Iron Deficiency Anemia (13)

Question 1

Which anemia is the most common and most important cause of a microcytic hypochromic anemia?

Answer 1

Iron deficiency anemia

Question 2

What are the possible causes of iron deficiency?

Answer 2

1) Inadequate intake of iron, which may result from a diet low in iron or from the inability to absorb iron.
2) Increased demand for iron such as pregnancy, rapid growth (infants, children)…
3) Excessive loss of iron, for ex, due to acute or chronic hemorrhage.

Question 3

In the human being, iron is an essential component of:

Answer 3

• Hemoglobin that contains about two-thirds of body iron
• Myoglobin in muscle cells
• Most cells of the body (have iron containing enzymes) such as cytochromes, peroxidases and catalase.

Question 4

How much iron does the body require for Hemoglobin synthesis in RBCs?

Answer 4

The body requires around 25 mg of iron daily, mostly used for the production of haemoglobin in erythrocytes.

Question 5

Are dietary iron consumptions sufficient for the body’s need?

Answer 5

No. Daily absorption of dietary iron by the intestine limited to 1– 2 mg to compensate for daily iron losses (which are about 1mg per day).

Question 6

How does the human body meet its iron requirements?

Answer 6

To meet this requirement, the body recycles most of the necessary iron from the breakdown of senescent red blood cells by macrophages in the spleen, making it available to plasma transferrin. This iron absorption and recycling process is tightly controlled by the hepatic hormone hepcidin.

Question 7

What is the role of hepcidin in iron metabolism?

Answer 7

Hepcidin is a hormone produced by the liver that plays a crucial role in regulating iron metabolism. It helps control iron absorption in the intestines and iron release from macrophages, thereby maintaining iron balance in the body. Hepcidin levels are influenced by factors such as iron stores, erythropoietic activity, and inflammation.

Question 8

How is iron transported in the bloodstream?

Answer 8

Iron circulates in the plasma bound to the glycoprotein transferrin, which has high-affinity binding sites for Fe (III). Transferrin binding helps maintain iron in a soluble form and serves as a major vehicle for delivering iron into cells through the transferrin receptor (TfR1).

Question 9

What is the normal saturation level of transferrin in humans?

Answer 9

In humans, plasma transferrin is normally about 30% saturated with iron. Although it can range from 20-50%.

Question 10

A transferrin saturation of ___ indicates iron deficiency, whereas ___ saturation is a sign of iron
overload.

Answer 10

A transferrin saturation <16% indicates iron deficiency, whereas >45% saturation is a sign of iron
overload.

Question 11

How is iron released into the circulation?

Answer 11

Iron is released into the circulation from duodenal enterocytes, which absorb 1-2 mg of dietary iron per day, and from macrophages, which recycle 20-25 mg of iron from aging red blood cells.

Question 12

What role do hepatocytes play in systemic iron metabolism?

Answer 12

Hepatocytes have a dual role in systemic iron metabolism. They serve as the major site of iron storage and also secrete the regulatory hormone hepcidin. Hepcidin controls systemic iron fluxes and plasma iron levels by binding to the iron exporter ferroportin on the surface of iron-releasing cells, triggering its degradation and reducing iron transfer to transferrin.

Question 13

Distribution of iron in the adult human body and regulation of iron traffic.

Answer 13

Circulating iron is bound to transferrin (holo-Tf) and delivered to tissues (black arrows). Holo-Tf is primarily replenished by iron recycled from tissue macrophages (thick red arrow), but also by dietary iron absorbed by duodenal enterocytes (thin red arrow). Under conditions of iron deficiency, iron
stored in hepatocytes can also be mobilized (thin red arrow). Iron efflux to the bloodstream is
inhibited by the liver-derived peptide hormone hepcidin, which binds to the iron exporter
ferroportin (FPN) and promotes its degradation.

Question 14

What are the two kinds of dietary iron?

Answer 14

• Non-Heme iron (Fe3+)
• Heme-iron (Fe2+)

Each has its own method of absorption and own reaction to dietary interaction.

Question 15

Where is the most active site for iron absorption in the body?

Answer 15

The most active site for iron absorption (taking in dietary iron) is in the duodenum and upper jejunum of the small intestine.

Question 16

How are the two dietary irons absorbed by the small intestine?

Answer 16

In the duodenum, ferrous iron is taken up directly by the lining cells through receptors specific for iron.

On the other hand, ferric ion (Non-heme iron) is reduced into ferrous iron before being taken up by a specific channel.

Question 17

How is iron absorbed by the duodenum?

Answer 17

Iron can be absorbed in two forms: as ferrous iron (Fe++) or as heme. In the duodenum, ferrous iron is taken up by the lining cells through receptors specific for iron. Heme, found in foods of animal origin, is split in the intestinal cell, releasing its iron as Fe++ to join the ferrous iron taken up directly by the mucosal cell.

Question 18

What factors influence the entry of iron into the duodenal cell lining?

Answer 18

The entry of ferrous iron (Fe++) into the duodenal cell lining is increased in the presence of high levels of erythropoietin (EPO). Excess EPO leads to an excess of iron absorption.

Question 19

What happens to the absorbed iron in the duodenal cell lining?

Answer 19

The fate of absorbed iron depends on the body’s iron needs.

If the body requires more iron than usual (such as during periods of growth, pregnancy, or iron deficiency), increased EPO allow the iron to pass from the intestinal cell into the bloodstream.

If the body does not need much iron and has excess iron, the absorbed iron is captured by ferritin within the duodenal cell lining and stored there. Some of this stored iron is lost daily with the shedding of intestinal mucosa and is excreted in the stool.

Question 20

What happens if the excess absorbed iron is not shed from the body?

Answer 20

If the excess absorbed iron is not shed, it can lead to iron overload and toxicity. In individuals with a deficiency in the mechanism for shedding excess iron, the iron continues to be absorbed, leading to its deposition in vital organs such as the heart, kidney, liver, and pancreas. This condition is known as hemochromatosis and can result in damage to these organs.

Question 21

What happened to the absorbed iron that is carried into the bloodstream? Where is it carried to?

Answer 21

The iron that is absorbed into the blood stream from the intestine does not travel free, but it is immediately bound to transferrin, which is synthesized by liver cells. One molecule of transferrin binds two atoms of Fe+++ iron

The iron bound to transferrin is transported to certain specific cells in the body, (cells
with receptors to transferrin). These include:
1. The erythroid series including the reticulocytes
2. Muscle cells to form myoglobin
3. Placental cells in pregnant women
4. Histiocytes in the B.M.
5. Hepatic cells

Question 22

In what form is iron carried in the plasma?

Answer 22

In the plasma, Fe++ turns into Fe+++, the moment it is absorbed and taken up by transferrin.

Question 23

What happens when transferrin carries the iron to the erythroblasts found in the B.M?

Answer 23

Transferrin comes and sticks to the cell membrane receptor and then the whole complex is taken and iron is liberated in the cell; it is first changed to Fe++, and then it enters the mitochondria in which a series of enzyme controlled reactions occurs the result of which is a substance called heme. Then the heme leaves the mitochondria and comes to the
cytoplasm to meet the globins synthesized on the ribosomes. Some iron is not changed into heme, but remains stored in the RBC as ferritin.

Question 24

Where are iron stores (ferritin) found in the body?

Answer 24

Iron stores are found in the liver, BM (in histiocytes or sinusoids) and spleen, however, the majority of the stores are found in the liver.

Question 25

How is iron stored in the bone marrow?

Answer 25

As erythroblasts mature in the bone marrow, they become smaller and their nucleus shrinks and is eventually extruded. The extruded nucleus, along with a thin rim of hemoglobin (Hb), is taken up by histiocytes (macrophages) in the bone marrow. The Hb is broken down to release iron, which is then stored within the histiocytes. As more red blood cells (RBCs) mature, a significant amount of Hb is wasted and stored as iron in the histiocytes of the bone marrow.

If there is a high rate of death around the histiocyte (ineffective erythropoiesis) then the amount of Hb wasted is much higher —> the histiocytes become loaded with Fe.

Question 26

What happens to defective or rigid red blood cells?

Answer 26

Defective or rigid red blood cells are unable to pass through the sinusoidal lining of the bone marrow safely. Instead, they are caught and phagocytized by the endothelial lining. This contributes to iron storage in the sinusoids of the bone marrow.

Question 27

In a normal person, approximately ___ of the RBCs produced daily are defective and are thus phagocytized by the endothelial lining.

Answer 27

5%

Question 28

How is iron stored in the spleen?

Answer 28

Normal red blood cells, after circulating in the bloodstream for about 100-120 days (lifespan), are taken up by the spleen. The hemoglobin of these RBCs is broken down, releasing iron that is stored in the macrophages of the spleen.

Question 29

What are the two forms in which iron is stored in the body?

Answer 29

Iron is stored in the body in the forms of ferritin and hemosiderin.

Question 30

What is ferritin and how does it store iron?

Answer 30

Ferritin is a complex protein molecule called apoferritin that binds and stores iron in a soluble form (Fe+++). It acts as an iron buffer, taking up excess iron or releasing iron as needed. Ferritin can be mobilized and released when the body requires iron. The released iron binds to transferrin to go to the B.M. to be utilized in Hb synthesis. Small amounts of ferritin, derived from iron stores, circulate in the plasma.

Question 31

What does the amount of serum ferritin reflect?

Answer 31

The amount of serum ferritin closely reflects iron stores, thus providing a readily measured assessment of body iron stores.

Question 32

What is hemosiderin and how does it differ from ferritin?

Answer 32

Hemosiderin is a form of storage iron that is derived from ferritin. It is a complex molecule that is insoluble in water (H2O insoluble). Unlike ferritin, hemosiderin is a more stable form of storage iron and remains within macrophages. It serves as a long-term storage form of iron.

Question 33

How is iron storage assessed or measured in the body?

Answer 33

Iron stores can be examined by staining ferritin and hemosiderin using the Perl’s Prussian blue reaction, often done in bone marrow evaluation.

Question 34

How is the release of iron from storage regulated?

Answer 34

> When iron stores are sufficient, hepcidin degrades of the iron exporter protein ferroportin on the surface of enterocytes. Reduction in ferroportin causes absorbed dietary iron to remain in the enterocyte, where it is lost by enterocyte shedding.

> Conversely, when iron stores are low, hepcidin production and secretion are suppressed, allowing increased iron efflux from enterocytes into the bloodstream by DMT-1

Question 35

What are the sequential phases of iron deficiency?

Answer 35

• Stage 1 (Prelatent)
  • Decrease in storage iron
• Stage 2 (Latent)
  • Decrease in iron for erythropoiesis (leading to low MCV and MCH)
• Stage 3 (Anemia)
  • Decrease in circulating red blood cell parameters (Hemoglobin, RBC, Hct…) &
  • Decrease in oxygen delivery to peripheral tissues (Low Hemoglobin)

Question 36

What are the typical laboratory findings in early iron deficiency states?

Answer 36

In early iron deficiency states, the stained blood film often shows normochromic normocytic erythrocytes, and normal Hb, Hct and RBC indices.

**Everything is normal **

Question 37

What are the laboratory findings in later stages of iron deficiency anemia?

Answer 37

In later stages of Fe deficiency anemia, Hb and Hct are low and the peripheral blood shows anisocytosis and poikilocytosis (including elliptocytes, cigar shaped RBC(s) and target cells). The RBC(s) are characteristically microcytic and hypochromic (The MCV, MCH and MCHC are low). In addition, a small number of +*hypersegmented neutrophils** may be seen.

Question 38

What is the typical platelet count finding in iron deficiency anemia, and how does it respond to iron therapy?

Answer 38

In iron deficiency anemia, the platelet count is often elevated, with levels exceeding 450,000/mm3. However, this elevation in platelet count tends to normalize after iron therapy is initiated.

Question 39

What is the typical reticulocyte count finding in iron deficiency anemia, and how does it respond to iron therapy?

Answer 39

Reticulocytes are usually normal or decreased except following iron therapy, because iron is a limiting factor for RBC production.

Question 40

How is the Total Iron Binding Capacity (TIBC), or in other words, the amount of total transferrin, calculated?

Answer 40

TIBC (Total Transferrin) = Serum iron (Bound transferrin) + Unsaturated Iron Binding Capacity (UIBC) (Unbound/Free transferrin)

Normally the transferrin is only 1/3 saturated with Fe+++. This amount of iron in the plasma ranges: 60-120 ug/100ml of plasma. This leaves 2/3 of our transferrin free so that any excess of iron that comes is not free but becomes bound to it.

TIBC= [Transferrin-iron] x 3
(not accurate)

Question 41

Calculate the TIBC based on the normal range of serum iron found in the body.

Answer 41

The amount of serum iron in the plasma ranges from 60-120 ųg/100ml of plasma

Based on rough calculation,
TIBC = (60-120) x 3 = 180-360 ųg/100ml of plasma

Question 42

How is the TIBC affected in iron deficiency anemia?

Answer 42

In iron deficiency anemia, the serum iron (S.I.) is decreased since there is no iron for transferrin to bind.

As a result, the TIBC increases characteristically as a compensation mechanism.

Question 43

How does the presence of iron in bone marrow macrophages differ between iron deficiency and normal conditions?

Answer 43

In iron deficiency, there is a complete absence of iron from the bone marrow stores. The iron stores are depleted before anemia develops. In contrast, in normal conditions, a Prussian blue stain of the bone marrow shows coarse granular storage iron present in macrophages.

Question 44

What is the definitive test for diagnosing iron deficiency?

Answer 44

The Prussian blue stained bone marrow test is the definitive test for diagnosing iron deficiency. A positive iron stain indicates the presence of iron in the bone marrow macrophages, suggesting normal iron stores. In contrast, a negative iron stain, as seen in iron deficiency, demonstrates the absence of iron in the bone marrow macrophages.

Question 45

How does the percentage of sideroblasts in the bone marrow change in iron deficiency as compared to the normal range?

Answer 45

In iron deficiency, the percentage of sideroblasts in the bone marrow decreases. Sideroblasts are immature red blood cell precursors that contain iron in their mitochondria. The normal range of sideroblasts in the bone marrow is typically between 20% and 50%.

Question 46

What is the normal serum ferritin range for both females and males?

Answer 46

The normal range of serum ferritin is generally:

10-150 ng/ml in females
20-300 ng/ml in males

Question 47

How is Transferrin saturation calculated?

Answer 47

Transferrin saturation (% sat)
= Serum iron x100/TIBC

Question 48

How can serum soluble transferrin receptor (sTfR) levels be used to diagnose iron deficiency?

Answer 48

Measurement of serum soluble transferrin receptor levels provides an additional means to diagnose iron deficiency. When iron stores are low, the expression of transferrin receptors (TfR) is enhanced to acquire more iron, resulting in increased levels of TfR. Therefore, an inverse relationship exists between TfR levels and body iron stores.

TfRs are also present in the circulation, and the circulating serum TfR (sTfR) level reflects total body
TfR concentration.

Question 49

What is the advantage of using soluble transferrin receptor (sTfR) measurement compared to ferritin in certain situations?

Answer 49

Ferritin is typically the preferred test to evaluate stored iron, but it can be influenced by acute phase reactants and may be increased in the presence of inflammation or chronic diseases. In such cases, ferritin may not accurately reflect iron stores and can falsely indicate adequacy in iron reserves.

In contrast, the soluble transferrin receptor (sTfR) test is not an acute phase reactant and may be ordered as an alternative to ferritin to evaluate stored iron when a chronic illness is present or suspected.

Question 50

Sum up what iron panel results would be required to diagnose iron deficiency anemia

Answer 50

• Serum Iron ⬇️
• Serum ferritin ⬇️
• Transferrin Saturation ⬇️
• TIBC ⬆️ or Transferrin ⬆️ (Positive Feedback)
• sTfR ⬆️ (Positive Feedback)

Question 51

What is the first principle of therapy for iron deficiency anemia?

Answer 51

The first principle of therapy for iron deficiency anemia is to identify and correct the underlying cause (inadequate dietary intake, chronic blood loss, or absorption issues)

Question 52

How is ferrous iron typically administered in the treatment of iron deficiency anemia?

Answer 52

Ferrous iron is commonly given orally for the treatment of iron deficiency anemia. The typical dosage is around 200 mg per day, divided into three doses that are taken between meals. This dosage is aimed at providing 20-40 mg of absorbed iron per day, which, with the iron produced by turnover of dead cells, will be sufficient to increase production to 2 or 3 times normal.

Question 53

What is the expected response to iron therapy in iron deficiency anemia?

Answer 53

Following iron therapy, the reticulocyte count, which reflects the production of new red blood cells, will increase and reach a peak within 5 to 10 days. Subsequently, the reticulocyte count will gradually decrease toward normal levels.

Additionally, the peripheral blood smear may show red blood cell dimorphism, with a combination of microcytic hypochromic red blood cells and normocytic normochromic red blood cells.

Question 54

How long should iron therapy be continued after all tests have returned to normal?

Answer 54

After all tests have returned to normal, it is generally recommended to continue iron therapy for at least two months to replenish iron stores.

Question 55

What should be done if iron therapy does not produce the expected results?

Answer 55

If iron therapy does not yield the expected results, it is necessary to discontinue the therapy and reevaluate the diagnosis. (incorrect diagnosis or the presence of an underlying condition)