Hemoglobin Catabolism and Bilirubin Formation

When normal erythrocytes come to the end of their life span, normally about 120 days, they are removed from the blood stream by reticuloendothelial cells by a process known as Extravascular Hemolysis. The chief site of phagocytosis is the spleen, but in hemolytic disease the liver and bone marrow also assume this function. Within the reticuloendothelial cells, hemoglobin is degraded to bilirubin by a series of degradations that first involve the splitting of globin from the heme, followed by the opening of the porphyrin ring at the alpha-methene bridge, yielding biliverdin and carbon monoxide. The globin is returned to the plasma protein and amino acid pool, and the heme iron is returned to the plasma iron pool.

The formation of bilirubin is an intracellular process. Bilirubin then passes out of the cell into the blood where it is bound to albumin. In this form the bilirubin is unconjugated and indirect reacting. Unconjugated bilirubin is cleared rapidly from the blood by the parenchymal cells of the liver where it is conjugated with glucuronic acid. In this form the bilirubin is conjugated and direct reacting. The preferred usage is to call the unconjugated form simply bilirubin and the conjugated form conjugated bilirubin. The enzyme glucuronyl transferase is required for conjugation. In the conjugated form it is secreted into the bile ducts of the liver and passes into the small intestine by way of the common bile duct.

Most of the conjugated bilirubin in human beings is in the form of the diglucuronide with a minor component as the monoglucuronide. In normal serum the total bilirubin concentrations is 0.1 to 1.0 mg/dl. Of this it is common to find normally 0 to 0.2 mg/dl of the direct-reacting pigment. If no block exists in the bile duct system, bilirubin glucuronide is excreted into the duodenum through the ampulla of Vater. In the intestine it is reduced by bacterial action to the colorless compound mesobilirubinogen. Urobilinogen, stercobilinogen, and other related compounds are formed from mesobilirubinogen and excreted in both urine and feces. Urobilinogen is partially absorbed from the colon into the blood. a little is excreted in the urine, and 35% to 70% of it is returned to the liver by the portal circulation. It is then reexcreted by the liver cells. When parenchymal liver damage exists, absorbed urobilinogen cannot be excreted by the liver cells, is rejected, and remains in the bloodstream. It then appears in the urine in large amounts. On the other hand, sterilization, even partial, of the bacterial flora of the gastrointestinal tract by antibiotics reduces the conversion of bilirubin to urobilinogen, resulting in low fecal and urinary urobilinogen excretion. The final step, oxidation of urobilinogen and stercobilinogen to urobilin and stercobilin, probably occurs chiefly when excreta are allowed to stand. It is important that examinations for urobilinogen and stercobilinogen be carried out on freshly passed specimens.

Red cells which lyse while circulating in the blood vessels are catabolized by a process known as intravascular hemolysis. Normally only a small portion of RBC breakdown occurs in this manner. Hemoglobin released from the red cells undergoes one of two initial changes when released into the plasma. The tetramer may split in two forming a hemoglobin dimer, or the hemoglobin may oxidize into methemoglobin.

The hemoglobin dimer binds with a plasma transport protein known as haptoglobin, where it is carried to the liver and metabolized in the same manner as with extravascular hemolysis, with the iron being returned to the iron stores and the release of bilirubin. If the hemopexin binding capacity is exceeded, the free dimers travel to the kidneys where they are excreted as hemoglobin (hemoglobinuria), or methemoglobin, and the iron is deposited in tubular epithelial cells as hemosiderin.

Methemoglobin in plasma disintegrates, with the globin portion being released from the heme. This heme molecule may bind with hemopexin, which carries it to the liver, or, when the hemopexin binding capacity is reached, it may bind with albumin forming methemalbumin. In this form it cannot be transferred to the liver, and thus circulates in the plasma until additional hemopexin may be synthesized or released for binding. It is the methemalbumin which imparts the brownish color to plasma in patients suffering from severe intravascular hemolysis.

document.docTuesday, April 11, 2023