**Iron-Deficiency Anemia**

Claudia Burz, Andrei Cismaru, Vlad Pop and Anca Bojan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80940

### **Abstract**

Iron is an important element in living systems as it participates in a series of metabolic processes including DNA synthesis and oxygen and electron transport. Iron deficiency is the most common cause of anemia globally being an important healthcare problem. If left untreated, iron-deficiency anemia (IDA) can cause significant morbidity and often is the result of a more serious underlying condition. Correcting iron deficiency and replenishing iron reserves are important objectives of a well-conducted treatment, but diagnosis should prompt further investigation to establish the cause for potential reversal. Age, tolerance, preferred route of administration, and severity of anemia are some of the patient's characteristics which require an individualized approach.

**Keywords:** anemia, iron deficiency, hemoglobin, ferritin, transferrin, hepcidin, erythropoiesis

### **1. Introduction**

Anemia is the most common hematologic disorder, iron deficiency being the leading cause- worldwide [1]. Often, anemia is the presenting sign of a more serious underlying condition which left untreated can generate consequent morbidity [2]. Likewise, it can worsen preexisting comorbidities such as cardiac and pulmonary disease. The World Health Organization (WHO) defines anemia as hemoglobin levels lower than 13g/dL in men and 12g/dL in women- (**Table 1**) with variations in age and pregnancy. Moreover, altitude and smoking status can- influence baseline hemoglobin [3, 4]. Red blood cells (RBC) are responsible for hemoglobin- levels. Deficits in their production, increased destruction, or loss through bleeding are the main- three mechanisms by which anemia occurs. Risk factors include female gender, extremes of

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**Table 1.** Severity of anemia in different age groups, sex, and pregnancy status (g/dL).-

age, pregnancy, and lactation. There are several types of anemia such as thalassemia, sickle cell disease, aplastic anemia, hemolytic anemia, pernicious anemia, and iron-deficiency anemia. In- this chapter we will focus on a comprehensive characterization of iron-deficiency anemia (IDA).-

### **2. Definition-**

Iron deficiency and IDA are serious health problems in the whole world. Iron has a vital role for many biologic functions including energy production, respiration, and cell proliferation. IDA is the end-stage result of the lack of iron in the body resulting from inadequate iron intake, increased iron loss, or excessive iron requirements [5]. As a consequence, erythropoiesis is insufficient to fulfill the body's physiologic needs. IDA diminishes working performance by constraining muscles to depend on anaerobic metabolism in order to greater attain muscle extent in contrast to healthy individuals. As a result, in affected patients the capability to perform physical labor is decreased. Furthermore, in children, both growth and learning capacities are affected.-

Using the severity criteria, anemia is classified into mild (11g/dL to normal), moderate- (8g/dL to 11g/L), and severe (less than 8g/dL) in adult males and adult nonpregnant- females (**Table 1**) [6]. Severe anemia may produce hypoxemia enhancing the occurrence of coronary insufficiency and myocardial ischemia. Also, it may aggravate underlying cardiac- and pulmonary disorders.

### **3. Epidemiology**

Anemia is a public health problem that affects populations in both developed and undeveloped countries. According to the WHO data on the prevalence of anemia for the period between the years 1993 and 2005, anemia affects 24.8% of the population globally, which corresponds to approximately one in four people. The highest prevalence was reported in preschool-aged children (47.4%), whereas the lowest prevalence is in men (12.7%). Although the prevalence in nonpregnant women was reported at 30.2%, they represent the population group with the largest number of individuals affected (468.4 million).-


**Table 2.** Prevalence of anemia in different WHO regions (in percentage (%)).-

Typically, IDA represents approximately a half of all types of anemia, but the cases may vary among population groups and in different areas according to local conditions [7].

The WHO areas of Africa and Southeast Asia have the highest risk, where about two-third of preschool-aged children and half of all women are affected [8]. Prevalence in pregnant and nonpregnant women is similar in Europe and the Americas, whereas preschool children's prevalence of anemia is different in these two WHO regions (**Table 2**).-

### **4. Etiology**

The diagnosis of IDA is not sufficient; the cause of iron deficiency has to be identified. Iron deficiency occurs by disturbing the balance of iron metabolism, respectively, by **reducing the intake** or by excess **blood loss** [9].

The main situations responsible for reduced iron intake, directly or indirectly, are insufficient food intake, poor absorption, or increased requirements [10].

Regarding the insufficient food intake, this situation is rarely encountered as iron requirements are relatively low. It is more common in severe diets and vegetarianism, as heme iron, the one contained in red meat, has two times greater bioavailability than the non-heme iron from eggs and vegetables [11].

Several conditions may interfere with iron absorption, the most frequent being:


Some physiological conditions are associated with increased needs of iron and secondary apparition of IDA. Pregnancy, prematurity, twins, intense growth, and development periods during adolescence could be responsible of IDA [15–17].

The most common cause of iron deficiency remains blood loss, especially from the digestive track in men and from menstrual bleeding in women [18]:


Other conditions, more rarely observed, are frequent phlebotomies in blood donors, chronic kidney disease, and dialysis [29, 30].

## **5. Physiopathology**

### **5.1. General aspects**

IDA occurs through the disruption of iron metabolism. For a better understanding of the mechanisms by which iron balance can be altered, some important elements of iron metabolism must be taken into consideration:

	- **a.** The functional compartment from which 70% of the total iron (2.8 g) consists in iron from hemoglobin and myoglobin and < 1% in cellular enzymes involved in oxidative metabolism: catalases, cytochromes, and myeloperoxidases.
	- **b.** Transport compartment which represents 0.1% of the total iron, 4 mg, consists of transferrin or siderophilin. It is synthesized by the liver and has the role of transporting iron to cells. Each molecule fixes one or two atoms of trivalent iron. The evaluation of this compartment is made by:
		- Measurement of serum transferrin using immunological method.-
		- Measurement of total iron-binding capacity.-
		- Measurement of transferrin saturation-
	- **c.** The storage compartment represents 29% of total iron (1 g) and is contained in macrophages and hepatocytes under the form of:

### **5.2. The iron cycle**

A balanced diet accounts for 10–20 mg of iron per day, of which 5% is absorbed, sufficient for covering the losses [31]. To provide the stores with the sufficient amount of iron, approximately 1 g is necessary, equivalent to the absorbed quantity in 2–3 years.-

The iron intake consists of two forms [11]:


Iron absorption is impaired by antacids, phytates, and tannic acid. It takes place mostly in the duodenum and proximal intestine. Under conditions of rapid intestinal transit, the contact time of intestinal content with iron is reduced, and absorption is diminished. Trivalent iron is reduced to ferrous iron by the other food components or by reductase enzymes in intestinal brush cells [11, 36].

Ferrous iron is transported from the apical pole of the cell to the basal pole by the transport protein, divalent metal transporter 1 (DMT1). From this point, it is transported into the blood by ferroportin, as ferrous iron. Ferroportin's activity is regulated by hepcidin, an acute-phase protein synthesized by the liver. Hepcidin inhibits intestinal absorption of iron by accelerating degradation of ferroportin. The iron is then taken up by the transferrin. The iron-transferrin complex circulates in the blood until it interacts with specific receptors for transferrin. The complex coupled with transferrin receptors is internalized, and the iron is released and used for the synthesis of heme, while the transferrin-receptor complex reaches the cell surface where transferrin is released in the blood. At this point, a small amount of transferrin receptors can be released in the blood and can be dosed as free circulating receptors [9, 11].

In erythroid precursors, excess iron binds to apoferritin to form ferritin. This process also takes place in other cells that express transferrin receptors, for example, hepatocytes. Hepcidin inhibits iron release from macrophages. Iron incorporated in hemoglobin enters the circulation providing oxygen to tissues [37, 38].

The lifespan of a RBC is 120days [33]. Then, erythrocytes are recognized as senescent cells by the reticuloendothelial system (RES) and hepatocytes, and as a result, they are destroyed by the- phagocytes [39]. Hemoglobin is decomposed to globin and restores the deposit of amino acids. The iron is transported to the cell surface where it is taken by transferrin (iron recycling) [40].

The absorption is controlled by an active mechanism. It is influenced by several factors. RBC hyperplasia stimulates the absorption of iron, even if iron storages are normal or increased and hepcidin levels are reduced. The molecular mechanism behind is unknown. Patients with associated anemia and ineffective erythropoiesis (thalassemia intermedia) have an excessive absorption of iron. In IDA, the hepcidin level is low, and iron is more efficiently absorbed from food. During inflammation, hepcidin levels increase, due to the fact that it is an acutephase protein. This determines macrophages to retain the iron and to reduce iron absorption, determining iron deficiency [33, 41, 42].

Ferroportin acts also on the erythrocyte precursors, promoting the export of the iron to RBC precursors (**Figure 1**) [43].

#### **5.3. Stages of iron deficiency-**

The first stage of iron deficiency is the reduction of iron stores. In order to compensate the deficiency, the iron is released from the stores, initially from ferritin, which is easily available, and then from hemosiderin. Thus, iron intestinal absorption and transferrin synthesis intensify, but on the other hand, the iron saturation of transferrin is reduced, and total binding capacity of transferrin increases. At this stage, due to the mobilization of iron from the stores, the levels of circulating iron are normal [44].

**Figure 1.** Schematic representation of iron circuit in the human body.

The second stage is represented by the total depletion of iron stores. At this moment the serum iron is low, but erythropoiesis is not affected [44].

The last stage is represented by the hypochromic microcytic anemia. At this stage, the quantity of iron delivered to the erythroblasts is insufficient, the synthesis of hemoglobin is reduced, and hypochromia occurs. Afterward, by enhancing the mitotic erythroblast activity, microcytosis occurs. The number of RBC is diminished, but not lower than the amount of hemoglobin. Due to the hypoxia, erythropoietin synthesis is stimulated, but the erythropoiesis cannot increase because of the low amounts of hemoglobin. Therefore, reticulocyte count will be normal or decreased. Iron deficiency causes the reduction of other body components that contain iron, such as myoglobin, cytochromes, and catalases, which are responsible for the late extrahematologic signs of iron deficiency [44, 45].
