Anemia - Iron-Deficiency Disease Background

Introduction

Anemia is a condition wherein the blood has low levels of red blood cells (RBC), hemoglobin (oxygen-carrying pigment in whole blood) or hematocrit (intact RBC in the blood) making it insufficient to address the physiologic needs of the body.  

Based on the World Health Organization (WHO), anemia is defined as having the following hemoglobin concentrations¹:

• Men (≥15 years old): <13 g/dL
• Women (non-pregnant, ≥15 years old): <12 g/dL
• Women (pregnant): <11 g/dL in the first and third trimesters, declines by 0.5 g/dL in the second trimester
• Children (12 to 14 years old): <12 g/dL
• Children (5 to 11 years old): <11.5 g/dL
• Children (6 months to 4 years old): <11 g/dL

Iron-deficiency anemia is anemia due to low iron stores in the body; low hemoglobin or hematocrit associated with microcytic and hypochromic erythrocytes and low RBC count. Reduced availability of iron is the most important cause of anemia due to impaired erythropoiesis. Iron-deficiency is the most common cause of microcytic anemia, although almost half of the patients have normocytic erythrocytes.  

¹Values for the definition of anemia may vary between countries. Please refer to available guidelines from local health authorities.

Epidemiology

As much as one third of the world population has anemia, with approximately half of the cases resulting from iron deficiency. Roughly 1.24 billion people suffer from iron-deficiency anemia. Iron-deficiency anemia commonly affects the developing fetus, children, women of the reproductive age, individuals with chronic and inflammatory diseases, and the elderly. It has high prevalence among children during rapid growth and erythroid expansion especially in premature and low birth weight babies, in toddlers, and those in preschool and pregnant women. Based on the Global Burden of Disease Study in 2016, iron-deficiency anemia is 1 of the 5 leading causes of years lived with disability burden and is the first cause in women. It is also the most common nutritional deficiency in the world. Iron-deficiency is the most common cause of microcytic anemia, although almost half of the patients have normocytic erythrocytes. Although the most affected group by iron-deficiency anemia was non-pregnant women of reproductive age group, the elderly and the younger age group were also affected. 

In Malaysia, the overall prevalence of anemia is estimated to be at 24.2%, with iron deficiency being the most common cause. Iron-deficiency is also the most common cause of anemia in the Philippine population, with infants and pregnant women being the most affected. 

Anemia - Iron-Deficiency_Disease Background

Pathophysiology

The development and rapidity of progress of iron-deficiency anemia depend on the individual’s iron stores, which are, in turn, dependent upon age, sex, rate of growth, and the balance between iron absorption and loss.  

Iron deficiency impacts iron homeostasis, leading to adaptive mechanisms on the hepcidin-ferroportin (FPN) axis, the iron regulatory protein (IRP)/iron response element (IRE) machinery, and other regulators. With iron deficiency, the goal is to optimize iron usage by erythropoiesis and to counteract the physiological inhibition of iron absorption. Liver hepcidin is the hormone that is responsible for limiting iron entry into the plasma. By binding to FPN, the receptor of hepcidin, iron export is blocked by occluding the exporter cavity and inducing its degradation. At the same time, iron restriction leads to limitation of the expansion of early erythropoiesis as iron deprivation blunts erythropoietin (EPO) responsiveness of the early progenitors. For example, EPO is not elevated in iron deficiency without anemia. However, in the presence of anemia and hypoxia, EPO levels increase exponentially, suppressing hepcidin to enhance iron supply. 

Etiology

Causes of Anemia  

Normocytic anemia, when RBC morphology is unremarkable, can be caused by blood loss (most common cause), decreased RBC production due to low RBC production or destruction of RBC precursors within the bone marrow (eg chronic disease), or increased RBC destruction (eg hemolysis).

Macrocytic anemia is anemia wherein the RBC is larger than the nucleus of a small lymphocyte on a peripheral smear due to: 

• Megaloblastic causes: Folate and vitamin B12 deficiency, human immunodeficiency virus (HIV) infection, rare inborn errors of metabolism, myelodysplastic syndrome or congenital dyserythropoietic anemia
• Non-megaloblastic causes: Marked reticulocytosis, aplastic anemia, abnormal nucleic acid metabolism of erythroid precursors interfering with nucleic acid synthesis, abnormal RBC maturation, other causes such as Down syndrome, alcohol abuse, liver disease, and hypothyroidism

Microcytic anemia when RBCs appear smaller due to the following pathologic processes: 

• Reduced iron availability or iron-deficiency anemia
• Acquired disorders of heme synthesis (eg thalassemia)
• Reduced globin production
• Rare congenital disorders including sideroblastic anemias, porphyria, and defects of iron absorption transport, utilization and recycling
• Inflammation or chronic disease
• Lead poisoning

Anemia – Iron-Deficiency  

The most common and important cause of iron deficiency is overt blood loss. In premenopausal women, menstrual blood loss is a common cause, while gastrointestinal (GI) blood loss is more commonly observed in men and postmenopausal women. Inadequate iron intake is another cause of iron-deficiency anemia, particularly among the elderly, individuals with malnutrition, those adhering to a vegan diet, and people with alcoholism and pica. Iron malabsorption may also play a role and can result from intestinal mucosal disorders (most commonly celiac disease), impaired gastric acid secretion, gastrectomy, gastric or intestinal bypass procedures, and Helicobacter pylori colonization. Increased iron demand (seen during periods of rapid growth in children, as well as during menstruation, pregnancy, and lactation) can also be a cause of iron-deficiency anemia. Increased iron loss can occur in cases of frequent epistaxis.  

Other important causes include occult bleeding, congenital iron deficiency such as iron-refractory iron-deficiency anemia, intravascular hemolysis, pulmonary hemosiderosis, chronic diseases or genetic disorders (eg chronic hematuria and chronic bleeding diathesis), and chronic therapy with anticoagulants, anti-inflammatory drugs, antiplatelet drugs, or proton pump inhibitors (PPIs). Additionally, frequent blood donations and helminthiasis in pregnant women from low- and middle-income countries contribute to iron deficiency. A response to erythropoietin treatment may also be associated with iron-deficiency anemia. 

Classification

Absolute iron deficiency is when the iron stores in the bone marrow and other parts of the monocyte-macrophage system in the liver and spleen are absent, resulting in iron being unavailable for normal or increased rates of erythropoiesis. Functional iron deficiency is when there is insufficient availability of iron for incorporation into erythroid precursors despite normal or increased body iron stores. This is usually due to anemia of inflammation, chronic infections, malignancy, parasitic infections, malaria, iatrogenic blood loss from procedures or use of erythropoiesis-stimulating agents