Unconjugated Bilirubin is a breakdown product of heme (a part of hemoglobin in red blood cells). Unconjugated bilirubin is very hydrophobic and relies on transportation on albumin that is circulating in the blood. This is why addition of high concentration hydrophobic drugs (certain antibiotics, diuretics) and high free fatty acids can cause elevated unconjugated bilirubin. Heme can also come from myoglobin, found mostly in muscle, cytochromes, found mostly in mitochondria, catalase, peroxidase, and nitric oxide synthase.
The liver is responsible for clearing the blood of unconjugated bilirubin and about 30% of bilirubin is taken up by a normal liver each pass through the liver. It does this by the following mechanism: Bilirubin is taken up into hepatocytes, conjugated (modified to make it water-soluble) by UDP-glucuronyl-transferase, and secreted into the bile by CMOAT (MRP2), which is excreted into the intestine. In the intestine, conjugated bilirubin may be (1) metabolized by colonic bacteria, (2) eliminated, (3) reabsorbed. Metabolism of bilirubin into urobilinogen followed by reabsorption of urobilinogen accounts for the yellow color of urine as we urinate a downstream product of urobilinogen. Further metabolism of urobilinogen into stercobilin while in the bowels accounts for the brown color of stool. Thus having white or clay colored stool is an indicator for a blockage in bilirubin processing and thus potential liver dysfunction or cholestatis.
Increased total bilirubin (TBIL) causes jaundice, and can indicate a number of problems: Prehepatic: Increased bilirubin production. This can be due to a number of causes, including hemolytic anemia and internal hemorrhage.Hepatic: Problems with the liver, which are reflected as deficiencies in bilirubin metabolism (e.g., reduced hepatocyte uptake, impaired conjugation of bilirubin, and reduced hepatocyte secretion of bilirubin). Some examples would be cirrhosis and viral hepatitis.3. Posthepatic: Obstruction of the bile ducts, reflected as deficiencies in bilirubin excretion. (Obstruction can be located either within the liver or in the bile duct.
The diagnosis is narrowed down further by looking at the levels of direct bilirubin.If direct (i.e. conjugated) bilirubin is normal, then the problem is an excess of unconjugated bilirubin (indirect bilirubin), and the location of the problem is upstream of bilirubin conjugation in the liver. Hemolysis, viral hepatitis, or cirrhosis can be suspected.If direct bilirubin is elevated, then the liver is conjugating bilirubin normally, but is not able to excrete it. Bile duct obstruction by gallstones or cancer should be suspected.
About 5% of the population have Gilbert's disease, a mutation (or variation) in the UDP-glucuronyl-transferase promotor that manifests itself as jaundice when the individual is stressed (ie starves). Autosomal recessive knockouts of UDP-glucuronyl-transferase itself can lead to Crigler-Najjar Syndrome and elevations of unconjugated bilirubin. Defects in CMOAT (MRP2) results in Dubin-Johnson Syndrome and elevations of conjugated bilirubin.
Neonates are especially vulnerable to bilirubin levels due to an immature blood-brain barrier that predisposed them to kernicterus / bilirubin encephalopathy which can result in permanent neurological damage. Neonates also have a low amount of functional UDP-glucuronyl-transferase and can have elevated unconjugated bilirubin since conjugated is limited. For this reason, newborns are often treated with UV light to turn the hydrophobic, albumin-binding unconjugated bilirubin into a form that is more hydrophilic and able to be secreted out via urine, sparing the neonate's brain.