From the Guidelines
Anemia of chronic disease is primarily caused by the inhibitory effect of inflammation on erythropoietin response and iron metabolism, leading to a functional iron deficiency and reduced erythropoiesis, as evidenced by recent research 1. The mechanism of anemia of chronic disease involves several key processes, including the upregulation of hepcidin production in the liver by inflammatory cytokines, which reduces iron export from macrophages and intestinal iron absorption, creating a functional iron deficiency despite adequate iron stores.
- Inflammatory cytokines, such as those found in patients with active inflammation, play a crucial role in this process by reducing erythropoietin production and inhibiting erythropoiesis in the bone marrow 1.
- The direct inhibition of erythropoietic activity in the bone marrow by inflammation also contributes to the development of anemia of chronic disease.
- Additionally, the reduction in red blood cell lifespan, although less significant, is another factor that contributes to the anemia. The classification of anemia by MCV and reticulocytes, as shown in Table 2 of the study 1, highlights the various types of anemia, including microcytic, normocytic, and macrocytic anemia, and their possible causes.
- The study 1 notes that not all patients with anemia show signs of functional iron deficiency, and that multiple mechanisms may be involved in producing anemia, making diagnosis and treatment more complex. Overall, the complex interplay of these mechanisms results in a normocytic, normochromic anemia that is typically mild to moderate in severity, with hemoglobin rarely falling below 8 g/dL unless other factors are involved, as supported by the evidence 1.
From the Research
Mechanism of Anemia of Chronic Disease
The mechanism of anemia of chronic disease (ACD) involves several key factors, including:
- Immune activation with an increase in inflammatory cytokines, leading to an increase in hepcidin levels 2, 3, 4
- Inappropriate erythropoietin levels or hyporesponsiveness to erythropoietin, contributing to the anemia 2, 4
- Reduced red blood cell survival, further contributing to the anemia 2
- Hepcidin, the central regulator of iron metabolism, plays a key role in the pathophysiology of ACD, binding to the iron export protein ferroportin and causing its degradation, leading to iron trapping within macrophages and hepatocytes, resulting in functional iron deficiency 2, 4
Role of Hepcidin
Hepcidin is regulated by iron stores, inflammation, and erythropoiesis via the BMP-SMAD and JAK-STAT signaling pathways 2
- Increased hepcidin levels lead to decreased iron availability for erythropoiesis, contributing to the development of anemia 3, 4
- Serum hepcidin levels can be useful in identifying iron deficiency in patients with ACD 4
Treatment of Anemia of Chronic Disease
Treatment of ACD should primarily be directed at the underlying disease 2, 3, 4
- Conventional therapy such as red blood cell transfusions, iron, and erythropoietin may be considered 2
- Novel agents targeting the hepcidin-ferroportin axis and signaling pathways (BMP-SMAD, JAK-STAT) involved in hepcidin production may also be considered 2
- Erythropoiesis stimulating agents (ESAs) may be used to stimulate the production of red blood cells, but their use should be carefully considered due to potential risks and benefits 5, 6