Iron overload after complement inhibitor treatment of Paroxysmal Nocturnal Hemoglobinuria
Authors: Anem Waheed, David J. Kuter
Journal: American Journal of Hematology (2021)

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon bone marrow disorder associated with hemolytic anemia, thrombosis, and cytopenias. Prior to 2007, treatment for PNH was limited and patients with PNH were treated with corticosteroids, anticoagulation for thrombosis, and iron supplementation for their chronic iron deficiency secondary to intravascular hemolysis.1 In fact a hallmark feature of PNH was iron deficiency and iron supplementation continues to be recommended as a treatment for the manifestations of PNH. With the introduction of C5 complement factor inhibitor treatments, potential long term manifestations of treatment need to be considered including the possibility of iron overload. An acquired genetic mutation in phosphatidylinositol glycan class A (PIGA) gene leads to two missing glycosylphosphatidylinositol (GPI) anchored proteins including CD55 and CD59.2 A deficiency of these complement regulatory proteins in red cells results in increased complement activation leading to intravascular hemolysis with iron loss. Therefore, many PNH patients at initial presentation have signs and symptoms of intravascular hemolysis and resultant iron deficiency. While extravascular hemolysis is also increased at disease onset, intravascular hemolysis signs and symptoms predominate prior to treatment with complement inhibitors.1 Treatment options and management for PNH were revolutionized with the approval of the C5 complement inhibitors eculizumab in 2007 and subsequently with ravulizumab in 2018.3, 4 Both complement inhibitors block terminal complement by binding to C5 and preventing formation of the membrane attack complex. Therefore, intravascular hemolysis subsides with initiation of these treatments. These patients have improvements in their hemoglobin and many no longer require blood transfusions. Notably, patients on these treatments will continue to experience significant extravascular hemolysis as the complement inhibitors do not compensate for CD55 deficiency and therefore lead to C3d deposition on PNH red cells.5 The effect of treatment on iron metabolism has not been well studied, but with reduction in intravascular hemolysis renal iron clearance should decline; in contrast, extravascular hemolysis usually results in retention of total body iron by the reticuloendothelial system. We raise the concern that C5 treatments for PNH might increase iron overload. We analyzed 5 PNH patients who started treatment with complement inhibitors and describe their baseline characteristics and subsequent outcomes (Table S1). Despite stopping oral iron supplementation, the mean increase of ferritin after 6 months of complement inhibitor treatment was 279 μg/L, indicating increased iron stores as intravascular hemolysis subsided. As indicated for each patient in the Figure 1, there was a trend to marked increases in ferritin over time with concern for possible iron overload. Indeed, Patients 1, 2 and 4 eventually demonstrated iron overload on MRI imaging; one is undergoing therapeutic phlebotomy. None of the five patients had changes in liver function tests. None had homozygosity or compound heterozygosity for the hemochromatosis genes H63D or C282Y. Hepcidin is produced in the liver and regulates iron uptake as it inhibits the activity of ferroporotin-1, the only significant cellular iron exporter.6 Hepcidin is suppressed when more iron is needed to support increased red blood cell production. Under usual conditions, hepcidin is elevated in setting of infection, inflammation, and normal iron stores. Suppression of hepcidin can lead to iron overload in setting of ineffective erythropoiesis, hereditary hemochromatosis, and hemolytic anemias such as we now postulate for PNH. We expect that the patients we have described would have low hepcidin levels prior to treatment with complement inhibitors as they are clearly iron deficient; we postulate that hepcidin might remain suppressed after complement inhibition due to the continued extravascular hemolytic anemia. We suggest that longitudinal assessment (Fe, TIBC, ferritin) be done in PNH patients being treated with C5 complement inhibitors and that iron supplementation be stopped once patients are iron replete. In those demonstrating evidence for iron overload, assessment of hepatic iron should be considered. It is certainly unclear whether treatment (iron chelators, therapeutic phlebotomy if tolerated, or future hepcidin agonists) is indicated to reduce the iron overload. The development of novel inhibitors of Complement Factor B, Complement Factor D or C3 might provide protection against both intravascular and extravascular hemolysis therefore mitigating the potential for iron overload. Iron overload remains a potentially unrecognized complication of novel treatments for PNH and warrants further investigation. Both Anem Waheed and David J. Kuter collected the data and wrote the manuscript together. Anem Waheed: None. David J. Kuter: Research: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ). Consulting: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Platelet Disorder Support Association, Principia, Protalex, Protalix, Rigel, Sanofi, Genzyme, Shionogi, Shire, Takeda (Bioverativ), UCB, Up-To-Date, Zafgen. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1 Characteristics of patients: Values are shown are pre-complement inhibitor and atleast 6 months post-complement inhibitor initiation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.