levels were quite a bit higher at 12 months of age in α-thalassaemia major infants than in those with β-thalassaemia major, likely due to the aggressive transfusions required to suppress fast migrating haemoglobin. However, overall, the ferritins were lower that TDT-β after time in this group [30]. Interestingly, while the relation between ferritin and LIC was linear in both groups, the slopes of the relations were very different with ferritin in TDT-α (α-thalassaemia major) being significantly lower than in TDT-β at a given LIC [30]. Very interestingly, when marrow suppression was increased by increasing transfusion, the ferritin relative to LIC increased [30, 31], consistent with the increase in hepcidin relative to iron loading predicted by the biology described above [10, 11]. Patients with TDT-α seem to have intellectual, growth, and brain MRI differences at older ages [32], but these are not likely related to iron and there is no evidence that supports or refutes possible importance of in utero iron exposure and subsequent toxicity. The role of α-globin gene expression in small arterioles, its interaction with oxidants and in regulation of blood flow [33–36] and of high oxygen binding of HbH and Hb Bart’s [37] make untangling causes of organ damage in α-thalassaemia syndromes very difficult.

The development of iron overload in transfusion-dependent and non-transfusion dependent patients with α-thalassaemia syndromes appears to parallel that in transfusion-dependent and non-transfusion dependent patients with β-thalassaemia; however, there are not enough comparative data. In a series of 27 β-thalassaemia intermedia and 10 haemoglobin H disease (HbH) individuals, LIC and the relation between LIC and ferritin were the same by age 50 years in NTDT-β, although LIC was slightly lower in HbH [38]. About 46% of NTDT HbH over 18 years old had a ferritin over 800 ng/mL, and 64% had LIC greater than 5 mg/g DW compared to 56% and 72% for NTDT-β and 78% and 95% for haemoglobin E-β-thalassaemia [39]. Patients with HbH Constant Spring seem to be particularly affected, with 37% having a ferritin between 800 and 2500 ng/mL and 7% with ferritin greater than 2500, and 60% being TDT [40]. A longitudinal study of 86 patients with HbH disease demonstrated that ferritin is fairly stable throughout childhood and adolescence, then increases with age after 18 years old [41]. Patients with non-deletional HbH disease, on the other hand, often have elevated ferritin at a young age that continues to increase over time due to their transfusion dependence. Similar to what has been shown in NTDT-β and consistent with the iron biology we have described, patients with deletional ΗbH disease demonstrate preferential iron storage in the liver, sparing the heart [38]. The α-thalassaemia syndromes in general are NTDT, but some non-deletional α-thalassaemia and all α-thalassaemia major patients are transfusion-dependent. The rate and pattern of iron accumulation in NTDT-β is much slower from that of TDT-β [42], and the same seems to be true of NTDT-α and TDT-α. The complications of thalassaemia differ between TDT and NTDT, likely because transfusion suppresses IE, and thus IE-related complications like osteoporosis, bony deformity, and pulmonary hypertension are less observed. At least in NTDT-β, serum ferritin over 800 ng/mL is a strong predictor of decreased morbidity-free survival [43]. It is likely that ferritin is a reflection of severity of IE and does not imply that iron overload is causing the morbidity. The iron loading, of course, is much greater in TDT and results in more cardiac iron loading and endocrine failure. Ferritin is generally lower in NTDT than in TDT at the same LIC [44].

Clinical measurement and management of iron overload

Liver iron concentration (LIC) is the best measure of total body iron loading, as it is linearly related to total body iron content (r=0.98, p < 0.01) [1]. MRI measurement of LIC only detects aggregated ferritin-Fe³⁺ (haemosiderin) present in tissue; thus, while MRI-LIC is an excellent measure of total body iron, it represents the non-reactive Fe³⁺. Pancreatic and cardiac iron is an indicator of reactive Fe²⁺ exposure as extra-hepatic organs only load pathologically when there is circulating Fe²⁺. Of note, the pancreas loads before the heart and pituitary gland [21]. Additionally, the spleen in thalassaemia can be 30% of the volume of the liver and can contribute significantly to total body iron. There is some evidence that in the presence of treatments that modulate IE and differentially affect splenic iron, the LIC may not reflect total iron accurately [45]. Clinically relevant iron and ferritin levels are presented in Table 1.

Table 1

Monitoring iron overload and chelation

Magnetic resonance imaging (MRI) can assess LIC with greater accuracy and safety than liver biopsy, which has fallen out of favour due to sampling error and bleeding risk [2]. An estimate of total body iron by MRI assessment of LIC is the main parameter used to initiate and modify iron chelation therapy. Presence of cardiac iron or pancreatic iron means there have been prolonged periods when chelation has not been present or adequate to lower NTBI/LPI. We mention pancreatic and pituitary iron measurement here because they are helpful, even if non-essential, for management. Though the measurement does not require special equipment, the techniques are not established in more than a few centres worldwide.

Box

Ferritin levels are routinely available, correlate with total iron in populations of patients and can be used to infer total iron and change in iron. However, they can be misleading in individuals because of significant measurement-to-measurement variability (more...)

LIC measurement by MRI is the gold standard for assessing iron overload and regulating chelator dosing. Monitoring of cardiac iron by MRI is critical in all TDT patients with thalassaemia or other disorders associated with IE [2, 3].

Iron chelators are effective in reducing iron [52, 53], and they improve clinical outcome in thalassaemia [54]. Humans have no iron export mechanism, and iron overload cannot resolve in the absence of chelation therapy or chronic blood loss. Phlebotomy is not an appropriate approach in thalassaemia patients. Iron toxicity is known to cause cardiac failure, arrythmia, abnormal cardiac beat-to-beat variability, autonomic dysfunction, endocrine failure, elevated liver enzymes, and bone marrow suppression. These complications can be reversed with chelation and removal of NTBI/LPI, even when significant organ loading by Fe³⁺ measured by MRI persists. NTBI/LPI levels drop to near zero immediately upon starting chelation and return immediately when chelators stop [24]. NTBI/LPI are not seen by MRI but can be inferred by elevation of transferrin saturation and presence of iron in extra-hepatic sites (heart, pancreas). This biology informs the clinical approach to protection from iron toxicity, namely, chelator should be in circulation all the time to keep NTBI low. Removal of stored iron takes longer. Chelation takes 4 to 6 months to decrease the LIC by 50% and up to 14 months to reduce cardiac iron by 50% [55]. The presence of circulating chelator prevents entry of Fe²⁺ into extra-hepatic sites and protects from Fe²⁺-mediated oxidant damage [18, 56–58].

Box

The protective effect of chelators in the presence of high tissue Fe³⁺ is a clinically important concept and is clearly demonstrated in a study of thalassaemia patients with severe cardiac iron loading (T2* < 5.6 ms) and low ejection fraction (more...)

It seems prudent to keep the LIC between 2.5 and 3.5 mg/g DW at all times with no pancreatic or cardiac iron. You cannot achieve this without MRI monitoring and by carefully monitoring for chelator toxicity. Toxicity is particularly an issue at low LIC with deferasirox, and less so with deferiprone. If all you have is ferritin with no access to MRI iron measures, try to keep it between 300 and 800 for NTDT, and between 800 and 1500 for TDT.

Treatment guidelines for monitoring and treating iron overload in NTDT are available [51]. Basically, chelation should be started when the LIC is greater than 5 mg/g DW or the serum ferritin is greater than 500 ng/mL with a goal of keeping the LIC between 2 to 5 mg/g DW or the ferritin between 300 and 800 ng/mL [49]. Deferasirox doses in the range of 10 to 15 mg/kg/day have been suggested for NTDT [60]. We would not suggest trying to target low levels of iron if MRI measurement of LIC is not available.

Box

It is certainly true that patients with higher transfusion burden need more chelator, and experienced thalassaemia experts have recommended modulating the dose of chelator based on amount of transfusion. The major variable in chelation efficacy is adherence (more...)

The exception to this is severe cardiac iron loading (T2* less than 8 to 10 ms) and presence of heart failure or serous arrythmia. This is primarily a risk with TDT patients, and it is a medical emergency. Cardiomyopathy due to iron is almost always reversible if properly and aggressively treated. Importantly, there are very few cardiologists who are aware that this cardiomyopathy is reversible, or who are aware of the treatment, so immediately contacting a cardiologist familiar with iron cardiomyopathy is critical. The treatment is outlined in “Cardiovascular function and treatment in beta-thalassaemia major: a consensus statement from the American Heart Association” [61]. Start continuous (24/7) infusion of deferoxamine 50 mg/kg/24 hours and find a thalassaemia cardiologist. Delay in starting this chelation can be life-threatening [61].

A key issue with chelation is to work with the patient to come up with a regimen that they can tolerate and will take. We suggest combinations of medications to mitigate toxicity of the drugs. The main cause of chelation failure is adherence to prescribed medication.

Box

Organ damage from iron should be routinely monitored. There are no clear issues that differentiate α-thal NTDT/TDT from β-thalassaemia with respect to iron. We suggest monitoring growth velocity in children as a measure of pituitary function (more...)

Table 1 provides key points regarding iron overload monitoring and chelation based on our experience.

Three licensed iron chelators are available in the United States and Europe, with key differences in route of administration, half-life, and toxicities, which are summarized in Table 2. All three chelators are very effective at controlling iron individually or in combination [18]. Deferiprone is most effective at protecting and restoring cardiac function [64]. Severe renal complications with deferasirox are rare, but can be fatal and they are preventable by monitoring. Of course, adherence to therapy is more important than the chelator’s mechanism of action in removing iron deposition and protecting from iron toxicity [65], so the primary goal is to apply an effective plan that the patient can closely follow.

Table 2

Currently available iron chelators (adapted from Coates & Wood, 2017 [57])

Summary and recommendations

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