Bad liver and a broken heart

In this issue of Blood, the CORDELIA study presented by Pennell and colleagues shows that deferasirox (DFX; Exjade, Novartis) is not inferior to deferoxamine (DFO; Desferal, Novartis) for the removal of cardiac iron in β-thalassemia.¹  CORDELIA also supports previous findings²  that efficacy of cardiac iron removal is better if liver iron concentration (LIC) is low.

As discussed by the authors,¹  patients with transfusion-dependent anemia of any type rapidly become iron overloaded. Unless the excess iron is removed, patients develop pan-endocrine failure, liver failure, and ultimately death from cardiac failure or arrhythmia, usually in the second decade of life.

The development of noninvasive techniques to measure tissue iron (reviewed in Wood³ ) in the past decade resulted in tremendous advances in our understanding of clinical iron overload. The ability to sequentially monitor individual organ iron uptake and removal in humans and the current understanding of iron homeostasis (reviewed in Ganz⁴ ) allows us to begin to understand the mechanisms of transfusional iron overload in patients.

The distribution of iron loading in various organs depends in part on differences in iron-regulatory proteins. Iron levels in humans normally are controlled through modulation of iron absorption and regulation of iron recycled by macrophage phagocytosis of senescent erythrocytes. Iron enters the plasma from enterocytes and macrophages via ferroportin (FPN) and binds to plasma transferrin. Once approximately 30% of transferrin is saturated, non–transferrin-bound iron (NTBI) and labile plasma iron (LPI) begin to appear in plasma and significantly rise at Tf saturation >60%. Trf1 is plentiful in erythroid precursors and liver but is not a major regulator of uptake in endocrine organs or heart. NTBI/LPI is thought to enter the heart through voltage-regulated calcium channels and can easily enter the liver and pancreas through other non–transferrin-mediated mechanisms. Once iron enters the heart, the rate of iron transport into the heart increases significantly. FPN is the only known cellular iron exporter and is present in high levels on duodenal enterocytes, macrophages, liver, and placenta but in low levels in heart and pancreas. It is regulated at the transcriptional level and by the iron-regulatory peptide hepcidin. When hepcidin binds to FPN, it causes FPN to be internalized, blocking cellular iron export and lowering plasma iron levels. Hepcidin is made in the liver, and its expression is increased by transferrin saturation and inflammation and decreased by iron deficiency and erythroid activity. Thus, increased erythroid activity, as seen in β-thalassemia, where erythropoiesis is ineffective, decreases hepcidin, even in the face of iron overload, causing increased iron absorption (reviewed in Ganz⁴ ).

This fascinating cellular physiology has been worked out primarily in transgenic mice and cell culture. However, albeit via circumstantial evidence, these data seem to fit nicely with what is observed by magnetic resonance imaging monitoring of iron loading and unloading in humans. The liver, which can load easily via transferrin-mediated or non–transferrin-mediated processes, takes up iron very quickly. The heart and pancreas, which load primarily through non–transferrin-mediated processes, load with iron later, only after transferrin has become completely saturated, the liver has loaded, and NTBI/LPI levels have been high for a while. Conversely, iron unloads fastest (T1/2 about 4.5 months) from the liver, which expresses the iron exporter FPN, and slowest from the heart (T1/2 17 months), which contains very little FPN.³ 

What does all of this have to do with CORDELIA? First, this is a large, well-designed, and well-executed study in β-thalassemia patients with cardiac iron that clearly confirms previous single-arm studies^2,5-7  showing that DFX can reduce cardiac iron burden. Second, it demonstrates for the first time that DFX is at least as good, if not better, than DFO for the treatment of cardiac iron overload with normal cardiac function. What is most interesting about this study is the suggestion that the ability to clear cardiac iron is better in patients whose liver iron is lower to start (Figure 2D-F in Pennell et al¹ ). In particular, DFX seems to be better than DFO at clearing cardiac iron when the baseline LIC is <7 mg/g. The difference between DFO and DFX, as well as the effectiveness at lowering cardiac iron, seems to disappear when the baseline LIC is higher. This is consistent with our findings that LIC and, more importantly, the ability to clear the liver of iron predicted which patients would clear their heart with DFX.²  Considering that LPI rises quickly when LIC rises and that a decrease in LPI is associated with clearance of cardiac iron by DFX,³  it is logical to hypothesize that a lower LIC would improve clearance of cardiac iron by reducing the pool of free iron that can re-enter the heart. Table 1 is based on rough estimates from the cited articles but shows the reduction in cardiac iron in several studies where the baseline LIC could be deduced and classified in a similar fashion to CORDELIA. All studies showed a decrease in cardiac iron after 1 year, except for the “nonresponder” group in our study.²  With the exception of one study,⁸  DFO was the least effective. Whether as a single agent⁹  or in combination,^8,10  deferiprone (DFP) was the most effective at reducing cardiac iron. There is a suggestion that less cardiac clearance occurs in the high-LIC group, especially in the 2 studies that specifically addressed this question.^1,2  We cannot really tell if LIC has an effect on DFP clearance of heart iron. However, it is very clear from Table 1 that DFP is the only agent associated with significant improvement in left ventricular ejection fraction (LVEF) within 1 year.^8-10  We and others have observed LVEF improvement in selected patients after a longer treatment with chelators other than DFP.² 

Table 1 makes it clear that several chelators are available that are effective at clearing liver and cardiac iron, and future studies will help elucidate mechanisms of action. None of these studies solve the overwhelmingly largest problem in the management of transfusional iron overload, which is the fact that patients do not take their medication and that deaths continue to occur because of poor adherence.