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Blood physiology. Red Blood Cell Breakdown. Hemoglobin in RBC’s is broken down to bilirubin. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases.
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Red Blood Cell Breakdown • Hemoglobin in RBC’s is broken down to bilirubin. • Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. • Bilirubin is responsible for the yellow color of bruises, the straw-yellow color of urine, the brown color of feces, and the yellow discoloration in jaundice.
Red Blood Cell Breakdown • When RBC’s are old, their cell membranes become irregular and they become trapped in the reticular fibers in the spleen. A macrophage engulfs it, and breaks down the hemoglobin, which is made from heme (a porphyrrin ring), globin chains, and iron. These three segments of hemoglobin are detached from each other and liberated. Porphyrrin ring with iron (Fe) in the center
Red Blood Cell Breakdown • The globin chains (proteins) are broken down into amino acids (the building blocks of proteins), which are used for synthesis of any other proteins wherever they are needed. The alpha and beta chains are the globins. The heme units are the porphyrin rings.
Iron • Iron is essential to nearly all cells but also is quite toxic. • Iron is essential for its role in oxidation-reduction reactions needed for metabolism. • Its toxicity comes from its propensity to form oxygen radicals that damage cells. • Therefore, it has to be transported in the blood by special proteins, taken to cells that need it, and stored in those cells by being bound to other special proteins. • When hemoglobin is broken down, the iron (Fe+2)is released into plasma; a protein called apoferrin binds to it (now the apoferrin is called transferrin), and takes it into cells that can use or store it. The iron is stored in most body cells as ferritin (Fe+3) or as hemosiderin in white blood cells.
Apoferrin Iron Iron is transported to cells Transferrin Iron
Unconjugated (indirect) Bilirubin • The porphyrin ring is converted in the macrophage to unconjugated bilirubin, which is released into the blood. • Since unconjugated bilirubin is hydrophobic (not soluble in water), it needs to bind to albumin, which is a protein carrier. It will then be taken to the liver to be conjugated. • Total bilirubin and conjugated (direct) bilirubin levels can be measured in a blood test, whereas indirect bilirubin levels have to be calculated by subtracting direct bilirubin from total bilirubin.
IN BLOOD Albumin Unconjugated bilirubin Unconjugated bilirubin Unconjugated bilirubin is transported to liver Albumin
Unconjugated Hyperbilirubinemia • A high level of unconjugated (or indirect) bilirubin in a blood test is called Unconjugated Hyperbilirubinemia. • It can result from increased production of bilirubin because too many RBC’s are broken down (Hemolytic anemia such as malaria or Sickle Cell Disease). • It can also be caused from a liver problem that causes impaired conjugation, or impaired hepatic reuptake of bilirubin. • It can also occur naturally in newborns.
Conjugated (direct) Bilirubin • The unconjugated bilirubin It is taken to the liver, and enters a hepatocyte (liver cell). • Within the hepatocyte, it is conjugated (joined) with glucuronic acid, which makes it hydrophilic (water soluble). • It is now called conjugated bilirubin (or direct bilirubin). • The conjugated bilirubin first travels to the gallbladder as bile and then into the small intestine, where 95% of it is reabsorbed, goes back to the liver, back to the gall bladder, and is put back into the intestines again. This process is known as enterohepatic circulation.
IN LIVER Glucuronic acid Unconjugated bilirubin Glucuronic acid Conjugated bilirubin Conjugated bilirubin is transported to gall bladder, then to intestines. 95% is reabsorbed back to liver, then to gall bladder again. 5% goes through intestines
Conjugated (direct) Bilirubin • The other 5% is metabolized by colon bacteria to form urobilinogen, most of which is further oxidized to stercobilin, which gives feces its brown color. • A small amount of the urobilinogen is oxidized to uribilin and is excreted in the urine, which gives urine its yellow color.
IN COLON 95% Back to liver 5% goes to colon where bacteria there break it down. Urobilinogen 1% 99% Glucuronic acid Conjugated bilirubin Uribilin Turns feces brown Turns urine yellow Stercobilin
Conjugated (direct) Bilirubin • If there is a blockage of the bile duct, the conjugated bilirubin can only exit the body by the urine; it can only be oxidized to uribilin, so the high levels of uribilin will turn the urine a deep orange-yellow color. • Without the brown color in the feces, they will look white. • White stools indicate obstruction in the bile duct.
RBC Breakdown • http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter21/animation__hemoglobin_breakdown.html
Conjugated Hyperbilirubinemia • High serum levels of conjugated bilirubin mean that the liver is doing one of its jobs (conjugating the bilirubin), but the bilirubin is not being excreted in the stools. It can be caused by several things: • Liver disease, especially hepatitis. Although the liver conjugates the bilirubin, it is not reabsorbing it to be released into the intestines. • Obstruction of the bile duct. Hemolytic diseases such as malaria and Sickle Cell disease may predispose patients to biliary obstruction through the formation of pigment gallstones. • Obstructed bowels (especially from parasite infections, like tapeworms). • Systemic illness, such as sepsis or cardiogenic shock.
Excess Bilirubin • If there is excess unconjugated bilirubin, it will cause jaundice. • If there is excess conjugated bilirubin, it will turn the urine dark amber.
Excess Bilirubin • A patient may have increased urine bilirubin or increased urine urobilinogen. They may also have increased levels of serum (blood) bilirubin. • Performing blood and urine tests helps to identify the underlying pathology (what is causing the problem). • An elevated level of conjugated serum bilirubin implies liver disease. Therefore, because only conjugated bilirubin appears in urine, bilirubinuria also implies liver disease. • Unconjugated bilirubin is tightly bound to albumin, not filtered by the kidney, so it is never in the urine even with raised serum levels of unconjugated bilirubin.
Bilirubin in the Urine • If there is bilirubin in the urine (called bilirubinuria), it is always conjugated. Usually, their blood levels of conjugated bilirubin are also high. • In the assessment of a patient with raised total bilirubin, urinalysis for bilirubin and urobilinogen may be helpful in identifying the underlying pathology.
Common causes of raised bilirubin and urobilinogen • Raised conjugated bilirubin (bilirubinuria) • Liver disease • Drug toxicity • Raised unconjugated bilirubin (no bilirubinuria) • Hemolysis • Post viral hepatitis • Mild chronic hepatitis • Urinary urobilinogen • Liver damage • Hemolytic disease • Severe infections
Fetal vs. Adult Hemoglobin • Oxygen is carried on hemoglobin molecules inside red blood cells. • When a deoxygenated RBC from the capillary bed in the placenta of the fetus passes close to an oxygenated RBC in the mother’s blood vessel, the oxygen is pulled off the mother’s red blood cell and is pulled into the fetus’ red blood cell. • Why does this happen?
Fetal vs. Adult Hemoglobin • There are two types of hemoglobin: fetal hemoglobin and adult hemoglobin. • Fetal hemoglobin has a higher affinity for oxygen (attracts and holds onto oxygen more strongly) than does adult hemoglobin. • This causes oxygen to be pulled off the hemoglobin in the mother’s red blood cells, and the oxygen diffuses through her blood vessel into the blood vessel of the fetus, and into the hemoglobin in the red blood cell of the fetus.
Fetal vs. Adult Hemoglobin • When a baby is born, the placenta detaches and the fetus must oxygenate their own RBC’s from their lungs. • Since fetal hemoglobin has a high affinity for oxygen, it will not release the oxygen into the tissues very easily, so the old RBC’s with fetal hemoglobin need to go to the spleen to be destroyed during the first week of life, while new RBC’s with adult hemoglobin are made in the bone marrow and released into the blood stream.
Fetal vs. Adult Hemoglobin • Newborn hepatocytes are not mature enough to add the glucouronic acid to the porphyrin ring to conjugate it, so their liver often cannot handle this high level of hemolysis. • When the liver has reached its maximum capacity for conjugating the bilirubin, the excess unconjugated bilirubin leaks into the bloodstream, causing jaundice, which is common in newborns and not usually harmful. • Treatment is exposure to ultraviolet light, to assist the breakdown process of bilirubin.
Bilirubin Toxicity • However, too much unconjugated hyperbilirubinaemia in a newborn can lead to accumulation of bilirubin in the brain, causing irreversible damage, manifesting as seizures or abnormal reflexes and eye movements. • Kernicterus is a bilirubin-induced brain dysfunction. • This occurs more in newborns because the blood–brain barrier has yet to develop fully, and bilirubin can freely pass into the brain. • Newborns also are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult).
Videos • Kernicterus in kids • http://www.youtube.com/watch?v=BK-AMZXu5i8
Jaundice • When a person has jaundice, is it high levels of conjugated or unconjugated bilirubin? It depends on what is causing the jaundice. • Pre-hepatic jaundice: the bilirubin has not been conjugated yet because there is too much of it from hemolytic anemia • Hepatic jaundice: the bilirubin has not been conjugated yet because of liver damage such as alcoholism • Post-hepatic jaundice: the bilirubin has been conjugated but bile duct is obstructed.
Jaundice • Pre-hepaticjaundice is caused by anything which causes an increased rate of hemolysis (breakdown of red blood cells). • This can be caused by such things as malaria, sickle cell anemia, Hereditary Spherocytosis, Hemolytic Disease of the Newborn (HDN), glucose 6-phosphate dehydrogenase deficiency (G6DH). • Pre-hepatic jaundice will have increased unconjugated bilirubin in the serum.
Jaundice • Hepatic jaundice is from the inability of hepatocytes to conjugate and excrete bilirubin. This includes acute hepatitis, hepatotoxicity and alcoholic liver disease. Hepatic jaundice will have increased unconjugated bilirubin in the serum. In alcoholics, their conjugated bilirubin can also be high. • Post-hepaticjaundice, also called obstructive jaundice, is caused by a blockage in the bile duct (portal hypertension), usually by gallstones. Post-hepatic jaundice will have increased conjugated bilirubin in the serum.
Jaundice in alcoholics • In alcoholics, their unconjugated bilirubin levels are high in the serum because their hepatocytes are damaged. • Their conjugated bilirubin levels are high because they also lack albumin, ascites occurs, and the abdominal fluid puts pressure on bile duct, so the conjugated bilirubin is not removed from body. • It gets reabsorbed by intestines, and the serum levels of conjugated bilirubin are also increased. • Treatment for ascites is to drain the excess fluid out of the abdominal cavity and have the patient take a diuretic.
Hemosiderin • When blood leaves a ruptured blood vessel, the red blood cell dies, and the hemoglobin of the cell is released into the extracellular space. • White blood cells called macrophages engulf (phagocytose) the hemoglobin to degrade it, producing hemosiderin and then biliverdin. • Hemosiderin is causes the purple color of 2-day old bruises. • Biliverdin is the pigment responsible for the greenish color of 5-day old bruises. • Biliverdin breaks down into bilirubin, causing the bruise to turn yellow in 7-10 days.
The heme portion (porphyrin ring) of hemoglobin breaks down into biliverdin (which is green),which breaks down into unconjugated bilirubin (which is yellow)
Bruises • The appearance of a bruise changes over time, and you can tell how old a bruise is by its color. This is important in documenting domestic abuse and child abuse cases. • When a bruise is brand new, it will appear reddish due to the color of the blood that leaked from the capillaries under the skin. • At 1-2 days old, a bruise will take on a bluish or purple color. The swelling at the site of the bruise will cause oxygen to be cut off, and hemoglobin will turn blue. • At 6 days old, a bruise will turn a greenish color as the hemoglobin breaks down to biliverdin. • At 8-9 days old, the biliverdin will break down to unconjugated bilirubin, which is yellow. • At 10-14 days, the bilirubin will be oxidized and turn brown. • The skin should look normal 2-3 weeks after an injury.
