Tomas Ganz

Current iron overload therapeutics have inherent drawbacks including perpetuated low hepcidin. Here, we unveiled that lactate, a potent hepcidin agonist, effectively reduced serum and hepatic iron levels in mouse models of iron overload with an improved erythropoiesis in β-thalassemic mice.

Iron's primary role in mammalian biology is to bind oxygen in hemoglobin and myoglobin and to catalyze the enzymatic transfer of electrons by iron‐dependent enzymes, including cytochromes, peroxidases, ribonucleotide reductases, and catalases. All known disorders of iron metabolism can be considered abnormalities of iron balance. On the cellular and molecular levels, hepcidin inhibits the efflux of cellular iron into extracellular fluid or plasma, exerting its effect on the major cell types involved in iron transport: enterocytes, macrophages, hepatocytes, and placental syncytiotrophoblast. The hypoferremic effect of hepcidin is due to its ability to inhibit the major mechanisms that deliver iron to plasma: intestinal iron absorption and the release of iron from recycling compartments and stores in the spleen and the liver. Iron homeostasis requires the coordinated regulation of iron …

Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers, and genetic disorders. For instance, hyperlactatemia leads to iron restriction by upregulating hepatic hepcidin expression. Increasing evidence also points to lactate as a crucial signaling molecule rather than merely a metabolic byproduct. Here, we discuss the mutual influence between anemia and hyperlactatemia. This opinion calls for a reconsideration of the multifaceted roles of lactate and lactylation in anemia and emphasizes the need to fill knowledge gaps, including the dose dependence of lactate's effects, its sources, and its subcellular localization.

Anemia of chronic disease is the second most common form of anemia and is seen in the setting of chronic infections, inflammatory disorders including rheumatological conditions and inflammatory bowel diseases, certain malignancies, and chronic kidney diseases. Hypoferremia, a decrease in serum iron concentration, is the defining feature of anemia of inflammation. Serum ferritin concentrations, reflecting inflammation and iron stores, are increased in anemia of inflammation and decreased in iron deficiency. Bone marrow aspiration or biopsy is now rarely necessary for the diagnosis of anemia of inflammation. Hypoferremia of inflammation is mediated by inflammatory cytokines, including prominently interleukin (IL)‐6, which increase rapidly in the first few hours of infection and induce the synthesis of the iron‐regulatory hormone hepcidin. Decreased iron absorption usually does not contribute much to …

Aims Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community‐dwelling older adults irrespective of their kidney function. Methods In this case‐cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub‐cohort [including 193 HF cases] and 221 additional HF cases [N = 414 total HF cases]) aged ≥ 65 years without HF (41% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as “iron replete” (27.3%), “functional iron deficiency” (7.7%), “iron …

Abstract As a functional component of erythrocyte hemoglobin, iron is essential for oxygen delivery to all tissues in the body. The liver-derived peptide hepcidin is the master regulator of iron homeostasis. During anemia, the erythroid hormone erythroferrone regulates hepcidin synthesis to ensure the adequate supply of iron to the bone marrow for red blood cell production. However, mounting evidence suggested that another factor may exert a similar function. We identified the hepatokine fibrinogen-like 1 (FGL1) as a previously undescribed suppressor of hepcidin that is induced in the liver in response to hypoxia during the recovery from anemia, and in thalassemic mice. We demonstrated that FGL1 is a potent suppressor of hepcidin in vitro and in vivo. Deletion of Fgl1 in mice results in higher hepcidin levels at baseline and after bleeding. FGL1 exerts its activity by directly binding to bone morphogenetic …

BackgroundMurine data suggest that the placenta downregulates ferroportin (FPN) when iron is limited to prioritize iron for its own needs. Human data on the impact of maternal and neonatal iron status on placental FPN expression are conflicting.ObjectivesThis study aimed to identify determinants of placental FPN protein abundance and to assess the utility of the placental iron deficiency index (PIDI) as a measure of maternal/fetal iron status in newborns at high risk for anemia.MethodsPlacental FPN protein abundance was measured by western blots in placentae collected from 133 neonates born to adolescents (17.4 ± 1.1 y) carrying singletons (delivery gestational age [GA]: 39.9 ± 1.3 wk) and from 130 neonates born to 65 females (30.4 ± 5.2 y) carrying multiples (delivery GA: 35.0 ± 2.8 wk). Placental FPN and the PIDI (FPN:transferrin receptor 1) were evaluated in relation to neonatal and maternal iron-related …

Primum non nocere! Can iron deficiency, an abnormality that causes anemia, benefit people with sickle cell disease (SCD) who already have an anemia? The published literature we review appears to answer this question in the affirmative: basic science considerations, animal model experiments, and noncontrolled clinical observations all suggest a therapeutic potential of iron restriction in SCD. This is because SCD's clinical manifestations are ultimately attributable to the polymerization of hemoglobin S (HbS), a process strongly influenced by intracellular HbS concentration. Even small decrements in HbS concentration greatly reduce polymerization, and iron deficiency lowers erythrocyte hemoglobin concentration. Thus, iron deficiency could improve SCD by changing its clinical features to those of a more benign anemia (i.e., a condition with fewer or no vaso‐occlusive events). We propose that well‐designed …