Elna Saah, MD
In ballet, a balancé, which directly translates to “balanced” and consists of a dancer moving while balancing on alternating feet (per ballethub.com), is a foundational step for success. Complex moves can subsequently be built upon this basic step. Iron homeostasis is tightly regulated by a delicate but complex system involving the gastrointestinal tract and reticuloendothelial system. Two sessions, appropriately presented in tandem, reviewed our current understanding of the pathophysiology of iron homeostasis, starting with the landmark discovery of hepcidin, the master key to iron regulation, almost two decades ago. Hepcidin exerts an “iron-clad” grip on iron homeostasis by balancing intestinal absorption and macrophage release. The Scientific Program session “Well-regulated Vs Malfunctioning Mechanisms of Iron Metabolism” (Q&A available on demand) focused on one side of disequilibrium, disorders of iron overload (IOL). The Education Program session “Out of Balance: Anemias Due to Disordered Iron Homeostasis” (Q&A available on demand) pivoted to the other end of iron disequilibrium, focusing on conditions of iron deficiency.
The Scientific Program session mentioned above took a deep dive into the hepcidin and ferroportin axis, as the cellular mediators of iron metabolism and the resultant contribution of iron status to morbidity/mortality in diseases of ineffective hematopoiesis. Dr. Yatrik Shah described the interplay of cell autonomous oxygen signaling pathways with systemic hepcidin signaling to control intestinal iron absorption via intestinal HIF-2, suggesting therefore that intestinal HIF-2 may be essential for the local absorptive response to systemic iron deficiency and iron overload.
Dr. Francesca Vinchi elucidated the role of macrophages in iron homeostasis and inflammation. She highlighted their crucial role in the orchestration of inflammatory and tissue remodeling processes through the acquisition of distinct functional phenotypes in response to the surrounding microenvironment. Both facets are tightly interconnected: Macrophage polarization dictates the expression of iron-regulated genes and determines cell iron handling while iron availability affects macrophage immune effector functions. Recent observations support a role for free heme and iron in shaping macrophage plasticity toward a proinflammatory phenotype. These findings have implications for the pathophysiology of diseases hallmarked by elevated circulating heme and iron, including hemolytic diseases and transfusion- or intravenous iron-dependent anemias, as well as conditions associated with increased local heme and iron accumulation, including trauma, atherosclerosis, and tumors.
We caught up with Dr. Vinchi, and she left us with a few key points. First, macrophages develop different functional phenotypes according to the iron source. Second, their observation in sickle mouse models showed that free heme/iron–activated macrophages are proinflammatory and functionally defective, highlighting their implication in the proinflammatory phenotype, contributing to sterile inflammation. Besides being proinflammatory, they are functionally defective in their phagocytic and efferocytic capacity. The proinflammatory and functionally defective macrophages further support tissue damage and fibrosis in the diseased models. Conversely, transfusions induce an anti-inflammatory skewing of macrophages that could on one side contribute to the reduction of sterile inflammation in highly inflammatory disease, but on the other, reduce an effective immune cell response during pathogen infections in transfusion-dependent conditions such as myelodysplastic syndromes (MDS). Presenting their data using atherosclerotic mice models, Dr. Vinchi emphasized the third point: macrophage functional response is driven by the balance between extracellular iron levels and intracellular iron content. Iron-depleted macrophages are atheroprotective, and their exposure to excessive circulating non–transferrin bound iron induces their skewing toward a proinflammatory and proatherogenic phenotype, further aggravating the progression of atherosclerosis. The contribution of macrophages to the disease is determined by the skewing they acquire based on the balance between intracellular and extracellular iron levels. Last of the four take-home points highlighted is the potential for manipulation of heme/iron-activated macrophages for therapeutic purposes, counteracting or taking advantage of their proinflammatory properties. Once again, in their humanized sickle mouse models, they were able to block heme-mediated macrophage inflammatory skewing through therapies with the heme scavenger hemopexin or anti-inflammatory cytokines. This can also be applied in the induction of tumoral cell killing and modulation of tumor growth. Dr. Nobert Gatterman addressed the impact of iron overload and chelation in patients with MDS. He shared the current registry data, corroborated by the Telesto trial, which has shown benefit in instituting iron chelation therapy in low-risk patients with MDS.
The Education Program session tipped the scales of our attention to the other extreme — the global health issue of iron deficiency. Hepcidin, the master key protein, is responsible for control of iron absorption in the intestine and release by the macrophages. Disorders of iron deficiency could be the result of a decrease in total body iron (as in nutritional or blood loss) or a decrease in iron bioavailability (as in inflammatory states or congenital defects in iron absorption).
Dr. Kleber Fertrin discussed the challenge of diagnosing and managing iron deficiency in patients with chronic inflammatory conditions. He reviewed the evidence for monitoring of iron homeostasis, including how biomarkers of iron status behave in true iron deficiency in the setting of low-grade inflammation, clearly distilling the patients unlikely to benefit from iron supplementation. He continued explaining that where iron replacement therapy is indicated, timing of initiation and route of administration (per oral vs. parenteral) are pertinent considerations in the management of chronic inflammatory states.
Dr. Maria Domenica Cappellini provided a comprehensive overview of microcytic erythrocyte disorders. She approached them in three subgroups: the hemoglobinopathies, defects in heme synthesis, and defects in iron availability or acquisition by the erythroid precursors. She led our attention thereafter to the more increasingly recognized hereditary abnormalities that result in actual or functional iron deficiency. Most notable is iron-resistant iron deficiency anemia, a defect in iron regulation caused by a mutation in the Tempura-6 gene, responsible for hepcidin synthesis. She elaborated on how the defect results in increased hepcidin levels, which then leads to a decrease in gastrointestinal iron absorption and macrophage release.
Dr. Micahel Zimmerman provided a focus on the issue of nutritional iron deficiency, which is a major global concern affecting women, children, and older individuals. Gleaning from his years of experience in Africa, he highlighted the two-edged effects of oral iron replacement in infants. The authors observed that iron replacement does, as expected, reduce anemia, but on the flipside, it impairs intestinal absorption, leading to “dysbiosis,” which they postulate may affect adaptive immunity (and vaccine response).
We spoke with session Chair Dr. Capellini, whose excitement about iron homeostasis seems to be ever-increasing. “We have learned a lot about iron homeostasis and iron control — how to deal with diagnosis and management. Not all things need exogenous iron replacement,” she explained. “Back to the basics: establish etiology of iron deficiency, correct the underlying condition before iron replacement. It’s all about balance. Most importantly, there are emerging approaches targeting iron control: hepcidin, Tempura-6 gene, and ferroportin inhibitors. These advances have allowed us to explore new therapeutics and expand our repertoire beyond just iron supplementation.”
While a globally familiar topic, this session brought humbly to light the saying by the notable Greek philosopher, Socrates: “The only true wisdom is in knowing you know nothing.” Herein lies the beauty of the information age. By leaps and bounds, the more we discover, the more we know and realize there is still plenty to be known!
Dr. Saah indicated no relevant conflicts of interest.