Iron deficiency anemia pathophysiology: Difference between revisions

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Overview

Pathophysiology

Physiology

Iron is needed for the synthesis of haemoglobin, new DNA synthesis and is a major component of oxidation and reduction enzymes.

In the human body, iron mainly exists as bound to protein (hemoprotein), as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferring, and ferritin).
The body requires iron for the synthesis of its oxygen transport proteins, (hemoglobin and myoglobin), and for the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and oxidation-reductions.
Human iron metabolism is controlled by various factors.
60% of the body iron is found in the hemoglobin present in circulating erythrocytes, 25% is contained in tranferrin and ferritin, and the remaining 15% is bound to myoglobin in muscle tissue and in a variety of enzymes involved in the oxidative metabolism and many other cell functions.
Iron is bound and transported in the body via transferrin and stored in ferritin molecules.

Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma from intestinal enterocytes or reticuloendothelial macrophages.
The binding of transferrin to the cell-surface transferrin receptor (TfR) 1 results in endocytosis and uptake of iron.
Internalized iron is transported to mitochondria for the synthesis of heme or other iron containing enzymes.
Excess iron is stored in cytosolic ferritin.

Absorption of iron

Iron absorption occurs by the enterocytes in the duodenum and upper jejunum.
Dietary iron occurs in two forms: heme and nonheme. The primary sources of heme iron are hemoglobin and myoglobin from consumption of meat, poultry, and fish, whereas nonheme iron is obtained from cereals, pulses, legumes, fruits, and vegetables.
In the blood, it is transported by transferrin to the cells or the bone marrow for erythropoiesis.
Iron absorption is controlled by ferroportin which allows or does not allow iron from the mucosal cell into the plasma.
Iron is absorbed in Fe⁺² (ferric) state
The iron is consumed in Fe+3 (ferrous) state and is reduced to Fe+2 state by the acidic gastric pH by enzyme ferric reductase.

Fe+2 is absorbed by the enterocytes and exported across the basolateral membrane into the bloodstream via Fe+2 transporter ferroportin.
The ferroportin-mediated efflux of Fe+2 is coupled by its reoxidation to Fe+3, catalyzed by ferroxidase hephaestin that interacts with ferroportin.
The total iron content of transferrin is dynamic and undergoes changes to sustain erythropoiesis.
Senescent RBCs are cleared by reticuloendothelial macrophages, which metabolize hemoglobin and heme, and release iron into the bloodstream.
The transferrin iron pool is replenished by iron recycled from RBCs and by newly absorbed dietary iron
Macrophages export Fe+2 from their plasma membrane via ferroportin, in a process coupled by reoxidation of Fe+2 to Fe+3 by ceruloplasmin and followed by the loading of Fe+3 to transferrin.

Regulation of iron homeostasis

Iron balance is mainly regulated at the point of absorption.
Hepcidin is a circulating peptide hormone secreted by the liver that plays a central role in the regulation of iron homeostasis.
This hormone is produced by hepatocytes and is a negative regulator of iron entry into plasma.
Hepcidin acts by binding to ferroportin.
Binding of hepcidin induces ferroportin degradation.
The loss of ferroportin from the cell surface prevents iron entry into plasma and decreased iron levels in the body.
Decreased expression of hepcidin leads to increased cell surface ferroportin and increased iron absorption.
Plasma hepcidin levels are regulated by cytokines, plasma iron, anemia, and hypoxia.
Overexpression of hepcidin leads to the anemia of chronic disease, while low hepcidin production results in hereditary hemochromatosis (HFE)
with consequent iron accumulation in vital organs [Figure 2]. Most hereditary iron disorders result from inadequate hepcidin production relative to the degree of tissue iron accumulation. Impaired hepcidin expression has been shown to result from mutations in any of 4 different genes: TfR2, HFE, hemochromatosis type 2 (HFE2), and hepcidin antimicrobial peptide (HAMP). Mutations in HAMP, the gene that encodes hepcidin, result in iron overload disease, as the absence of hepcidin permits constitutively high iron absorption. The role for other genes (TFR2, HFE, and HFE2) in the regulation of hepcidin production has been unclear.[27]

Storage

Ferritin concentration together with that of hemosiderin reflects the body iron stores.
They store iron in an insoluble form and are present primarily in the liver, spleen, and bone marrow.
Serum ferritin is the most convenient laboratory test to estimate iron stores.

Factors effecting iron absorption

Factors that enhance iron uptake are:
- Ascorbate and citrate increase iron uptake by acting as weak chelators.
- Iron is readily transferred from these compounds into the mucosal lining cells.

Factors inhibiting iron absorption are:
- Phytate (myo-inositol hexakisphosphate) is the main inhibitor of iron absorption.
- Calcium
- Animal proteins such as milk proteins, egg proteins, and albumin, have been shown to inhibit iron absorption.
- Proteins from soybean also decrease iron absorption.
- Suppresion of gastri acide such as use of antacids suprress iron absorption.
- Lead competes with iron for the absorption and blocks its absorption by competetive inhibition.

Iron requirement

Recommended Dietary Allowances (RDAs) for Iron
Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	0.27 mg*	0.27 mg*
7–12 months	11 mg	11 mg
1–3 years	7 mg	7 mg
4–8 years	10 mg	10 mg
9–13 years	8 mg	8 mg
14–18 years	11 mg	15 mg	27 mg	10 mg
19–50 years	8 mg	18 mg	27 mg	9 mg
51+ years	8 mg	8 mg

Pathogenesis

Iron deficiency anemia occurs when there is:
- Low dietary intake.
- Increased demands of iron.
- Impaired absorption of iron.
- Excessive loss of iron (blood loss).
- Increased hepcidin (chronic inflammation)
Low dietary intake:
- Iron is obtained from foods such as:
  - meat, such as lamb, pork, chicken, and beef
  - beans
  - pumpkin and squash seeds
  - leafy greens, such as spinach
  - raisins and other dried fruit
  - eggs
  - seafood, such as clams, sardines, shrimp, and oysters
  - iron-fortified dry and instant cereals Foods high in vitamin C include:
  - fruits such as oranges, grapefruits, strawberries, kiwis, guavas, papayas, pineapples, melons, and mangoes
    - broccoli
  - red and green bell peppers
  - Brussels sprouts
  - cauliflower
  - tomatoes
  - leafy greens
- Increased demands of iron
  - Growth, the requirement of iron increases during the developmental period from infancy to adolescence and during adolescence.
  - Pregnancy, during pregnancy the demand for iron is increased.
- Impaired absorption of iron:
  - Malabsorption
  - Deficiency of vitamin C in diet.
- Excessive loss of iron (blood loss)
  - The only means of excertion for iron is through blood loss.
  - Any source of external and internal bleeding can cause iron deficiency depending on the blood loss.
- Increased hepcidin
  - In chonric inflammatory conditions, the levels of hepcidin increase.
  - Increased hepcidin causes ferriportin degeneration and impaired iron absorption.
Iron is required for haemoglobin synthesis, so deficiency of iron leads to depletion of haemoglobin.
Decrease in haemoglobin leads to anemia.
Due to low haemoglobin, oxygen is not tranported effectively to cells and results in hypoxia.

Population	Hb Diagnostic of anaemia (g/dL)a
Children aged 6 months to 6 years old	<11.0
Children aged 6-14 years old	<12.0
Adult men	<13.0
Adult non-pregnant women	<12.0
Adult pregnant women	<11.0

Histology

(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey)

Iron deficiency anemia
Iron deficiency anemia
Iron deficiency anemia

Video

External Link

Center for disease control and prevention

References

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 ==Pathophysiology==
-There are several mechanisms that control [[human iron metabolism]] and safeguard against iron deficiency. The capacity of the body to absorb iron from the diet depends on the amount of iron in the body, the rate of red blood cell production, the amount and kind of iron in the diet, and the presence of absorption enhancers and inhibitors in the diet. Iron deficiency represents a spectrum ranging from iron depletion, which causes no physiological impairments, to [[iron deficiency anemia]], which affects the functioning of several  organ systems. A impairment in any of the above physiology can give rise to Iron deficiency anemia.
 ===Physiology===
-* In the human body, iron is present in all cells and has several vital functions such as:
+*Iron is needed for the synthesis of haemoglobin, new DNA synthesis and is a major component of oxidation and reduction enzymes.
-** A carrier of oxygen to the tissues from the lungs in the form of [[hemoglobin]] (Hb)
-** Facilitator of oxygen use and storage in the muscles as [[myoglobin]]
-** Transport medium for electrons within the cells in the form of [[cytochromes]]
-** Integral part of enzyme reactions in various tissues.
-* Total body iron averages approximately 3.8 g in men and 2.3 g in women.
-===Iron Hemostasis (Absorption and Bioavailability)===
+*In the human body, iron mainly exists as bound to protein (hemoprotein), as heme compounds (hemoglobin or myoglobin), heme enzymes, or nonheme compounds (flavin-iron enzymes, transferring, and ferritin).
-* There are several mechanisms that control [[human iron metabolism]] and safeguard against iron deficiency. The capacity of the body to absorb iron from the diet depends on the amount of iron in the body, the rate of red blood cell production, the amount and kind of iron in the diet, and the presence of absorption enhancers and inhibitors in the diet.
+*The body requires iron for the synthesis of its oxygen transport proteins, (hemoglobin and myoglobin), and for the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and oxidation-reductions.
-====Gastrointestinal Tract====
+*Human iron metabolism is controlled by various factors.
-* Regulation of iron balance occurs mainly in the gastrointestinal tract through absorption.
+*60% of the body iron is found in the hemoglobin present in circulating erythrocytes, 25% is contained in tranferrin and ferritin, and the remaining 15% is bound to myoglobin in muscle tissue and in a variety of enzymes involved in the oxidative metabolism and many other cell functions.
-* When the absorptive mechanism is operating normally, a person maintains functional iron and tends to establish iron stores.
+*Iron is bound and transported in the body via transferrin and stored in ferritin molecules.
-* The percentage of iron absorbed (i.e., iron bioavailability) can vary from less than 1% to greater than 50%.
-* The main factor controlling iron absorption is the amount of iron stored in the body.
-* The gastrointestinal tract increases iron absorption when the body's iron stores are low and decreases absorption when stores are sufficient. An increased rate of red blood cell production can also stimulate iron uptake severalfold.
-* Among adults, absorption of dietary iron averages approximately 6% for men and 13% for nonpregnant women in their childbearing years.
-* The higher absorption efficiency of these women reflects primarily their lower iron stores as a result of menstruation and pregnancy.
-* Among iron-deficient persons, iron absorption is also high. Absorption of iron increases during pregnancy, but the amount of the increase is not well defined; as iron stores increase postpartum, iron absorption decreases.
-====Dietary Composition====
-* Iron bioavailability also depends on dietary composition. Heme iron, which is found only in meat, poultry, and fish, is two to three times more absorbable than non-heme iron, which is found in plant-based foods and iron-fortified foods.
-* The bioavailability of non-heme iron is strongly affected by the kind of other foods ingested at the same meal.
-* Enhancers of iron absorption are heme iron (in meat, poultry, and fish) and [[vitamin C]]; inhibitors of iron absorption include polyphenols (in certain vegetables), tannins (in tea), phytates (in bran), and calcium (in dairy products).
-* Vegetarian diets, by definition, are low in [[heme]] iron. However, iron bioavailability in a vegeterian diet can be increased by careful planning of meals to include other sources of iron and enhancers of iron absorption.
-* In the diet of an infant, before the introduction of solid foods, the amount of iron absorbed depends on the amount and bioavailability of iron in breast milk or formula.
-====Iron Turn Over====
+*Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma from intestinal enterocytes or reticuloendothelial macrophages.
-* [[Red blood cell]] formation and destruction is responsible for most iron turnover in the body.
+*The binding of transferrin to the cell-surface transferrin receptor (TfR) 1 results in endocytosis and uptake of iron.
-* In adult men, approximately 95% of the iron required for the production of red blood cells is recycled from the breakdown of red blood cells and only 5% comes from dietary sources.
+*Internalized iron is transported to mitochondria for the synthesis of heme or other iron containing enzymes.
-* In contrast, an infant is estimated to derive approximately 70% of red blood cell iron from the breakdown of red blood cells and 30% from the diet.
+*Excess iron is stored in cytosolic ferritin.
-* In adults, approximately 1 mg of iron is lost daily through feces and desquamated mucosal and skin cells.
+====Absorption of iron====
-* Women of childbearing age require additional iron to compensate for menstrual blood loss (an average of 0.3-0.5 mg daily during the childbearing years) and for tissue growth during pregnancy and blood loss at delivery and postpartum (an average of 3 mg daily over 280 days' gestation).
+*Iron absorption occurs by the enterocytes in the duodenum and upper jejunum.
-* In all persons, a minute amount of iron is lost daily from physiological gastrointestinal blood loss.
+*Dietary iron occurs in two forms: heme and nonheme. The primary sources of heme iron are hemoglobin and myoglobin from consumption of meat, poultry, and fish, whereas nonheme iron is obtained from cereals, pulses, legumes, fruits, and vegetables.
-* Pathological gastrointestinal iron loss through gastrointestinal bleeding occurs in infants and children sensitive to cow's milk and in adults who have peptic ulcer disease, inflammatory bowel syndrome, or bowel cancer.
+*In the blood, it is transported by transferrin to the cells or the bone marrow for erythropoiesis.
-* Hookworm infections, although not common in the United States, are also associated with gastrointestinal blood loss and iron depletion
+*Iron absorption is controlled by ferroportin which allows or does not allow iron from the mucosal cell into the plasma.
+*Iron is absorbed in Fe<sup>+2</sup> (ferric) state
+*The iron is consumed in Fe+3 (ferrous) state and is reduced to Fe+2 state by the acidic gastric pH by enzyme ferric reductase.
+*
-====Iron Stores====
+*Fe+2 is absorbed by the enterocytes and exported across the basolateral membrane into the bloodstream via Fe+2 transporter ferroportin.
-* Iron present in the body beyond what is immediately needed for functional purposes is stored as the soluble protein complex ferritin or the insoluble protein complex hemosiderin.
+*The ferroportin-mediated efflux of Fe+2 is coupled by its reoxidation to Fe+3, catalyzed by ferroxidase hephaestin that interacts with ferroportin.
-* [[Ferritin]] and [[hemosiderin]] are present primarily in the [[liver]], [[bone marrow]], [[spleen]], and [[skeletal muscle]]s. Small amounts of ferritin also circulate in the plasma.
+*The total iron content of transferrin is dynamic and undergoes changes to sustain erythropoiesis.
-* In healthy persons, most iron is stored as ferritin (an estimated 70% in men and 80% in women) and smaller amounts are stored as hemosiderin. When long-term negative iron balance occurs, iron stores are depleted before iron deficiency begins.
+*Senescent RBCs are cleared by reticuloendothelial macrophages, which metabolize hemoglobin and heme, and release iron into the bloodstream.
-* Men store approximately 1.0-1.4 g of body iron, women approximately 0.2-0.4 g (18,28), and children even less.
+*The transferrin iron pool is replenished by iron recycled from RBCs and by newly absorbed dietary iron
-* Full-term infants of normal or high birthweight are born with high body iron (an average of 75 mg/kg body weight), to which iron stores contribute approximately 25%.
+*Macrophages export Fe+2 from their plasma membrane via ferroportin, in a process coupled by reoxidation of Fe+2 to Fe+3 by ceruloplasmin and followed by the loading of Fe+3 to transferrin.
-* Preterm or low-birthweight infants are born with the same ratio of total body iron to body weight, but because their body weight is low, the amount of stored iron is low too.
+====Regulation of iron homeostasis====
+*Iron balance is mainly regulated at the point of absorption.
-Iron deficiency represents a spectrum ranging from iron depletion, which causes no physiological impairments, to [[iron deficiency anemia]], which affects the functioning of several  organ systems. A impairment in any of the above physiology can give rise to Iron deficiency anemia.
+*Hepcidin is a circulating peptide hormone secreted by the liver that plays a central role in the regulation of iron homeostasis.
+*This hormone is produced by hepatocytes and is a negative regulator of iron entry into plasma.
+*Hepcidin acts by binding to ferroportin.
+*Binding of hepcidin induces ferroportin degradation.
+*The loss of ferroportin from the cell surface prevents iron entry into plasma and decreased iron levels in the body.
+*Decreased expression of hepcidin leads to increased cell surface ferroportin and increased iron absorption.
+*Plasma hepcidin levels are regulated by cytokines, plasma iron, anemia, and hypoxia.
+*Overexpression of hepcidin leads to the anemia of chronic disease, while low hepcidin production results in hereditary hemochromatosis (HFE)
+*with consequent iron accumulation in vital organs [Figure 2]. Most hereditary iron disorders result from inadequate hepcidin production relative to the degree of tissue iron accumulation. Impaired hepcidin expression has been shown to result from mutations in any of 4 different genes: TfR2, HFE, hemochromatosis type 2 (HFE2), and hepcidin antimicrobial peptide (HAMP). Mutations in HAMP, the gene that encodes hepcidin, result in iron overload disease, as the absence of hepcidin permits constitutively high iron absorption. The role for other genes (TFR2, HFE, and HFE2) in the regulation of hepcidin production has been unclear.[27]
+====Storage====
+*Ferritin concentration together with that of hemosiderin reflects the body iron stores.
+*They store iron in an insoluble form and are present primarily in the liver, spleen, and bone marrow.
+*Serum ferritin is the most convenient laboratory test to estimate iron stores.
+====Factors effecting iron absorption====
+*Factors that enhance iron uptake are:
+**Ascorbate and citrate increase iron uptake by acting as weak chelators.
+**Iron is readily transferred from these compounds into the mucosal lining cells.
+*Factors inhibiting iron absorption are:
+**Phytate (myo-inositol hexakisphosphate) is the main inhibitor of iron absorption.
+**Calcium
+**Animal proteins such as milk proteins, egg proteins, and albumin, have been shown to inhibit iron absorption.
+**Proteins from soybean also decrease iron absorption.
+**Suppresion of gastri acide such as use of antacids suprress iron absorption.
+**Lead competes with iron for the absorption and blocks its absorption by competetive inhibition.
+====Iron requirement====
+{| class="wikitable"
+|+Recommended Dietary Allowances (RDAs) for Iron
+!Age
+!Male
+!Female
+!Pregnancy
+!Lactation
+|-
+|Birth to 6 months
+|0.27 mg*
+|0.27 mg*
+|
+|
+|-
+|7–12 months
+|11 mg
+|11 mg
+|
+|
+|-
+|1–3 years
+|7 mg
+|7 mg
+|
+|
+|-
+|4–8 years
+|10 mg
+|10 mg
+|
+|
+|-
+|9–13 years
+|8 mg
+|8 mg
+|
+|
+|-
+|14–18 years
+|11 mg
+|15 mg
+|27 mg
+|10 mg
+|-
+|19–50 years
+|8 mg
+|18 mg
+|27 mg
+|9 mg
+|-
+|51+ years
+|8 mg
+|8 mg
+|
+|
+|}
+===Pathogenesis===
+*Iron deficiency anemia occurs when there is:
+**Low dietary intake.
+**Increased demands of iron.
+**Impaired absorption of iron.
+**Excessive loss of iron (blood loss).
+**Increased hepcidin (chronic inflammation)
+*Low dietary intake:
+**Iron is obtained from foods such as:
+***meat, such as lamb, pork, chicken, and beef
+***beans
+***pumpkin and squash seeds
+***leafy greens, such as spinach
+***raisins and other dried fruit
+***eggs
+***seafood, such as clams, sardines, shrimp, and oysters
+***iron-fortified dry and instant cereals Foods high in vitamin C include:
+***fruits such as oranges, grapefruits, strawberries, kiwis, guavas, papayas, pineapples, melons, and mangoes
+****broccoli
+***red and green bell peppers
+***Brussels sprouts
+***cauliflower
+***tomatoes
+***leafy greens
+**Increased demands of iron
+***Growth, the requirement of iron increases during the developmental period from infancy to adolescence and during adolescence.
+***Pregnancy, during pregnancy the demand for iron is increased.
+**Impaired absorption of iron:
+***[[Malabsorption]]
+***Deficiency of vitamin C in diet.
+**Excessive loss of iron (blood loss)
+***The only means of excertion for iron is through blood loss.
+***Any source of external and internal bleeding can cause iron deficiency depending on the blood loss.
+**Increased hepcidin
+***In chonric inflammatory conditions, the levels of hepcidin increase.
+***Increased hepcidin causes ferriportin degeneration and impaired iron absorption.
+*Iron is required for haemoglobin synthesis, so deficiency of iron leads to depletion of haemoglobin.
+*Decrease in haemoglobin leads to anemia.
+*Due to low haemoglobin, oxygen is not tranported effectively to cells and results in hypoxia.
+{| class="wikitable"
+!Population
+!Hb Diagnostic of anaemia (g/dL)a
+|-
+|Children aged 6 months to 6 years old
+|<11.0
+|-
+|Children aged 6-14 years old
+|<12.0
+|-
+|Adult men
+|<13.0
+|-
+|Adult non-pregnant women
+|<12.0
+|-
+|Adult pregnant women
+|<11.0
+|}
 ===Histology===
 (Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey)