Bilirubin secretion

Hematopoiesis occurs in the liver during the first two trimesters and transfers to the fetal bone marrow during the third trimester. The liver is also responsible for production of specific proteins (such as albumin and clotting factors), metabolism and detoxification of many compounds, and secretion of substances such as bilirubin. A clinically useful protein produced by the liver is AFP. Detoxification and bilirubin secretion mechanisms are immature until late in pregnancy and even in the first few months after birth. Thus premature infants often have high serum bilirubin concentrations and metabolize drugs poorly. 

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. 

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.

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. 

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. 

Detection of liver injury has commonly been associated with alternations in serum levels of certain hepatic enzymes and proteins. Elevation in bilirubin levels following exposure (Barnes and Jones 1967) has been detected in humans, as have decreased serum levels of secreted liver proteins (e.g., albumin and fibrinogen) (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). Elevations in serum levels of enzymes (e.g., ALT, AST, LDFI, OCT) have been reported following acute- and intermediate-duration exposures to carbon tetrachloride in animals (Bruckner et al. 1986 FI ayes et al. 1986 Sakata et al. 1987). 

Mydriasis may occur and may precipitate an attack of acute glaucoma in some patients. Other reported but rare adverse effects include various blood dyscrasias a positive Coombs test with evidence of hemolysis hot flushes aggravation or precipitation of gout abnormalities of smell or taste brownish discoloration of saliva, urine, or vaginal secretions priapism and mild—usually transient—elevations of blood urea nitrogen and of serum transaminases, alkaline phosphatase, and bilirubin. 

Impaired liver function or blocked bile secretion causes bilirubin to leak from the liver into the blood, resulting in a yellowing of the skin and eyeballs, a con-... 

The extract from Berberis vulgaris as well as that of the alkaloids berberine, oxyacanthine, berbamine, jatrorrhizine, and columbamine stimulate secretion of the bile (480, 481). The strongest effect was produced by berberine, followed by berbamine and oxyacanthine. The choleretic effect of berberine was also studied by Vartazaryan (482). Turova et al. (483) examined the effect of berberine on 225 patients with chronic cholecystitis. Peroral doses of 5-20 mg three times daily before meals over a period of 24-48 hours caused disappearance of the clinical symptoms, decrease in the level of bilirubin, and increase in the bile volume in the gall bladder. Berberine also had a favorable effect in patients with toxic hepatitis induced by intoxication. No side effects were observed on the liver functions or the blood composition. The effect of berberine on the stimulation of bile secretion was also studied by Samaj et al. (484). 

The bilirubin that is produced in phagocytic cells from degradation of hemoglobin represents the majority of the bilirubin that is produced and must be eliminated. This initially requires transport of bilirubin from the phagocytic cells to the liver. Normally, bilirubin is secreted from phagocytic cells and complexed with albumin for transport to the liver. It is essential that bilirubin is transported through the circulation bound to albumin. The toxicity of... 

Figure 22-3. Transport and hepatic metabolism of bilirubin. Bilirubin that is produced in phagocytes is transported to liver as an albumin-bilirubin complex. Uptake into the hepatocytes takes place in liver sinusoids. Within the hepatocyte, bilirubin is transported to the endoplasmic reticulum (microsomes) bound to glutathione S-transferase (GST). Bilirubin is made water soluble by addition of one or two glucuronic acid moieties obtained from UPD-glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. The product, conjugated bilirubin, is transported across the bile canalicular membrane for secretion into the biliary system, with subsequent movement into the intestines.

The transfer of conjugated bilirubin in the hepatocyte across the bile canaliculus deposits the conjugated bilirubin along with other hepatic secretions into the biliary system for transport to the small intestine. This transport process is catalyzed by one or more members... 

Bile is a mixture of electrolytes, bile acids, cholesterol, phospholipids and bilirubin. Adults produce between 400 and 800 ml of bile daily. Hepatocytes secrete bile into canaliculi, then into bile ducts, where it is modified by addition of a bicarbonate-rich secretion from ductal epithelial cells. Further modification occurs in the gall bladder, where it is concentrated up to fivefold, through absorption of water and electrolytes. Gallstones, most of which are composed... 

In liver, bilirubin undergoes enzymic conjugation and is secreted in bile in the form of water-soluble derivatives. A large body of literature279 exists on the separation and identification of bilirubin conjugates appearing in normal and pathologic bile, icteric sera, and urine. 

Possible increase in serum conjugated bilirubin Obstruction of bile flow commonly due to common bile duct stone or pancreatic carcinoma Failure of bile secretion Extrahepatic cholestasis Intrahepatic cholestasis... 

This volume of secretion is supplemented in the ductules by ca. 150 ml ductular bile, resulting in a daily production of ca. 600 ml. Bile formation is lower at night than during the day. The most important constituents of the so-called liver bile are the bile acids, phospholipids, proteins, cholesterol and bilirubin. The term bile lipids includes cholesterol, bile salts and phospholipids. The manner in which cholesterol is excreted into the gall bladder is not yet known, nor have any cholesterol-specific transport systems been detected. Cholesterol is primarily broken down into bile acids, (see above) (s. tab. 3.5)... 

Jaundice is also caused by dysfunction in the secretion of bilirubin. The mechanisms involved in the excretion of bilirubin into the biliary capillaries are, however, still largely unresolved, which is why the starting points of the disruptive factors are still unknown. This dysfunction is a postmicrosomal regurgitation jaundice with increased levels of both unconjugated and conjugated bilirubin. 

Congenital defects include the Dubin-Johnson syndrome and Rotor syndrome, (s. tab. 12.4) Both of these diseases present a genetically determined disorder in the secretion of bilirubin. 

Additional cholestasis Isolated defects in the transport mechanisms of bilirubin not only display jaundice, but also an impairment in the secretion of bile. The outcome is additional intrahepatic, nonobstructive cholestasis. 

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