- Heme, the small-molecule component of hemoglobin, critical for oxygen transport must undergo a complex process of metabolism and degradation described here. Roughly 80% of heme destined for degradation and excretion comes from Senescent erythrocytes which have circulated for on average 3 months. The other 20% comes from premature erythrocytes in the bone marrow which are destroyed prior to release into the circulation and a minor component is derived from other cell types.
|Conversion to Bilirubin (Bilirubin Production)|
- Senescent erythrocytes are phagocytosed and degraded largely by macrophages present in the spleen and liver. Within these cells, Heme is first converted to bilirubin in a two-step enzymatic process which employs "Biliverdin" as an intermediate. These steps result in oxidation and opening of the Heme ring. The macrophages then excrete the resultant bilirubin into the plasma. Because this bilirubin has not been chemically modified in any way it is considered "unconjugated".
- Unconjugated bilirubin is highly insoluble in water and it is transported in the plasma tightly but non-covalently bound to albumin. As a consequence, unconjugated bilirubin is never found in the urine under any circumstances. Hepatocytes of the liver dissociate the unconjugated bilirubin from albumin and uptake the bilirubin for further processing.
- Within the hepatocyte, the enzyme UGT1A1 covalently attaches one or two molecules of glucuronic acid to bilirubin, generating either bilirubin mono- or di-glucuronide. These glucronic acid-attached species of bilirubin are termed "Conjugated Bilirubin" and are now water soluble.
|Biliary Excretion and Transport|
- Conjugated bilirubin is excreted by Hepatocytes into their bile canaliculi by energy-dependent active transport. From there, the conjugated bilirubin travels through the biliary tree and ultimately into the duodenum as a component of bile.
- Conjugated Bilirubin cannot be transported past the GI mucosa and so travels down the GI Tract. However, the normal GI bacterial flora convert the vast majority of conjugated bilirubin to colorless "Urobilinogen" and a small amount to brown-colored "Urobilin". About 90% of urobilinogen is excreted along with the feces; however, about 10% is resorbed by the GI Mucosa and enters the blood stream where it is once again recaptured by hepatocytes and re-excreted in the bile. The majority of urobilin is also excreted in the feces, giving it the characteristic brown color; however, a small minority is resorbed by the GI mucosa and is ultimately excreted by the kidneys, giving urine its yellowish hue.