PHYSIOLOGY:
DEFINITION:
The goal of physiology is to explain the physical and chemical factors that are responsible for the origin, development, and progression of life. Each type of life, from the simple virus to the largest tree or the complicated human being, has its own functional characteristics. Therefore, the vast field of physiology can be divided into viral physiology, bacterial physiology, cellular physiology, plant physiology, human physiology, and many more subdivisions.
HUMAN PHYSIOLOGY:
In human physiology, we attempt to explain the specific characteristics and mechanisms of the human body that make it a living being.
BLOOD:
Composition of the Blood
Blood volume 80–85 ml/kg body weight
Blood osmolality 280–296 mOsm
Blood pH 7.35–7.45
The total blood volume in the average-sized adult is about 5 liters, constituting about 8% of the total body weight. Blood leaving the heart is referred to as arterial blood. Arterial blood, with the exception of that going to the lungs, is bright red because of a high concentration of oxyhemoglobin (the combination of oxygen and hemoglobin) in the red blood cells. Venous blood is blood returning to the heart. Except for the venous blood from the lungs, it contains less oxygen, and is therefore a darker red.
Blood is composed of a cellular portion, called formed elements, and a fluid portion, called plasma. When a blood sample is centrifuged, the heavier formed elements are packed into the bottom of the tube, leaving plasma at the top. The formed elements constitute approximately 45% of the total blood volume (a measurement called the hematocrit), and the plasma accounts for the remaining 55%.
Functions of the Blood
The functions of the blood can be divided into three broad areas: transportation, regulation, and protection.
1. Transportation. All of the substances essential for cellular metabolism are transported by the blood these substances can be categorized as follows:
a. Respiratory. Red blood cells, or erythrocytes, transport oxygen to the cells. In the lungs, oxygen from the inhaled air attaches to hemoglobin molecules within the erythrocytes and is transported to the cells for aerobic respiration. Carbon dioxide produced by cell respiration is carried by the blood to the lungs for elimination in the exhaled air.
b. Nutritive. The digestive system is responsible for the mechanical and chemical breakdown of food so that it can be absorbed through the intestinal wall into the blood and lymphatic vessels. The blood then carries these absorbed products of digestion through the liver and to the cells of the body.
c. Excretory. Metabolic wastes (such as urea), excess water and ions, and other molecules not needed by the body are carried by the blood to the kidneys and excreted in the urine.
2. Regulation. The circulatory system contributes to both hormonal and temperature regulation.
a. Hormonal. The blood carries hormones from their site of origin to distant target tissues, where they perform a variety of regulatory functions.
b. Temperature. Temperature regulation is aided by the diversion of blood from deeper to more superficial cutaneous vessels or vice versa. When the ambient temperature is high, diversion of blood from deep to superficial vessels helps to cool the body, and when the ambient temperature is low, the diversion of blood from superficial to deeper vessels helps to keep the body warm.
3. Protection. The circulatory system protects against blood loss from injury and against foreign microbes or toxins introduced into the body.
a. Clotting. The clotting mechanism protects against blood loss when vessels are damaged.
b. Immune. The immune function of the blood is performed by the leukocytes (white blood cells) that protect against
Plasma
Plasma consists of water and dissolved solutes. The major solute of the plasma in terms of its concentration is Na+. In addition to sodium, plasma contains many other ions, as well as organic molecules such as metabolites, hormones, enzymes, antibodies, and other proteins.
Plasma Proteins
Plasma proteins constitute 7% to 9% of the plasma. The three types of proteins are albumins, globulins, and fibrinogen.
1. Albumins account for most (60% to 80%) of the plasma proteins and are the smallest in size. They are produced by the liver and provide the osmotic pressure needed to draw water from the surrounding tissue fluid into the capillaries. This action is needed to maintain blood volume and pressure.
2. Globulins are grouped into three subtypes: alpha globulins, beta globulins, and gamma globulins. The alpha and beta globulins are produced by the liver and function in transporting lipids and fat-soluble vitamins. Gamma globulins are antibodies produced by lymphocytes (one of the formed elements found in blood and lymphoid tissues) and function in immunity.
3. Fibrinogen which accounts for only about 4% of the total plasma proteins, is an important clotting factor produced by the liver. During the process of clot formation (described later in this chapter), fibrinogen is converted into insoluble threads of fibrin. Thus, the fluid from clotted blood, called serum, does not contain fibrinogen, but it is otherwise identical to plasma.
4. Prothrombin, which is blood clotting factor II.
5. Transferrin which is involved in the transport of iron. As old erythrocytes are destroyed in the spleen (and liver), their iron is released into the plasma and gets bound to transferrin. Almost all of this iron is delivered by transferrin to the bone marrow to be incorporated into new erythrocytes.
Plasma Volume
A number of regulatory mechanisms in the body maintain homeostasis of the plasma volume. If the body should lose water, the remaining plasma becomes excessively concentrated, its osmolality increases. This is detected by osmoreceptors in the hypothalamus, resulting in a sensation of thirst and the release of antidiuretic hormone (ADH) from the posterior pituitary. This hormone promotes water retention by the kidneys, which together with increased intake of fluids-helps to compensate for the dehydration and lowered blood volume. These regulatory mechanisms, together with others that influence plasma volume, are very important in maintaining blood pressure.
THE FORMED ELEMENTS OF BLOOD
The formed elements of blood include two types of blood cells: erythrocytes, or red blood cells, and leukocytes, or white blood cells.
ERYTHROCYTES
Erythrocytes are flattened, biconcave discs, about 7 µm in diameter and 2.2 µm thick. Their unique shape relates to their function of transporting oxygen; it provides an increased surface area through which gas can diffuse. Erythrocytes lack nuclei and mitochondria (they obtain energy through anaerobic respiration). Partly because of these deficiencies, erythrocytes have a relatively short circulating life span of only about 120 days. Older erythrocytes are removed from the circulation by phagocytic cells in the liver, spleen, and lymph nodes called macrophages. Erythrocytes contain hemoglobin molecules, which give blood its red color. Each hemoglobin molecule consists of four protein chains called globins, each of which is bound to one heme, a red-pigmented molecule that contains iron. The plasma membrane of erythrocytes contains specific polysaccharides and proteins that differ from person to person, and these confer upon the blood its so-called type, or group.
Concentration of Red Blood Cells in the Blood.
In normal men, the average number of red blood cells per cubic millimeter is 5,200,000 (±300,000); in normal women, it is 4,700,000 (±300,000). Persons living at high altitudes have greater numbers of red blood cells.
Quantity of Hemoglobin in the blood The whole blood of men contains an average of 15 grams of hemoglobin per 100 milliliters of cells; for women, it contains an average of 14 grams per 100 milliliters. Each gram of pure hemoglobin is capable of combining with 1.34 milliliters of oxygen. Therefore, in a normal man, a maximum of about 20 milliliters of oxygen can be carried in combination with hemoglobin in each 100 milliliters of blood, and in a normal woman, 19 milliliters of oxygen can be carried.
FUNCTIONS
1. The iron group of heme is able to combine with oxygen in the lungs and release oxygen in the tissues.
2. RBC’s contain a large quantity of carbonic anhydrase, an enzyme that catalyzes the reversible reaction between carbon dioxide and water to form carbonic acid, increasing the rate of this reaction several thousand fold. The rapidity of this reaction makes it possible for the water of the blood to transport enormous quantities of CO2 in the form of bicarbonate ion from the tissues to the lungs, where it is reconverted to CO2 and expelled into the atmosphere as a body waste product.
3. The hemoglobin in the cells is an excellent acid-base buffer, so that the red blood cells are responsible for most of the acid-base buffering power of whole blood.
GENESIS OF BLOOD CELLS
PLURIPOTENTIAL HEMATOPOIETIC STEM CELLS, GROWTH INDUCERS, AND DIFFERENTIATION INDUCERS.
The blood cells begin their lives in the bone marrow from a single type of cell called the pluripotential hematopoietic stem cell, from which all the cells of the circulating blood are eventually derived. The successive divisions of the pluripotential cells to form the different circulating blood cells. As these cells reproduce, a small portion of them remains exactly like the original pluripotential cells and is retained in the bone marrow to maintain a supply of these, although their numbers diminish with age.
The intermediate stage cells are very much like the pluripotential stem cells, even though they have already become committed to a particular line of cells and are called committed stem cells.
The different committed stem cells, when grown in culture, will produce colonies of specific types of blood cells. A committed stem cell that produces erythrocytes is called a colony-forming unit–erythrocyte, and the abbreviation CFU-E is used to designate this type of stem cell. Growth and reproduction of the different stem cells are controlled by multiple proteins called growth inducers. Four major growth inducers have been described, each having different characteristics. One of these, interleukin-3, promotes growth and reproduction of virtually all the different types of committed stem cells, whereas the others induce growth of only specific types of cells.
The growth inducers promote growth but not differentiation of the cells. This is the function of another set of proteins called differentiation inducers. Each of these causes one type of committed stem cell to differentiate one or more steps toward a final adult blood cell.
Stages of Differentiation of Red Blood Cells:
The first cell that can be identified as belonging to the red blood cell series is the proerythroblast. Once the proerythroblast has been formed, it divides multiple times, eventually forming many mature red blood cells. The first-generation cells are called basophil erythroblasts because they stain with basic dyes; the cell at this time has accumulated very little hemoglobin.
At the same time, the endoplasmic reticulum is also reabsorbed. The cell at this stage is called a reticulocyte because it still contains a small amount of basophilic material, consisting of remnants of the Golgi apparatus, mitochondria, and a few other cytoplasmic organelles. During this reticulocyte stage, the cells pass from the bone marrow into the blood capillaries by diapedesis (squeezing through the pores of the capillary membrane).
The remaining basophilic material in the reticulocyte normally disappears within 1 to 2 days, and the cell is then a mature erythrocyte. Because of the short life of the reticulocytes, their concentration among all the red cells of the blood is normally slightly less than 1 per cent.
Regulation of Red Blood Cell Production—Role of Erythropoietin
The total mass of red blood cells in the circulatory system is regulated within narrow limits, so that an adequate number of red cells are always available to provide sufficient transport of oxygen from the lungs to the tissues.
Tissue Oxygenation Is the Most Essential Regulator of Red Blood Cell Production.
Any condition that causes the quantity of oxygen transported to the tissues to decrease ordinarily increases the rate of red blood cell production. Thus, when a person becomes extremely anemic as a result of hemorrhage or any other condition, the bone marrow immediately begins to produce large quantities of red blood cells. At very high altitudes, where the quantity of oxygen in the air is greatly decreased, insufficient oxygen is transported to the tissues, and red cell production is greatly increased. In this case, it is not the concentration of red blood cells in the blood that controls red cell production but the amount of oxygen transported to the tissues in relation to tissue demand for oxygen.
Erythropoietin Stimulates Red Cell Production, and Its Formation Increases in Response to Hypoxia.
The principal stimulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein. In the absence of erythropoietin, hypoxia has little or no effect in stimulating red blood cell production. But when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production, and the erythropoietin in turn enhances red blood cell production until the hypoxia is relieved.
Effect of Erythropoietin in Erythrogenesis.
When an animal or a person is placed in an atmosphere of low oxygen, erythropoietin begins to be formed within minutes to hours, and it reaches maximum production within 24 hours. Yet almost no new red blood cells appear in the circulating blood until about 5 days later.
From this fact, as well as other studies, it has been determined that the important effect of erythropoietin is to stimulate the production of proerythroblasts from hematopoietic stem cells in the bone marrow. In addition, once the proerythroblasts are formed, the erythropoietin causes these cells to pass more rapidly through the different erythroblastic stages than they normally do, further speeding up the production of new red blood cells.
Maturation of Red Blood Cells—Requirement for Vitamin B12 (Cyanocobalamin) and Folic Acid
Especially important for final maturation of the red blood cells are two vitamins, vitamin B12 and folic acid. Both of these are essential for the synthesis of DNA, because each in a different way is required for the formation of thymidine triphosphate, one of the essential building blocks of DNA. Therefore, lack of either vitamin B12 or folic acid causes abnormal and diminished DNA and, consequently, failure of nuclear maturation and cell division.
Maturation Failure Caused by Poor Absorption of Vitamin B12 from the Gastrointestinal Tract—Pernicious Anemia.
A common cause of red blood cell maturation failure is failure to absorb vitamin B12 from the gastrointestinal tract. This often occurs in the disease pernicious anemia, in which the basic abnormality is an atrophic gastric mucosa that fails to produce normal gastric secretions. The parietal cells of the gastric glands secrete a glycoprotein called intrinsic factor, which combines with vitamin B12 in food and makes the B12 available for absorption by the gut. It does this in the following way: (1) Intrinsic factor binds tightly with the vitamin B12. In this bound state, the B12 is protected from digestion by the gastrointestinal secretions.(2) Still in the bound state, intrinsic factor binds to specific receptor sites on the brush border membranes of the mucosal cells in the ileum. (3) Then, vitamin B12 is transported into the blood during the next few hours by the process of pinocytosis, carrying intrinsic factor and the vitamin together through the membrane. Lack of intrinsic factor, therefore, causes diminished availability of vitamin B12 because of faulty absorption of the vitamin.
Once vitamin B12 has been absorbed from the gastrointestinal tract, it is first stored in large quantities in the liver, and then released slowly as needed by the bone marrow. The minimum amount of vitamin B12 required each day to maintain normal red cell maturation is only 1 to 3 micrograms, and the normal storage in the liver and other body tissues is about 1000 times this amount. Therefore, 3 to 4 years of defective B12 absorption are usually required to cause maturation failure anemia.
Failure of Maturation Caused by Deficiency of Folic Acid (Pteroylglutamic Acid).
Folic acid is a normal constituent of green vegetables, some fruits, and meats (especially liver). However, it is easily destroyed during cooking. Also, people with gastrointestinal absorption abnormalities, often have serious difficulty absorbing both folic acid and vitamin B12. Therefore, in many instances of maturation failure, the cause is deficiency of intestinal absorption of both folic acid and vitamin B12.
Formation of Heamoglobin
First, succinyl-CoA, formed in the Krebs metabolic cycle, binds with glycine to form a pyrrole molecule. In turn, four pyrroles combine to form protoporphyrin IX, which then combines with iron to form the heme molecule. Finally, each heme molecule combines with a long polypeptide chain, a globin synthesized by ribosomes, forming a subunit of hemoglobin called a hemoglobin chain. Each chain has a molecular weight of about 16,000; four of these in turn bind together loosely to form the whole hemoglobin molecule. There are several slight variations in the different subunit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. The different types of chains are designated alpha chains, beta chains, gamma chains, and delta chains. The most common form of hemoglobin in the adult human being, hemoglobin A, is a combination of two alpha chains and two beta chains. Hemoglobin A has a molecular weight of 64,458. Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are four hemoglobin chains in each hemoglobin molecule, one finds four iron atoms in each hemoglobin molecule; each of these can bind loosely with one molecule of oxygen, making a total of four molecules of oxygen (or eight oxygen atoms) that can be transported by each hemoglobin molecule. The types of hemoglobin chains in the hemoglobin molecule determine the binding affinity of the hemoglobin for oxygen. Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. For instance, in sickle cell anemia, the amino acid valine is substituted for glutamic acid at one point in each of the two beta chains. When this type of hemoglobin is exposed to low oxygen, it forms elongated crystals inside the red blood cells that are sometimes 15 micrometers in length. These make it almost impossible for the cells to pass through many small capillaries, and the spiked ends of the crystals are likely to rupture the cell membranes, leading to sickle cell anemia.
Destruction (Fate) of Red Blood Cells
When red blood cells are delivered from the bone marrow into the circulatory system, they normally circulate an average of 120 days before being destroyed. Red cells do have cytoplasmic enzymes that are capable of metabolizing glucose and forming small amounts of adenosine triphosphate. These enzymes also (1) maintain pliability of the cell membrane, (2) maintain membrane transport of ions, (3) keep the iron of the cells’ hemoglobin in the ferrous form rather than ferric form, and (4) prevent oxidation of the proteins in the red cells. Even so, the metabolic systems of old red cells become progressively less active, and the cells become more and more fragile, presumably because their life processes wear out. Once the red cell membrane becomes fragile, the cell ruptures during passage through some tight spot of the circulation. Many of the red cells self-destruct in the spleen, When the spleen is removed, the number of old abnormal red cells circulating in the blood increases considerably.
Destruction of Hemoglobin:
When red blood cells burst and release their hemoglobin, the hemoglobin is phagocytized almost immediately by macrophages in many parts of the body, but especially by the Kupffer cells of the liver and macrophages of the spleen and bone marrow. During the next few hours to days, the macrophages release iron from the hemoglobin and pass it back into the blood, to be carried by transferrin either to the bone marrow for the production of new red blood cells or to the liver and other tissues for storage in the form of ferritin. The porphyrin portion of the hemoglobin molecule is converted by the macrophages, through a series of stages, into the bile pigment bilirubin, which is released into the blood and later removed from the body by secretion through the liver into the bile.
IRON METABOLISM
Because iron is important for the formation not only of hemoglobin but also of other essential elements in the body (e.g., myoglobin, cytochromes, cytochrome oxidase, peroxidase, catalase), it is important to understand the means by which iron is utilized in the body.
The total quantity of iron in the body averages 4 to 5 grams, about 65 per cent of which is in the form of hemoglobin. About 4 per cent is in the form of myoglobin, 1 per cent is in the form of the various heme compounds that promote intracellular oxidation, 0.1 per cent is combined with the protein transferrin in the blood plasma, and 15 to 30 per cent is stored for later use, mainly in the reticuloendothelial system and liver parenchymal cells, principally in the form of ferritin.
TRANSPORT AND STORAGE OF IRON:
When iron is absorbed from the small intestine, it immediately combines in the blood plasma with a beta globulin, apotransferrin, to form transferrin, which is then transported in the plasma. The iron is loosely bound in the transferrin and, consequently, can be released to any tissue cell at any point in the body.
Excess iron in the blood is deposited especially in the liver hepatocytes and less in the reticuloendothelial cells of the bone marrow.
In the cell cytoplasm, iron combines mainly with a protein, apoferritin, to form ferritin. Apoferritin has a molecular weight of about 460,000, and varying quantities of iron can combine in clusters of iron radicals with this large molecule; therefore, ferritin may contain only a small amount of iron or a large amount. This iron stored as ferritin is called storage iron.
Smaller quantities of the iron in the storage pool are in an extremely insoluble form called hemosiderin.
ANEMIAS
Anemia means deficiency of hemoglobin in the blood, which can be caused by either too few red blood cells or too little hemoglobin in the cells. Some types of anemia and their physiologic causes are the following.
Symptoms
These depend upon whether the anemia is sudden in onset, as in severe hemorrhage, or gradual. In all cases, however, the striking sign is pallor, the depth of which depends upon the severity of the anemia. The color of the skin may be misleading, except in cases due to severe hemorrhage, as the skin of many Caucasian people is normally pale. The best guide is the colour of the internal lining of the eyelid. When the onset of the anemia is sudden, the patient complains of weakness and giddiness, and loses consciousness if he or she tries to stand or sit up. The breathing is rapid and distressed, the pulse is rapid and the blood pressure is low.
1. BLOOD LOSS ANEMIA.
After rapid hemorrhage, the body replaces the fluid portion of the plasma in 1 to 3 days, but this leaves a low concentration of red blood cells. If a second hemorrhage does not occur, the red blood cell concentration usually returns to normal within 3 to 6 weeks. In chronic blood loss, a person frequently cannot absorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. Red cells are then produced that are much smaller than normal and have too little hemoglobin inside them, giving rise to microcytic, hypochromic anemia which corresponds to a large extent with what used to be known as ‘secondary anemia’. It takes its name from the characteristic changes in the blood.
Causes
•As a result of trauma. This is perhaps the simplest example of all, when, as a result of an accident involving a large artery, there is severe hemorrhage.
•Menstruation. The regular monthly loss of blood which women sustain as a result of menstruation always puts a strain on the blood-forming organs. If this loss is excessive, then over a period of time it may lead to quite severe anemia.
•Childbirth. A considerable amount of blood is always lost at childbirth; if this is severe, or if the woman was anemic during pregnancy, a severe degree of anemia may develop.
•Bleeding from the gastrointestinal tract. The best example here is anaemia due to ‘bleeding piles’ (HAEMORRHOIDS). Such bleeding, even though slight, is a common cause of anaemia in both men and women if maintained over a long period of time. The haemorrhage may be more acute and occur from a DUODENAL ULCER or gastric ulcer, when it is known as haematemesis.
•Certain blood diseases, such as PURPURA and HAEMOPHILIA, which are characterized by bleeding.
Treatment
If, of course, there is hemorrhage, this must be arrested, and if the loss of blood has been severe it may be necessary to give a blood transfusion. Care must be taken to ensure that the patient is having an adequate diet.
2. MEGALOBLASTIC HYPERCHROMIC ANAEMIA
There are various forms of anaemia of this type, such as those due to nutritional deficiencies, but the most important is that known as pernicious anaemia.
Pernicious Anemia
Based on the earlier discussions of vitamin B12, folic acid, and intrinsic factor from the stomach mucosa, one can readily understand that loss of any one of these can lead to slow reproduction of erythroblasts in the bone marrow. As a result, the red cells grow too large, with odd shapes, having fragile membranes and are called megaloblasts. These cells rupture easily, leaving the person in dire need of an adequate number of red cells.
Causes
1. An autoimmune disease in which sensitised lymphocytes (see LYMPHOCYTE) destroy the PARIETAL cells of the stomach. These cells normally produce INTRINSIC FACTOR, the carrier protein for vitamin B12 that permits its absorption in the terminal part of the ILEUM. Lack of the factor prevents vitamin B12 absorption and this causes macrocytic (or megaloblastic) anaemia. 2. Atrophy of the stomach mucosa, as occurs in pernicious anemia, or loss of the entire stomach after surgical total gastrectomy can lead to megaloblastic anemia.
Treatment
Consists of injections of vitamin B12 in the form of hydroxocobalamin which must be continued for life.
3. APLASTIC ANAEMIA
It is a disease in which the red blood corpuscles are very greatly reduced, and in which no attempt appears to be made in the bone marrow towards their regeneration. It is more accurately called hypoplastic anaemia as the degree of impairment of bone-marrow function is rarely complete, but in rather less than half the cases the condition is due to some toxic substance, such as benzol or certain drugs, or ionising radiations.
Causes
The cause in many cases is not known but might be due to
• The micro-organism responsible for the infection has a deleterious effect upon the blood-forming organs, just as it does upon other parts of the body.
• Toxins. In conditions such as chronic glomerulonephritis (see KIDNEYS, DISEASES OF) and URAEMIA there is a severe anaemia due to the effect of the disease upon blood formation. •Drugs. Certain drugs, such as aspirin and the non-steroidal anti-inflammatory drugs, may cause occult gastrointestinal bleeding.
• A person exposed to gamma ray radiation from a nuclear bomb blast can sustain complete destruction of bone marrow, followed in a few weeks by lethal anemia.
• Excessive x-ray treatment, certain industrial chemicals, and even drugs to which the person might be sensitive can cause the same effect.
Treatment
Consists primarily of regular blood transfusions. Although the disease is often fatal, the outlook has improved in recent years: around 25 per cent of patients recover when adequately treated, and others survive for several years. In severe cases promising results are being reported from the use of bone-marrow transplantation.
4. HEMOLYTIC ANEMIA.
Different abnormalities of the red blood cells, many of which are hereditarily acquired, make the cells fragile, so that they rupture easily as they go through the capillaries, especially through the spleen. Even though the number of red blood cells formed may be normal, or even much greater than normal in some hemolytic diseases, the life span of the fragile red cell is so short that the cells are destroyed faster than they can be formed and serious anemia results. Some of these types of anemia are the following.
Causes
1. In Sickle cell anemia, the cells have an abnormal type of hemoglobin called hemoglobin S, containing faulty beta chains in the hemoglobin molecule. When this hemoglobin is exposed to low concentrations of oxygen, it precipitates into long crystals inside the red blood cell. These crystals elongate the cell and give it the appearance of a sickle rather than a biconcave disc. The precipitated hemoglobin also damages the cell membrane, so that the cells become highly fragile, leading to serious anemia. It progresses rapidly, eventuating in a serious decrease in red blood cells within a few hours and, often, death.
2. In Erythroblastosis fetalis, Rh-positive red blood cells in the fetus are attacked by antibodies from an Rh-negative mother. These antibodies make the Rh-positive cells fragile, leading to rapid rupture and causing the child to be born with serious anemia. The extremely rapid formation of new red cells to make up for the destroyed cells in erythroblastosis fetalis causes a large number of early blast forms of red cells to be released from the bone marrow into the blood.
5. IRON DEFICIENCY ANEMIA
Anemia due to the deficient quantity of iron in the body is called iron deficiency anemia.
Causes
Inadequate absorption of iron: This may occur in diseases of intestinal malabsorption. A severe form of this anemia in women, known as chlorosis, used to be common but is seldom seen nowadays.
Inadequate intake of iron: The daily requirement of iron for an adult is 12 mg and 15–20 mg for an adult woman during pregnancy. This is well covered by an ordinary diet, so that by itself it is not a common cause. But if there is a steady loss of blood, as a result of heavy menstrual loss or ‘bleeding piles’, the intake of iron in the diet may not be sufficient to maintain adequate formation of haemoglobin.
Treatment
Consists primarily of giving sufficient iron by mouth to restore, and then maintain, a normal blood picture. A preparation of iron is available which can be given intravenously, but this is only used in cases which do not respond to iron given by mouth, or in cases in which it is essential to obtain a quick response.
BLOOD TYPES; TRANSFUSION; TISSUE AND ORGAN TRANSPLANTATION
O-A-B Blood Types
A and B Antigens—Agglutinogens
Two antigens—type A and type B—occur on the surfaces of the red blood cells in a large proportion of human beings. It is these antigens (also called agglutinogens because they often cause blood cell agglutination) that cause most blood transfusion reactions.
Major O-A-B Blood Types.
In transfusing blood from one person to another, the bloods of donors and recipients are normally classified into four major O-A-B blood types, depending on the presence or absence of the two agglutinogens, the A and B agglutinogens. When neither A nor B agglutinogen is present, the blood is type O. When only type A agglutinogen is present, the blood is type A. When only type B agglutinogen is present, the blood is type B. When both A and B agglutinogens are present, the blood is type AB.
Genetic Determination of the Agglutinogens.
Two genes, one on each of two paired chromosomes, determine the O-A-B blood type. These genes can be any one of three types but only one type on each of the two chromosomes: type O, type A, or type B. The type O gene is either functionless or almost functionless, so that it causes no significant type O agglutinogen on the cells. Conversely, the type A and type B genes do cause strong agglutinogens on the cells.
The six possible combinations of genes are OO, OA, OB, AA, BB, and AB. These combinations of genes are known as the genotypes, and each person is one of the six genotypes.
AGGLUTININS
When type A agglutinogen is not present in a person’s red blood cells, antibodies known as anti-A agglutinins develop in the plasma. Also, when type B agglutinogen is not present in the red blood cells, antibodies known as anti-B agglutinins develop in the plasma.
Titer of the Agglutinins at Different Ages:
Immediately after birth, the quantity of agglutinins in the plasma is almost zero. Two to 8 months after birth, an infant begins to produce agglutinins—anti-A agglutinins when type A agglutinogens are not present in the cells, and anti-B agglutinins when type B agglutinogens are not in the cells.
Origin of Agglutinins in the Plasma:
The agglutinins are gamma globulins, as are almost all antibodies, and they are produced by the same bone marrow and lymph gland cells that produce antibodies to any other antigens. Most of them are IgM and IgG immunoglobulin molecules.
Blood Typing
Before giving a transfusion to a person, it is necessary to determine the blood type of the recipient’s blood and the blood type of the donor blood so that the bloods can be appropriately matched. This is called blood typing and blood matching, and these are performed in the following way: The red blood cells are first separated from the plasma and diluted with saline. One portion is then mixed with anti-A agglutinin and another portion with anti-B agglutinin. After several minutes, the mixtures are observed under a microscope. If the red blood cells have become clumped— that is, “agglutinated”—one knows that an antibody-antigen reaction has resulted.
O red blood cells have no agglutinogens and therefore do not react with either the anti-A or the anti-B agglutinins. Type A blood has A agglutinogens and therefore agglutinates with anti-A agglutinins. Type B blood has B agglutinogens and agglutinates with anti-B agglutinins. Type AB blood has both A and B agglutinogens and agglutinates with both types of agglutinins.
RH BLOOD TYPES
Along with the O-A-B blood type system, the Rh blood type system is also important when transfusing blood. The major difference between the O-A-B system and the Rh system is the following: In the O-A-B system, the plasma agglutinins responsible for causing transfusion reactions develop spontaneously, whereas in the Rh system, spontaneous agglutinins almost never occur. Instead, the person must first be massively exposed to an Rh antigen, such as by transfusion of blood containing the Rh antigen, before enough agglutinins to cause a significant transfusion reaction will develop.
Rh Antigens—“Rh-Positive” and “Rh-Negative” People:
There are six common types of Rh antigens, each of which is called an Rh factor. These types are designated C, D, E, c, d, and e. The type D antigen is widely prevalent in the population and considerably more antigenic than the other Rh antigens. Anyone who has this type of antigen is said to be Rh positive, whereas a person who does not have type D antigen is said to be Rh negative.
RH IMMUNE RESPONSE
Formation of Anti-Rh Agglutinins:
When red blood cells containing Rh factor are injected into a person whose blood does not contain the Rh factor—that is, into an Rh-negative person—anti-Rh agglutinins develop slowly, reaching maximum concentration of agglutinins about 2 to 4 months later. This immune response occurs to a much greater extent in some people than in others. With multiple exposures to the Rh factor, an Rh-negative person eventually becomes strongly “sensitized” to Rh factor.
Characteristics of Rh Transfusion Reactions:
If an Rh-negative person has never before been exposed to Rh-positive blood, transfusion of Rh-positive blood into that person will likely cause no immediate reaction. However, anti-Rh antibodies can develop in sufficient quantities during the next 2 to 4 weeks to cause agglutination of those transfused cells that are still circulating in the blood. These cells are then hemolyzed by the tissue macrophage system. Thus, a delayed transfusion reaction occurs, although it is usually mild. On subsequent transfusion of Rh-positive blood into the same person, who is now already immunized against the Rh factor, the transfusion reaction is greatly enhanced and can be immediate and as severe as a transfusion reaction caused by mismatched type A or B blood.
Erythroblastosis Fetalis (“Hemolytic Disease of the Newborn”)
Erythroblastosis fetalis is a disease of the fetus and newborn child characterized by agglutination and phagocytosis of the fetus’s red blood cells. In most instances of erythroblastosis fetalis, the mother is Rh negative and the father Rh positive. The baby has inherited the Rh-positive antigen from the father, and the mother develops anti-Rh agglutinins from exposure to the fetus’s Rh antigen. In turn, the mother’s agglutinins diffuse through the placenta into the fetus and cause red blood cell agglutination.
Incidence of the Disease:
An Rh-negative mother having her first Rh-positive child usually does not develop sufficient anti-Rh agglutinins to cause any harm. However, about 3 per cent of second Rh-positive babies exhibit some signs of erythroblastosis fetalis; about 10 per cent of third babies exhibit the disease; and the incidence rises progressively with subsequent pregnancies.
Effect of the Mother’s Antibodies on the Fetus:
After anti-Rh antibodies have formed in the mother, they diffuse slowly through the placental membrane into the fetus’s blood. There they cause agglutination of the fetus’s blood. The agglutinated red blood cells subsequently hemolyze, releasing hemoglobin into the blood. The fetus’s macrophages then convert the hemoglobin into bilirubin, which causes the baby’s skin to become yellow (jaundiced).The antibodies can also attack and damage other cells of the body.
Clinical Picture of Erythroblastosis:
The jaundiced, erythroblastotic newborn baby is usually anemic at birth, and the anti-Rh agglutinins from the mother usually circulate in the infant’s blood for another 1 to 2 months after birth, destroying more and more red blood cells. The hematopoietic tissues of the infant attempt to replace the hemolyzed red blood cells. The liver and spleen become greatly enlarged and produce red blood cells in the same manner that they normally do during the middle of gestation.
Treatment of the Erythroblastotic Neonate:
One treatment for erythroblastosis fetalis is to replace the neonate’s blood with Rh-negative blood. About 400 milliliters of Rh-negative blood is infused over a period of 1.5 or more hours while the neonate’s own Rh-positive blood is being removed. This procedure may be repeated several times during the first few weeks of life, mainly to keep the bilirubin level low and thereby prevent kernicterus. By the time these transfused Rh-negative cells are replaced with the infant’s own Rh-positive cells, a process that requires 6 or more weeks, the anti- Rh agglutinins that had come from the mother will have been destroyed.
Prevention of Erythroblastosis Fetalis:
The anti-D antibody is also administered to Rh-negative women who deliver Rh-positive babies to prevent sensitization of the mothers to the D antigen. This greatly reduces the risk of developing large amounts of D antibodies during the second pregnancy. The mechanism by which Rh immunoglobulin globin prevents sensitization of the D antigen is not completely understood, but one effect of the anti-D antibody is to inhibit antigen-induced B lymphocyte antibody production in the expectant mother. The administered anti-D antibody also attaches to D antigen sites on Rh-positive fetal red blood cells that may cross the placenta and enter the circulation of the expectant mother, thereby interfering with the immune response to the D antigen.
Transfusion Reactions Resulting from Mismatched Blood Types:
If donor blood of one blood type is transfused into a recipient who has another blood type, a transfusion reaction is likely to occur in which the red blood cells of the donor blood are agglutinated. It is rare that the transfused blood causes agglutination of the recipient’s cells, for the following reason: The plasma portion of the donor blood immediately becomes diluted by all the plasma of the recipient, thereby decreasing the titer of the infused agglutinins to a level usually too low to cause agglutination. Conversely, the small amount of infused blood does not significantly dilute the agglutinins in the recipient’s plasma. Therefore, the recipient’s agglutinins can still agglutinate the mismatched donor cells.
Acute Kidney Shutdown After Transfusion Reactions:
One of the most lethal effects of transfusion reactions is kidney failure, which can begin within a few minutes to few hours and continue until the person dies of renal failure.
The kidney shutdown seems to result from three causes: First, the antigen-antibody reaction of the transfusion reaction releases toxic substances from the hemolyzing blood that cause powerful renal vasoconstriction.
Second, loss of circulating red cells in the recipient, along with production of toxic substances from the hemolyzed cells and from the immune reaction, often causes circulatory shock. The arterial blood pressure falls very low, and renal blood flow and urine output decrease. Third, if the total amount of free hemoglobin released into the circulating blood is greater than the quantity that can bind with “haptoglobin” (a plasma protein that binds small amounts of hemoglobin), much of the excess leaks through the glomerular membranes into the kidney tubules. If this amount is still slight, it can be reabsorbed through the tubular epithelium into the blood and will cause no harm; if it is great, then only a small percentage is reabsorbed.
Yet water continues to be reabsorbed, causing the tubular hemoglobin concentration to rise so high that the hemoglobin precipitates and blocks many of the kidney tubules. Thus, renal vasoconstriction, circulatory shock, and renal tubular blockage together cause acute renal shutdown.
Transplantation of Tissues and Organs
Most of the different antigens of red blood cells that cause transfusion reactions are also widely present in other cells of the body, and each bodily tissue has its own additional complement of antigens. Thus, foreign cells transplanted anywhere into the body of a recipient can produce immune reactions.
Autografts, Isografts, Allografts, and Xenografts.
A transplant of a tissue or whole organ from one part of the same animal to another part is called an autograft; from one identical twin to another, an isograft; from one human being to another or from any animal to another animal of the same species, an allograft; and from a lower animal to a human being or from an animal of one species to one of another species, a xenograft.
Transplantation of Cellular Tissues:
In the case of autografts and isografts, cells in the transplant contain virtually the same types of antigens as in the tissues of the recipient and will almost always continue to live normally and indefinitely. At the other extreme, in the case of xenografts, immune reactions almost always occur, causing death of the cells in the graft within 1 day to 5 weeks after transplantation unless some specific therapy is used to prevent the immune reactions. Some of the different cellular tissues and organs that have been transplanted as allografts, either experimentally or for therapeutic purposes, from one person to another are skin, kidney, heart, liver, glandular tissue, bone marrow, and lung. With proper “matching” of tissues between persons, many kidney allografts have been successful for at least 5 to 15 years, and allograft liver and heart transplants for 1 to 15 years.
