These are disorders in which the production of red blood cells is decreased due to low iron stores in the body and/or reduced iron utilization of the stores. The former is the most common nutritional disorder worldwide and accounts for about half of all cases of anemia. The development of anemia can result from insufficient iron intake, decreased iron absorption, increased demand for iron by the body, and increased iron losses. Correct identification of the underlying etiology and administration of appropriate therapy are the keys to the evaluation and management of this condition. As mentioned at the beginning, sideropenic anemia should be differentiated first from the anemia of chronic conditions, which generally occurs in subjects affected by chronic inflammatory diseases and presents many clinical and laboratory features similar to sideropenic anemia, even if it differs in evolution and treatment.

The regulation of the body’s iron balance is based on the meticulous control of intestinal absorption, as there is no excretory regulation. Daily losses, which in a normal male subject are between 1 mg and 2 mg and in the female are greater but variable depending on the physiological state (as shown in Fig. 1, they range from values simi lar to the male in childhood and menopause to values 30–100% greater in childbearing age, to values more than 3.5 times greater in pregnancy), are then rebalanced by absorption. In turn, absorption depends on the iron con tent of the diet. An average European diet contains 6 mg of iron per 1000 kcal; this corresponds to total values of 10–30 mg/day (Table 1). It should be borne in mind that, under conditions of normal balance regulation, the iron absorbed corresponds to 5–10% of the total content, and that under deficit conditions, this percentage may increase by 3–5 times. The localization of absorption begins in the stomach, proceeds to a maximum in the central part of the proximal jejunum, and then decreases caudally. Absorption is influenced by pH and redox potential. Of the various forms of iron presented for absorption, hemic iron (Fe2+) derived from hemoglobin, myoglobin, and hemic enzymes from animal-derived foods is the most easily absorbed. Proteases and gastric acid juice release heme from the apoproteins to which it is bound. The iron in heme is oxidized to hemin (Fe3+), and the molecule enters the enterocyte intact, from which it will then pass into the blood. European nonvegetarian diets contain approximately 10–15% heme iron. The latter is not affected by diet, in contrast to inorganic iron (Fe3+). It is generally complexed with phytates, oxalate, citrate, lactate, sugars, and amino acids and must be reduced to Fe2+ to be absorbed. Other foods and substances present in the diet can favor its absorption (ascorbates and animal meats through low molecular weight factors due to proteolysis that carry inorganic Fe−, keto sugars, amino acids, organic acids, and human milk) or slow down or even hinder its absorption (vegetable proteins, soy, egg white, cow’s milk, phytates, bran and vegetable fibers, polyphenols, phosphates and phosphoproteins, tannin, and other metals that compete for absorption, such as Zn, Cd, and Ca). The recommended amount of iron in the diet also depends on dietary habits; subjects with a predominantly or totally plant- based diet should include higher amounts of iron in the diet. Once entering the enterocyte cytoplasm through the apical membrane, absorbed Fe3+ is reduced to Fe2+ by a ferro- reductase and internalized via the divalent metal transporter (Fig. 2). In contrast, heme iron (Fe2+), transported internally by heme carrier protein 1, is released from the heme-by-heme oxygenase. Fe2+ in the cytoplasm can now take two routes: (1) the pathway by which iron is released into the circulation for use in erythropoiesis, which is mediated by ferroportin, a molecule located on the basolateral membrane that releases Fe2+, which is simultaneously oxidized to Fe3+ by the ferroxidase hephaestin and immediately bound to circulating transferrin; and (2) the intracellular deposition pathway, whereby iron is incorporated into the cell’s ferritin molecules when the cell receives the signal that no more iron is needed for erythropoiesis. Since the enterocyte is exfoliated after a few days, the iron inside it is eliminated with feces. A molecule, hepcidin, interferes with the mechanisms of iron entry into the circulation. It performs its function by inducing the lysosomal degradation of ferroportin. Hepcidin is expressed in the liver and is regulated by the BMP6 protein (bone morphogenic protein 6), together with its co-receptor hemojuveniline, and thus represents a mechanism for regulating iron absorption according to the needs and deposits existing mainly in the liver. Its action also occurs at the level of the reticuloendothelial macrophages.

Fig1. Iron demands in different physiological states in women. (Copyright EDISES 2021. Reproduced with permission)

Table1. Recommended daily intake of iron in food

Fig2. Molecules contributing to the iron cycle in the enterocyte. (Copyright EDISES 2021. Reproduced with permission)

Since hepcidin behaves as an acute-phase protein, it increases during inflammation upon induction by interleukin- 6 and inhibits iron absorption. In chronic inflammation, this prolonged effect results in anemia with features similar to those of iron deficiency anemia, from which, however, it must be differentiated. Indeed, anemia due to chronic inflammation results from the inability to allocate sufficient iron to erythropoiesis as it remains sequestered in the reticuloendothelial system.

Genetic mutations involving hepcidin are also known to cause juvenile hemochromatosis. This pathology can also be due to mutations in the hemojuvenilin regulator, which are the most frequent causes. Other important genes involved in iron regulation are transferrin receptor 2 (TfR2) and HFE. Some mutations of the latter, mainly C282Y and H63D, are responsible for hereditary hemochromatosis in adults, which occurs around 40 years of age. The laboratory analysis useful for the diagnosis of hemochromatosis is shown in Table 2.

Table2. Investigations for the diagnosis of hemochromatosis

The measurement of serum or plasma iron (sideremia) reflects the amount of iron bound to transferrin, which is continuously variable throughout the day as a function of diet and activity. Generally, sideremia values tend to be higher in the morning than in the evening and higher after meals than during fasting. For these reasons, sideremia is not reliable for assessing the iron status of the body.

The transport of iron in the circulation is mediated by transferrin, a molecule circulating in four main forms in various proportions:

• Apotransferrin, an iron-free protein

 • Monoferric transferrin with Fe bound to the carboxyl terminus

• Monoferric transferrin with Fe bound to the amino-terminal

• Holotransferrin, with two bound Fe atoms

Transferrin can be measured by two different methods. Specifically, it can be assessed by an immunometric assay of transferrin protein, whose values are expressed in g/L (IR 1.9–3.7), or by a functional method, which evaluates the total iron-binding capacity (TIBC) and is obtained after saturation of serum or plasma with Fe3+ and measurement of bound iron. The latter provides diagnostic information for microcytic anemias, such as the latent iron-binding capacity (LIBC) and the percentage of saturation of transferrin (TSat %), through the following calculations:

• TIBC μmol/L S-Fe μmol/L = LIBC μmol/L

• TSat % = Fe/TIBC × 100

The reference values are, respectively:

– S-Fe: 11.6–31.7 μmol/L (M) and 10.0–30.4 μmol/L (F)

– TIBC: 45–66 μmol/L

– Transferrin: 1.9–3.7 g/L

– TSat: 20–50% (M) and 15–50% (F)

– Absolute ratio of TIBC μmol/L over transferrin (g/L) ≈ 25.0

Unlike sideremia, the TIBC/transferrin ratio does not vary continuously in the blood; however, the diagnostic information of TIBC/transferrin in sideropenic anemia is delayed as it increases when iron stores are depleted.

Transferrin is mostly in the apo form (approximately 65–80%). Its function is to bind Fe3+, making it soluble to dampen its reactivity, and deliver it to cells via special transferrin receptors (TfRs). Figure 3 shows the mechanism through which iron is incorporated into cells. Cells receive Fe via TfRs, which are located on the cell membrane and are particularly represented in erythropoietic cells. Their expression varies according to the intracellular Fe concentration. Two types of TfRs are known, 1 and 2. TfR1 shows a much greater affinity for Fe and is ubiquitous in cells, while TfR2 has been shown to perform different functions, not yet fully elucidated. Once its function has ceased, the extracellular portion of TfR is released into the circulation as a soluble truncated monomer (sTfR) complexed with transferrin. The major release of plasma sTfR occurs from erythroblasts, secondarily from reticulocytes. Levels of sTfR are determined by bone marrow erythropoietic activity, which can cause variations from eightfold to more than 20-fold of normal values. Therefore, sTfR has been used as a sensitive index of the recovery of erythropoiesis. It should be noted that sTfR con centration is not affected by inflammation and thus may be useful in differentiating sideropenic anemia, in which sTfR is elevated, from chronic inflammatory conditions, in which sTfR does not vary.

Fig3. Iron metabolism. Holotransferrin binds to TfR1 on the cell surface and the complex undergoes endocytosis in the clathrin-coated vesicle. The proton pump acidifies the endosome and causes Fe3+ release. Step 3 reduces Fe3+ to Fe2+, which exits the endosome via diva lent metal transporter (DMT-1). Iron is utilized in mitochondria via mitoferrin or deposited (nonerythropoietic cells) as ferritin. A fraction of intracellular Fe (redox) remains to constitute the Labile Iron Pool (LIP). Apotransferrin and TfR1 go to the membrane and dissociate at neutral pH. The apotransferrin cycle resumes. (Copyright EDISES 2021. Reproduced with permission)

The reference values of sTfR are 2.2–5.0 mg/L in males and 1.9–4.4 mg/L in females.

Ferritin is the main form of iron storage in the body. Its globular conformation with a high MW (474 kDa) and 24 units of two types of chains (H and L) enclose within the shell over 4000 atoms of Fe3+ complexed with hydroxy phosphate in the form of ferrhydrite, so as to minimize any reactivity due to contact. Most organs have ferritin deposits, which vary greatly according to the general state of iron. The liver, spleen, and bone marrow are the organs with the largest iron deposits in the form of ferritin. The values of circulating ferritin are in constant equilibrium with those of the stores, with 1 μg of circulating ferritin approximately corresponding to 7.5 mg of iron in the stores. The exceptions are mainly due to inflammatory and neoplastic diseases, as well as hepatopathies. In such conditions, ferritinemia values are unpredict ably abnormally elevated and thus not reliable as biomarkers of the status of iron stores, even if the values are apparently in the normal range.

The reference values of ferritin are 18–250 μg/L in males and 14–150 μg/L in females.

Zinc protoporphyrin (ZnPP) is a surrogate biomarker of iron deficiency. Zinc fits into the protoporphyrin ring in the absence of iron, and, therefore, its measurement in red blood cells can give an assessment of the extent of erythropoietic iron deficiency. Normally, the Fe/Zn concentration ratio is 30,000/l. In the case of iron deficiency, a decrease in the ratio is observed. The test is not widely used but may be useful in some diagnostic conditions.

The differential diagnosis of iron deficiency anemia and similar conditions is based on a reasoned combination of the tests described above. In Table 3, the diagnostic criteria that should be mainly considered in the conditions of microcytic anemia resulting from iron deficiency, chronic inflammatory conditions, and the combination of the two conditions, to which sometimes difficulties in making a correct diagnosis are added, are presented. The iron overload condition is also reported in Table 3.

Table3. Differential diagnosis of iron deficiency anemia, chronic inflammatory condition, and iron overload

اخر الاخبار

اخبار العتبة العباسية المقدسة

مواكب العزاء الحسينية تواصل برنامجها العزائي لشهر المحرم الحرام 1447هـ

شعبة الخطابة النسوية تقيم مجلس عزاء بحلول شهر المحرم الحرام

قسم الشؤون الفكرية يواصل تنظيم الورش التربوية والدينية ضمن برنامج التطوير الحسيني

سماحة السيد الصافي يستعرض عددًا من الوثائق التي تبيّن ما تعرّض له خَدَمة الإمام الحسين (عليه السلام) من قمعٍ وتضييقٍ وانتهاكات

المزيد

الآخبار الصحية

دراسة تكشف علاقة خطيرة بين عمر الأم وصحة مولودها

دراسة تحذر.. اضطراب نوم بسيط قد يسبب الموت المبكر ؟

الاستحمام بالماء الساخن.. راحة مؤقتة وأضرار دائمة للبشرة

ماذا يحدث للجسم عند تخطي وجبة الإفطار؟

المزيد

الآخبار التكنلوجية

كيف تساعد الصيانة الوقائية في الحفاظ على كفاءة التكييف في سيارتك ؟

في ظاهرة غريبة حيرت العلماء.. كوكبنا قد يسجل أقصر يوم في التاريخ هذا الصيف!

السد الصيني العملاق يعيق دوران الأرض ويغيّر شكلها ؟

السعودية تطلق 10 تجارب علمية إلى محطة الفضاء الدولية

المزيد

مواضيع ذات صلة

Automated Differential Count

Differential Leukocyte Count (Leukocyte Formula)

Reticulocytes and related Indices

lactose tolerance test (Hydrogen breath test)

Lactoferrin

lactic dehydrogenase (LDH, Lactate dehydrogenase)

lactic acid (Lactate)

ischemia-modified albumin (IMA)

iron level and total iron-binding capacity (Fe and TIBC, Transferrin saturation, Transferrin)

Platelet Indices and Platelet Count

Red Cell Distribution

Flow Cytometry