Physiology of Iron Metabolism Notes

Hemoglobin and Iron Metabolism Introduction

Hemoglobin (Hb) is the iron-containing coloring matter of RBC. It is a chromoprotein forming 95% of dry weight of RBC and 30-34% of wet weight. The function of hemoglobin is to carry respiratory gases, oxygen, and carbon dioxide. It also acts as a buffer. The molecular weight of hemoglobin is 68,000.

Normal Hemoglobin Content

The average hemoglobin (Hb) content in the blood is 14 to 16 g/dL. However, the value varies depending upon the age and sex of the individual.

Age:

• At birth: 25 g/dL
• After 3rd month: 20 g/dL
• After 1 year: 17 g/dL
• From puberty onwards: 14-16 g/dL

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At the time of birth, hemoglobin content is very high because of the increased number of RBCs.

Sex

• In adult males: 15 g/dL
• In adult females: 14.5 g/dL

Functions Of Hemoglobin

Transport Of Respiratory Gases: The main function of hemoglobin is the transport of respiratory gases:

1. Oxygen from the lungs to tissues
2. Carbon dioxide from tissues to lungs.

1. Transport of Oxygen

• When oxygen binds with hemoglobin, a physical process called oxygenation occurs resulting in the formation of oxyhemoglobin. The iron remains in a ferrous state in this compound.
• Oxyhemoglobin is an unstable compound and the combination is reversible, i.e. when more oxygen is available it combines with hemoglobin, and whenever oxygen is required, hemoglobin can release oxygen readily.
• When oxygen is released from oxyhemoglobin, it is called reduced hemoglobin or ferrohemoglobin.

2. Transport of Carbon Dioxide

• When carbon dioxide binds with hemoglobin, carbhemoglobin is formed. It is also an unstable compound and the combination is reversible, i.e. carbon dioxide can be released from this compound.
• The affinity of hemoglobin for carbon dioxide is 20 times more than for oxygen.

Buffer Action: Hemoglobin acts as a buffer and plays an important role in adult hemoglobin, the globin contains two chains in acid-base balance.

Structure Of Hemoglobin

• Hemoglobin is a conjugated protein. It consists of a protein combined with an iron-containing pigment.
• The protein part is globin and the iron-containing pigment is heme. Heme also forms a part of the structure of myoglobin (oxygen-binding pigment in muscles) and neuroglobin (oxygen-binding pigment in brain).

Iron: Normally, it is present in ferrous (Fe⁺⁺) form. It is in unstable or loose form. In some abnormal conditions, the iron is converted into ferric (Fe⁺⁺⁺) state, which is a stable form.

Porphyrin:

• The pigment part of heme is called porphyrin. It is formed by four pyrrole rings (tetrapyrrole) called, 1, 2, 3, and 4. The pyrole rings are attached to one another by methane (CH4) bridges.
• The iron is attached to N- of each pyrrole ring and N of the globin molecule.

Globin: This contains four polypeptide chains. Among the four polypeptide chains, two are α chains and two are ẞ chains.

Types Of Normal Hemoglobin

Hemoglobin is of two types:

1. Adult hemoglobin – HbA
2. Fetal hemoglobin – HbF

The replacement of fetal hemoglobin by adult hemoglobin starts immediately after birth. It is completed at about 10th to 12th week after birth. Both types of hemoglobin differ from each other structurally and functionally.

Structural Difference: In adult hemoglobin, the globin contains two chains and two ẞ chains. In fetal hemoglobin, there are two α chains and two y chains instead of ẞ chains.

Functional Difference: Functionally, fetal hemoglobin has more affinity for oxygen than that of adult hemoglobin. And, the oxygen hemoglobin dissociation curve of fetal blood is shifted to left.

Abnormal Hemoglobin

• The abnormal types of hemoglobin or hemoglobin variants are the pathologic mutant forms of hemoglobin.
• These variants are produced because of structural changes in the polypeptide chains caused by mutation in the genes of the globin chains.
• Most of the mutations do not produce any serious problem. Occasionally few mutations result in some disorders.
• There are two categories of abnormal hemoglobin:

1. Hemoglobinopathies
2. Hemoglobin in thalassemia and related disorders.

1. Hemoglobinopathies: Hemoglobinopathy is a genetic disorder caused by abnormal polypeptide chains of hemoglobin. Some of the hemoglobinopathies are:

1. Hemoglobin S: It is found in sickle cell anemia. In this, the α chains are normal and ẞ chains are abnormal
2. Hemoglobin C: The ẞ chains are abnormal. It is found in people with hemoglobin C disease which is charac- terized by mild hemolytic anemia and splenomegaly.
3. Hemoglobin E: Here also the ẞ chains are abnormal. It is present in people with hemoglobin E disease which is also characterized by mild hemolytic anemia and splenomegaly
4. Hemoglobin M: It is the abnormal hemoglobin present in the form of methemoglobin. It occurs due to mutation of genes of both in α and ẞ chains resulting in abnormal replacement of amino acids. It is present in babies affected by hemoglobin M disease or blue baby syndrome. It is an inherited disease characterized by methemoglobinemia.

2. Hemoglobin in Thalassemia and Related Disorders:

• In thalassemia different types of abnormal hemoglobins are present. The polypeptide chains are decreased, absent, or abnormal.
• In thalassemia, the α chains are decreased, absent, or abnormal, and in ẞ thalassemia, the ẞ chains are decreased, absent, or abnormal.
• Some of the abnormal hemoglobins found in thalassemia are hemoglobin G, H, I, Bart’s, Kenya, Lepore, and constant spring.

Abnormal Hemoglobin Derivatives

• The term ‘Hemoglobin derivatives’ refers to a blood test to detect and measure the percentage of abnormal hemoglobin derivatives.
  Hemoglobin is the only carrier for the transport of oxygen without which tissue death occurs within few minutes.
• When hemoglobin is altered its oxygen-carrying capacity is decreased resulting in a lack of oxygen. So it is important to know about the causes and the effects of abnormal hemoglobin derivatives.
• Abnormal hemoglobin derivatives are formed by carbon monoxide poisoning or due to some drugs like nitrites, nitrates, and sulphonamides.

The abnormal hemoglobin derivatives are:

1. Carboxyhemoglobin
2. Methemoglobin
3. Sulfhemoglobin.

Normal percentage of hemoglobin derivatives in total hemoglobin:

1. Carboxyhemoglobin : 3-5 %
2. Methemoglobin: less than 3%
3. Sulfhemoglobin: trace (undetectable).

The abnormally high levels of hemoglobin derivates in the blood produce serious effects. These derivatives prevent the transport of oxygen resulting in oxygen lack in tissues which may be fatal.

Carboxyhemoglobin

• Carboxyhemoglobin or carbon mon oxyhemoglobin is the abnormal hemoglobin derivative formed by the combination of carbon monoxide with hemoglobin.
• Carbon monoxide is a colorless and odorless gas. Since hemoglobin has 200 times more affinity for carbon monoxide than oxygen it hinders the transport of oxygen resulting in tissue hypoxia.
• Normally, 1-3% of hemoglobin is in the form of carboxyhemoglobin.

Sources of Carbon Monoxide

1. Charcoal burning
2. Coal mines
3. Deep wells
4. Underground drainage system
5. The exhaust of gasoline engines
6. Gases from guns and other weapons
7. Heating system with poor or improper ventilation
8. Smoke from fire
9. Tobacco smoking.

Signs and Symptoms Of Carbon Monoxide Poisoning

1. While breathing air with less than 1% of CO, the Hb saturation is 15-20%, and mild symptoms like headache and nausea appear
2. While breathing air with more than 1% CO, the Hb saturation is 30-40%. It causes severe symptoms like:
   1. Convulsions
   2. Cardiorespiratory arrest
   3. Unconsciousness and coma.
3. When Hb saturation increase above 50%, death occurs.

Methemoglobin

• Methemoglobin is the abnormal hemoglobin derivative formed when iron molecule of hemoglobin is oxidized from normal ferrous state to a ferric state. Methemoglobin is also called ferrihemoglobin.
• Normal methemoglobin level is 0.6-2.5% of total hemoglobin.
• Under normal circumstances also body faces the threat of continuous production of methemoglobin.
• But it is counteracted by the erythrocyte protective system – the nicotinamide adenine dinucleotide (NADH) system which operates through two enzymes:

1. Diaphorase 1 (nicotinamide adenine dinucleotide phosphate (NADPH) dependent reductase) – responsible for 95% of the action
2. Diaphorase 2 (NADPH-dependent methemoglobin reductase) is responsible for 5% of the action. These two enzymes prevent the oxidation of ferrous iron into ferric iron.

Methemoglobinemia: Methemoglobinemia is a disorder with high level of methemoglobin in blood. It leads to tissue hypoxia which causes cyanosis and other symptoms. It is caused by a variety of factors:

1. Common factors of daily life:
   1. Well water contaminated with nitrates and nitrites
   2. Fires
   3. Laundry ink
   4. Match sticks and explosives
   5. Meat preservatives (which contain nitrates and nitrites)
   6. Mothballs (naphthalene balls)
   7. Room deodorizer propellants.
2. Exposure to industrial chemicals such as:
   1. Aromatic amines
   2. Fluorides
   3. Irritant gases like nitrous oxide and nitrobenzene
   4. Propylene glycol dinitrate.
3. Drugs:
   1. Antibacterial drugs like sulfonamides
   2. Antimalarial drugs like chloroquine
   3. Antiseptics
   4. Inhalant in cyanide antidote kit
   5. Local anesthetics like benzocain.
4. Hereditary trait: Deficiency of NADH dependant reductase or presence of abnormal hemoglobin M which is common in babies affected by blue baby syndrome. It is a pathological condition in infants characterized by bluish skin discoloration (cyanosis) caused by congenital heart defect.

Sulfhemoglobin

• Sulfhemoglobin is the abnormal hemoglobin derivative formed by the combination of hemoglobin with hydrogen sulfide.
• It is caused by drugs such as phenacetin or sulfonamides.
• Normal sulfhemoglobin level is less than 1% of total hemoglobin.
  Sulfhemoglobin cannot be converted back into hemoglobin.
• Only way to get rid of this from the body is to wait until the affected RBCs with sulfhemoglobin are destroyed after their life span.

Blood Level of Sulfhemoglobin

• Normally very negligible amount of sulfhemoglobin is present in blood which is nondetectable.
• But when its level rises above 10 gm/dL cyanosis occurs. Usually serious toxic effects are not noticed.

Synthesis Of Hemoglobin

• Synthesis of hemoglobin actually starts in proerythroblastic stage. However, hemoglobin appears in the intermediate normoblastic stage only. The production of hemoglobin is continued until the stage of reticulocyte.
• The heme portion of hemoglobin is synthesized in mitochondria. And the protein part, globin is synthesized in ribosomes.

Synthesis Of Heme: Heme is synthesized from succinyl CoA and glycine. The sequence of events in synthesis of hemoglobin:

1. The first step in heme synthesis takes place in the mitochondrion. Two molecules of succinyl CoA combine with two molecules of glycine and condense to form 8-aminolevulinic acid (ALA) by ALA synthase.
2. ALA is transported to the cytoplasm. Two molecules of ALA combine to form porphobilinogen in the presence of ALA dehydratase.
3. Porphobilinogen is converted into uroporphobilinogen 1 by uroporphobilinogen 1 synthase
4. Uroporphobilinogen 1 is converted into uroporpho- urobilinogen 3 by porphobilinogen 3 synthase
5. From uroporphobilinogen 3 a ring structure called coproporphyrinogen 3 is formed by uroporphobilinogen decarboxylase
6. Coproporphyrinogen 3 is transported back to the mitochondrion where it is oxidized to form proto-porphyrinogen 9 by coproporphyrinogen oxidase
7. Protoporphyrinogen 9 is converted into protoporphyrin 9 by protoporphyrinogen oxidase
8. Protoporphyrin 9 combines with iron to form heme in the presence of ferrochelatase.

Formation Of Globin

1. The polypeptide chains of globin are produced in the ribosomes. There are four types of polypeptide chains namely, alpha, beta, gamma, and delta chains.
2. Each of these chains differs from the others by the amino acid sequence. Each globin molecule is formed by the combination of 2 pairs of chains and each chain is made of 141-146 amino acids. Adult hemoglobin contains two alpha chains and two beta chains. Fetal hemoglobin contains two alpha chains and two gamma chains.

Configuration: Each polypeptide chain combines with one heme molecule. Thus, after the complete configuration, each hemoglobin molecule contains 4 polypeptide chains and 4 heme molecules.

Substances Necessary For Hemoglobin Synthesis: Various materials are essential for the formation of hemoglobin in the RBC.

Destruction Of Hemoglobin

• After the lifespan of 120 days, the RBC is destroyed in the reticuloendothelial system, particularly in the spleen and the hemoglobin is released into plasma. Soon, the hemoglobin is degraded in the reticuloendothelial cells and split into globin, iron, and porphyrin.
• Globin is utilized for the resynthesis of hemoglobin. Iron is stored in the body as ferritin and hemosiderin, which are reutilized for synthesis of new hemoglobin.
• Porphyrin is converted into a green pigment called biliverdin. In human being, most of the biliverdin is converted into a yellow pigment called bilirubin.
• Bilirubin and biliverdin are together called bile pigments.

Iron Metabolism

Importance Of Iron:

• Iron is an essential mineral and an important component of proteins involved in oxygen transport. So, human body needs iron for oxygen transport.
• Iron is important for the formation of hemoglobin and myoglobin. Iron is also necessary for the formation of other substances like cytochrome, cytochrome oxidase, peroxidase, and catalase.

Normal Value And Distribution Of Iron In The Body: The total quantity of iron in the body is about 4 grams. The approximate distribution of iron in the body is as follows:

• In the hemoglobin: 65-68%
• In the muscle as myoglobin: 4%
• As intracellular oxidative heme compound: 1%
• In the plasma as transferrin: 0.1%
• Stored in the reticuloendothelial system: 25-30%

Dietary Iron: Dietary iron is available in two forms called heme and nonheme.

Heme Iron: Heme iron is present in fish, meat, and chicken. Iron in these sources is found in the form of heme. Heme iron is absorbed easily from intestine.

Nonheme Iron:

• Iron in the form of nonheme is available in vegetables, grains, and cereals. Nonheme iron is not absorbed easily as heme iron.
• Cereals, flours, and products of grains that are enriched or fortified (strengthened) with iron become good dietary sources of nonheme iron, particularly for children and women.

Absorption Of Iron: Iron is absorbed mainly from the small intestine. it is absorbed through the intestinal cells by pinocytosis and transported into the blood. Bile is essential for the absorption of iron.

Transport Of Iron: Immediately after absorption into the blood, iron combines with a ẞ globulin called apo transferrin resulting in the formation of transferrin. And iron is transported in blood in the form of transferrin. Iron combines loosely with globin and can be released easily at any region of the body.

Storage Of Iron:

• Iron is stored in large quantities in reticuloendothelial cells and liver hepatocytes. In other cells also, it is stored in small quantities.
• In the cytoplasm of the cell, iron is stored as ferritin in large amount. Small quantity of iron is also stored as hemosiderin.

Daily Loss Of Iron

• In males, about 1 mg of iron is excreted every day through feces. In females, the amount of iron loss is very much high. This is because of the menstruation.
• One gram of hemoglobin contains 3.34 mg of iron. Normally, 100 ml of blood contains 15 gm of hemoglobin and about 50 mg of iron (3.34 x 15). So, if 100 mL of blood is lost from the body, there is a loss of about 50 mg of iron.
• In females, during every menstrual cycle, about 50 mL of blood is lost by which 25 mg of iron is lost. That is why the iron content is always less in females than in males.
• Iron is lost during hemorrhage and blood donation also. If 450 mL of blood is donated, about 225 mg of iron is lost.

Regulation Of Total Iron In The Body:

• Absorption and excretion of iron are maintained almost equally under normal physiological conditions.
• When the iron storage is saturated in the body, it automatically reduces the further absorption of iron from the gastrointestinal tract by a feedback mechanism.

The factors which reduce the absorption of iron are:

1. Stoppage of apo transferrin formation in the liver, so that, the iron cannot be absorbed from the intestine
2. Reduction in the release of iron from the transferrin so that, transferrin is completely saturated with iron and further absorption is prevented.