"DESTRUCTION OF RED BLOOD CELLS"
DESTRUCTION OF RED BLOOD CELLS The erythrocytes circulate normally about 120 days. The red blood cells are capable of metabolizing glucose by the glycolytic process, thus forming a small amount of ATP. The ATP in turn serves red cells in several important ways: 1. to maintain pliability of the cell membrane 2. to maintain membrane transport of ions 3. to keep the iron of the hemoglobin in the ferrous form 4. to prevent oxidation of the proteins in the red cells. But the metabolic system of the erythrocytes becomes progressively less active with time. As the cells become older they become progressively more fragile. The old erythrocytes may rupture during their passage through narrow capillaries mainly in the red pulp of the spleen. Here the spaces between trabeculae of the pulp are only 3 microns wide in comparison with the 8 microns diameter of the red cells. The old erythrocytes are recognized, phagocytosed and destroyed by the tissue macrophages mainly in the spleen, liver and bone marrow. The released hemoglobin is split into globin and hem. The globin is degraded to single amino acids. The hem ring is opened by the enzyme hemoxygenase to give free iron and a straight chain of four pyrrole nuclei. The free iron is released back into the blood to be carried by transferrin either to the bone marrow for production of new blood cells or to the liver and other tissues for storage in the form of ferritin or hemosiderin. The chain of four pyrrole nuclei is the substrate, from which the bile pigments are formed. The first pigment formed is biliverdin, but this is rapidly reduced by the enzyme biliverdinreductase to free bilirubin, which is released into the plasma. The free bilirubin combines with the plasma albumin and is transported to the liver. This albumin – bound bilirubin is water insoluble. Free bilirubin is absorbed through the hepatic cell membrane, and almost instantly combined with one of two proteins (called Z and Y proteins) inside the hepatic cell. Soon thereafter the bilirubin is also removed from these proteins and conjugated with glucuronic acid to form bilirubin-glucuronide. The water-soluble bilirubin-glucuronide is called conjugated bilirubin. The conjugated bilirubin is excreted into the bile canaliculi and then into the duodenum with the bile. A small portion of the conjugated bilirubin returns to the plasma, either directly into the liver sinusoids or indirectly by absorption into the blood from the bile ducts or lymphatics. In the intestine the bilirubin is converted by bacterial action into the substance urobilinogen, which is highly soluble. Some of the urobilinogen is reabsorbed through the intestinal mucosa into the blood. Most of this is reexcreted by the liver back into the gut (entero-hepatic circulation), but at about 5 per cent is excreted by the kidney, into the urine. After exposure to air in the urine, the urobilinogen becomes oxidized to urobilin. The 1 urobilinogen left in the intestine is converted into stercobilinogen and this is oxidized to form stercobilin. In a healthy adult man the plasma concentration of the total bilirubin does not exceed 22 mol/l. The conjugated bilirubin make 1/6 – 1/5 the total bilirubin. Jaundice A yellowish tint of the skin and other tissues is characteristic of jaundice or icterus. The usual cause of jaundice is a large quantity of bilirubin (both types) in the extracellular fluids. There are three basic types of icterus: 1. Increased destruction of red blood cells with rapid release of bilirubin into the blood causes the so-called hemolytic icterus. In this type of icterus the excretory function of the liver is not impaired, but the hepatic cells cannot excrete the bilirubin as rapidly as it is formed. The plasma concentration of free bilirubin increases. 2. The second type of icterus is called hepatocellular icterus, which is caused by damage to the hepatic cells (infection, drugs). In this type the rate of bilirubin formation is normal, but the hepatic cells are not capable of conjugating bilirubin with glucuronic acid and to excrete bilirubin into the bile. Therefore the plasma concentrations of both conjugated and free bilirubin rise to levels much above normal. 3. The blockage of the bile ducts causes obstructive icterus. The rate of bilirubin formation is normal too, but the conjugated bilirubin cannot pass from the hepatic cells into the gut. The conjugated bilirubin is returned to the blood and therefore plasma concentration of conjugated bilirubin increases. Diagnostic Differences between Free and Conjugated Bilirubin A simple test called van den Bergh reaction can be used to differentiate between both types of bilirubin in the plasma. If an immediate reaction occurs with the van den Bergh reagent (which gives the colorimetric change), the bilirubin is in the conjugated type. The reaction is called a direct van den Bergh reaction. However, to demonstrate the presence of free bilirubin, one must add alcohol to the plasma. This precipitates the protein and releases the free bilirubin from its protein complex so that it can then combine with the van den Bergh reagent. This reaction is called indirect van den Bergh reaction. Another major difference between free and conjugated bilirubin is that kidneys can excrete only the highly soluble conjugated bilirubin but not the albumin-bound free bilirubin. 2