Biology of Anemia: A Public Health Perspective

Abstract

Our goal is to present recent progress in understanding the biological mechanisms underlying anemia from a public health perspective. We describe important advances in understanding common causes of anemia and their interactions, including iron deficiency (ID), lack of other micronutrients, infection, inflammation, and genetic conditions. ID develops if the iron circulating in the blood cannot provide the amounts required for red blood cell production and tissue needs. ID anemia develops as iron-limited red blood cell production fails to maintain the hemoglobin concentration above the threshold used to define anemia. Globally, absolute ID (absent or reduced body iron stores that do not meet the need for iron of an individual but may respond to iron supplementation) contributes to only a limited proportion of anemia. Functional ID (adequate or increased iron stores that cannot meet the need for iron because of the effects of infection or inflammation and does not respond to iron supplementation) is frequently responsible for anemia in low- and middle-income countries. Absolute and functional ID may coexist. We highlight continued improvement in understanding the roles of infections and inflammation in causing a large proportion of anemia. Deficiencies of nutrients other than iron are less common but important in some settings. The importance of genetic conditions as causes of anemia depends upon the specific inherited red blood cell abnormalities and their prevalence in the settings examined. From a public health perspective, each setting has a distinctive composition of components underlying the common causes of anemia. We emphasize the coincidence between regions with a high prevalence of anemia attributed to ID (both absolute and functional), those with endemic infections, and those with widespread genetic conditions affecting red blood cells, especially in sub-Saharan Africa and regions in Asia and Oceania.

Keywords: absolute iron deficiency; anemia; functional iron deficiency; hemoglobinopathies; infection; inflammation; iron; iron deficiency; micronutrients; thalassemia.

Figure 1

Iron in the body: a balance between iron stores, usage, and hepcidin levels. Panel (A) gives an overview of the flow of iron into the body, where it is contained in the body, and its loss. Absolute iron deficiency (B) can arise when iron stores are insufficient to meet iron demand (hepcidin is downregulated). Functional iron deficiency (C) can develop when iron stores are replete but hepcidin is upregulated due to inflammation, compromising iron supply. Absolute and functional iron deficiency may coexist.

Figure 2

Maps of global prevalence of infections. Panels from L-R, top-bottom: (A) malaria [122] (B) soil-transmitted helminths [129], (C) schistosomiasis [130], (D) HIV [131] (E) tuberculosis [125], and (F) nontyphoidal Salmonella [126].

Figure 3

How malaria may cause anemia through iron maldistribution. During malaria infection, blood-stage malaria parasites (A) elicit increased production of hepcidin (B), which in turn block the absorption of iron through ferroportin (FPN) on enterocytes (C). Hepcidin may also degrade ferroportin on both infected and uninfected red blood cells (RBCs), which could lead to accumulation of intracellular iron, oxidative stress, and consequently hemolysis. Hemolyzed RBCs are taken up by the macrophage (D). Hepcidin inhibits recycling of iron recovered from hemolyzed RBCs back into the circulation leading to deficiency of the amount of biologically available iron. Consequently, little iron is available to produce new RBCs by the bone marrow leading to iron deficiency anemia (E) HCP1: heme carrier protein 1. Adapted from Muriuki et al. [172].

Figure 4

The link between anemia and invasive bacterial infections. Anemia may increase risk of bacterial infections through various mechanisms including 1) increased gut permeability of enteric pathogens; 2) increased hemolysis and destruction of red blood cells, which increases availability of NTBI and free heme; 3) reduced hepcidin levels due to increased production of ERFE, which suppresses hepcidin, increasing iron export from storage cells through ferroportin (FPN), the sole iron exporter; and 4) immune dysfunction including decreased production of interferon gamma (IFN-γ) and neutrophil mobilization. ERFE, erythroferrone; NTBI, non-transferrin-bound iron; ROS, reactive oxygen species; TfR: transferrin receptor; SCV: Salmonella-containing vacuole. Adapted from Abuga et al. [205].

Figure 5

A historical global map of malaria endemicity. This map represents malarial endemicity. Source: Piel et al. [221, page 3]. Malaria endemicity is classified by the parasite rate, that is, the proportion of the population found to carry asexual blood-stage malarial parasites. Holoendemic: a parasite rate <10%, mesoendemic: a parasite rate ≥10% and <50%, hyperendemic: a parasite rate ≥50% and <75%: holoen-demic a parasite rate ≥75%.