Bile Bilirubin

Excretion of bilirubin into bile Bilirubin diglucuronide is actively transported against a concentration gradient into the bile canaH culi and then into the bile. This energy-dependent, rate-limiting step is susceptible to impairment in liver disease. Unconjugated bilirubin is normally not excreted. 

Bilirubin is highly water-insoluble and therefore its elimination from the circulation requires its chemical conversion in the liver to water-soluble conjugates that are normally excreted into the bile. Bilirubin circulates in plasma tightly bound to albumin, and is taken up into the liver by a carrier-mediated process whose competitive inhibition... 

F. F. Rubaltelli, A. Novello, L. Zancan, et al. Serum and bile bilirubin pigments in the differential diagnosis of Crigler-Najjar disease. Pediatrics 553, (1994). 

Bilirubin is not used as such but is excreted by the liver cell. Bilirubin excretion starts with the conversion of bilirubin to bilirubin glucuronide, which was discovered rather recently. It was first observed that bile bilirubin hydrolysis yields two molecules of glucuronic acid per molecule of bilirubin. Bilirubin glucuronide was found in blood serum and was demonstrated to be the compound responsible for the classical van den Bergh reaction. 

Fig. 3. Diagrammatic representation of the fractionation procedure used for the isolation of the phenylazo derivatives of bile bilirubin. For details, see Section III, B. (Reproduced by courtesy of the Biochemical Jourtuil.)...

The overall procedure employed by the author (Kuende, 1970a) to isolate the phenylazo derivatives of the bile bilirubin is shown diagrammati-cally in Fig. 3. Human hepatic bile served as the source of bilirubin conjugates. A total of 15.3 liters of bile was processed in this investigation. The bile was sampled postoperatively from cholecystectomized patients through a T tube. Bile specimens from several patients were pooled, and were kept frozen until processed further. The isolation was carried out in three steps. Gare was taken to apply the mildest of conditions at all stages. 

Bilirubin [635-65-4] M 584.7, e450nm t OO in CHCI3, pKE t 3 0. An acyclic tetrapyrrole bile pigment with impurities which can be eliminated by successive Soxhiet extraction with diethyl ether and MeOH. It crystallises from CHCI3 as deep red-brown rhombs, plates or prisms, and is dried to constant weight at 80 under vacuum, [Gray et al. J Chem Soc 2264, 2276 1961.]... 

MRP2 (ABCC2) LTC4, bilirubin-glucuronide, estradiol 17 3-glucuronide, dianionic bile salts, anionic conjugates, glutathione disulfide, and others... 

Hyjjerbilirubinaemia is an abnormality observed mainly in neonates in whom the liver is insufficiently developed to be able to detoxify the bile pigment bilirubin. This situation is known as neonatal jaundice and can sometimes become a serious disease causing neurotoxic symptoms. Bilirubin is produced by the degradation of heme [the Fe(II) complex of protoporphyrin IX] by heme oxygenase to give biliverdin, which is reduced by biliverdin reductase to... 

Bilirubin formed in peripheral tissues is transported to the hver by plasma albumin. The further metabolism of bihtubin occuts primarily in the hver. It can be divided into thtee processes (1) uptake of bilirubin by hver parenchymal cells, (2) conjugation of bilirubin with glucuronate in the endoplasmic reticulum, and (3) secretion of conjugated bilirubin into the bile. Each of these processes will be considered separately. 

Bilirubin is nonpolar and would persist in cells (eg, bound to lipids) if not rendered water-soluble. Hepatocytes convert bilirubin to a polar form, which is readily excreted in the bile, by adding glucuronic acid molecules to it. This process is called conjugation and can employ polar molecules other than glucuronic acid (eg, sulfate). Many steroid hormones and drugs are also... 

Figure 32-15. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes, such as ligandin (a family of glutathione S-transferase) and Y protein, bind intracellular bilirubin and may prevent its efflux into the blood stream. The process affected in a number of conditions causing jaundice is also shown.

Conjugated hyperbilirubinemia commonly results from blockage of the hepatic or common bile ducts, most often due to a gallstone or to cancer of the head of the pancreas. Because of the obstruction, bilirubin diglu-curonide cannot be excreted. It thus regurgitates into the hepatic veins and lymphatics, and conjugated bilirubin appears in the blood and urine (choluric jaundice). 

This benign autosomal recessive disorder consists of conjugated hyperbilirubinemia in childhood or during adult life. The hyperbilirubinemia is caused by mutations in the gene encoding MRP-2 (see above), the protein involved in the secretion of conjugated bilirubin into bile. The centrilobular hepatocytes contain an abnormal black pigment that may be derived from epinephrine. 

The commonest causes of obstructive (posthepatic) jaundice are cancer of the head of the pancreas and a gallstone lodged in the common bile duct. The presence of bilirubin in the urine is sometimes referred to as choluria—therefore, hepatitis and obstruction of the common bile duct cause choluric Jaundice, whereas the Jaundice of hemolytic anemia is referred to as acholuric. The laboratory results in patients with hepatitis are variable, depending on the extent of damage to parenchymal cells and the extent of micro-obstruction to bile ductules. Serum levels of ALT and AST are usually markedly elevated in hepatitis, whereas serum levels of alkaline phosphatase are elevated in obstructive liver disease. 

In the hver, bilirubin is made water-soluble by conjugation with two molecules of glucuronic acid and is secreted into the bile. The action of bacterial enzymes in the gut produces urobihnogen and urobihn, which are excreted in the feces and urine. 

When RBCs reach the end of their life span, the globin is degraded to amino acids (which are reutilized in the body), the iron is released from heme and also reutilized, and the tetrapyrrole component of heme is converted to bilirubin, which is mainly excreted into the bowel via the bile. 

The Group II (biliary tract) enzymes are abnormal usually when the serum bilirubin concentration is also abnormal. Most commonly used is alkaline phosphatase which is a highly sensitive indicator of biliary tract obstruction, perhaps because the enzyme is synthesized as an induced response to obstruction of even small bile ducts. Most techniques used to identify the origin of an elevated serum alkaline phosphatase are not very useful from a clinical viewpoint (23). The simultaneous measurement of GMT activity has been found to be useful in differentiating between the hepatic and bony origin of alkaline phosphatase. An increased GMT activity in a patient with an increased ALP activity is a good indication that there is biliary biliary tract disease (62,63). 

Stocker, R and Ames, B. (1987). Potential role of conjugated bilirubin and copper in the metabolism of lipid peroxides in bile. Proc. Natl Acad. Sci. USA 84, 8130-8134. 

In the bile-duct-ligated rat, hepatic mitochondrial lipid peroxides are increased and correlate with serum levels of alkaline phosphatase, bilirubin and alanine aminotransferase (Sokol et al., 1991). Dietary vitamin E deficiency resulted in relatively higher lipid peroxide and bilirubin... 

The serum bilirubin or alkaline phosphatase may be elevated due to inflammation near the common bile duct. 

Liver Fever, lethargy, change in color or quantity of bile in patients w/ biliary T-tube, graft tenderness and swelling, back pain, anorexia, ileus, tachycardia, jaundice, ascites, encephalopathy Abnormal LFTs, increased bilirubin, alkaline phosphatase, transaminases, biopsy positive for mononuclear cell infiltrate with evidence of tissue damage... 

Bile acids The organic acids in bile contains sodium glycocholate and sodium taurocholate, cholesterol, biliverdin and bilirubin, mucus, fat, lecithin, and cells and cellular debris. 

Hyperbilirubinemia Abnormally high concentrations of the bile pigment bilirubin in the bloodstream. Hyperbilirubinemia is defined as a total serum bilirubin level greater than 5 mg/dL. 

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