When bilirubin in the blood exceeds 1 mg/dL (17.1 |lmol/L), hyperbilirubinemia exists. Hyperbilirubine-mia may be due to the production of more bilirubin than the normal liver can excrete, or it may result from the failure of a damaged liver to excrete bilirubin produced in normal amounts. In the absence of hepatic damage, obstruction of the excretory ducts of the liver—by preventing the excretion of bilirubin—will also cause hyperbilirubinemia. In all these situations, bilirubin accumulates in the blood, and when it reaches a certain concentration (approximately 2-2.5 mg/dL), h2c-
Figure 32-16. Structure of some bile pigments.
it diffuses into the tissues, which then become yellow. That condition is called jaundice or icterus.
In clinical studies of jaundice, measurement of bilirubin in the serum is of great value. A method for quantitatively assaying the bilirubin content of the serum was first devised by van den Bergh by application of Ehrlich's test for bilirubin in urine. The Ehrlich reaction is based on the coupling of diazotized sulfanilic acid (Ehrlich's diazo reagent) and bilirubin to produce a reddish-purple azo compound. In the original procedure as described by Ehrlich, methanol was used to provide a solution in which both bilirubin and the diazo regent were soluble. Van den Bergh inadvertently omitted the methanol on an occasion when assay of bile pigment in human bile was being attempted. To his surprise, normal development of the color occurred "directly." This form of bilirubin that would react without the addition of methanol was thus termed "direct-reacting." It was then found that this same direct reaction would also occur in serum from cases of jaundice due to biliary obstruction. However, it was still necessary to add methanol to detect bilirubin in normal serum or that which was present in excess in serum from cases of hemolytic jaundice where no evidence of obstruction was to be found. To that form of bilirubin which could be measured only after the addition of methanol, the term "indirect-reacting" was applied.
It was subsequently discovered that the indirect bilirubin is "free" (unconjugated) bilirubin en route to the liver from the reticuloendothelial tissues, where the bilirubin was originally produced by the breakdown of heme porphyrins. Since this bilirubin is not water-soluble, it requires methanol to initiate coupling with the diazo reagent. In the liver, the free bilirubin becomes conjugated with glucuronic acid, and the conjugate, bilirubin glucuronide, can then be excreted into the bile. Furthermore, conjugated bilirubin, being water-
soluble, can react directly with the diazo reagent, so that the "direct bilirubin" of van den Bergh is actually a bilirubin conjugate (bilirubin glucuronide).
Depending on the type of bilirubin present in plasma—ie, unconjugated or conjugated—hyperbilirubinemia may be classified as retention hyperbilirubinemia, due to overproduction, or regurgitation hy-perbilirubinemia, due to reflux into the bloodstream because of biliary obstruction.
Because of its hydrophobicity, only unconjugated bilirubin can cross the blood-brain barrier into the central nervous system; thus, encephalopathy due to hyperbilirubinemia (kernicterus) can occur only in connection with unconjugated bilirubin, as found in retention hyperbilirubinemia. On the other hand, because of its water-solubility, only conjugated bilirubin can appear in urine. Accordingly, choluric jaundice (choluria is the presence of bile pigments in the urine) occurs only in regurgitation hyperbilirubinemia, and acholuric jaundice occurs only in the presence of an excess of un-conjugated bilirubin.
Elevated Amounts of Unconjugated Bilirubin in Blood Occur in a Number of Conditions
A. Hemolytic Anemias_
Hemolytic anemias are important causes of unconju-gated hyperbilirubinemia, though unconjugated hyper-bilirubinemia is usually only slight (< 4 mg/dL; < 68.4 |mol/L) even in the event of extensive hemolysis because of the healthy liver's large capacity for handling bilirubin.
B. Neonatal "Physiologic Jaundice"_
This transient condition is the most common cause of unconjugated hyperbilirubinemia. It results from an ac celerated hemolysis around the time of birth and an immature hepatic system for the uptake, conjugation, and secretion of bilirubin. Not only is the bilirubin-UGT activity reduced, but there probably is reduced synthesis of the substrate for that enzyme, UDP-glucuronic acid. Since the increased amount of bilirubin is unconju-gated, it is capable of penetrating the blood-brain barrier when its concentration in plasma exceeds that which can be tightly bound by albumin (20-25 mg/dL). This can result in a hyperbilirubinemic toxic encephalopathy, or kernicterus, which can cause mental retardation. Because of the recognized inducibility of this bilirubin-metabolizing system, phenobarbital has been administered to jaundiced neonates and is effective in this disorder. In addition, exposure to blue light (phototherapy) promotes the hepatic excretion of unconjugated bilirubin by converting some of the bilirubin to other derivatives such as maleimide fragments and geometric isomers that are excreted in the bile.
C. Crigler-Najjar Syndrome, Type I; Congenital Nonhemolytic Jaundice_
Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative.
D. Crigler-Najjar Syndrome, Type II_
This rare inherited disorder also results from mutations in the gene encoding bilirubin-UGT, but some activity of the enzyme is retained and the condition has a more benign course than type I. Serum bilirubin concentrations usually do not exceed 20 mg/dL. Patients with this condition can respond to treatment with large doses of phenobarbital.
E. Gilbert Syndrome_
Again, this is caused by mutations in the gene encoding bilirubin-UGT, but approximately 30% of the enzyme's activity is preserved and the condition is entirely harmless.
F. Toxic Hyperbilirubinemia_
Unconjugated hyperbilirubinemia can result from toxin-induced liver dysfunction such as that caused by chloroform, arsphenamines, carbon tetrachloride, acetaminophen, hepatitis virus, cirrhosis, and Amanita mushroom poisoning. These acquired disorders are due to hepatic parenchymal cell damage, which impairs conjugation.
Obstruction in the Biliary Tree Is the Commonest Cause of Conjugated Hyperbilirubinemia
A. Obstruction of the Biliary Tree_
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).
The term cholestatic jaundice is used to include all cases of extrahepatic obstructive jaundice. It also covers those cases of jaundice that exhibit conjugated hyper-bilirubinemia due to micro-obstruction of intrahepatic biliary ductules by swollen, damaged hepatocytes (eg, as may occur in infectious hepatitis).
B. Dubin-Johnson Syndrome_
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 epi-nephrine.
C. Rotor Syndrome_
This is a rare benign condition characterized by chronic conjugated hyperbilirubinemia and normal liver histology. Its precise cause has not been identified, but it is thought to be due to an abnormality in hepatic storage.
Some Conjugated Bilirubin Can Bind Covalently to Albumin
When levels of conjugated bilirubin remain high in plasma, a fraction can bind covalently to albumin (delta bilirubin). Because it is bound covalently to albumin, this fraction has a longer half-life in plasma than does conventional conjugated bilirubin. Thus, it remains elevated during the recovery phase of obstructive jaundice after the remainder of the conjugated bilirubin has declined to normal levels; this explains why some patients continue to appear jaundiced after conjugated bilirubin levels have returned to normal.
Hemolytic anemia Hepatitis
Direct: 0.1-0.4 mg/dL Indirect: 0.2-0.7 mg/dL Î Indirect
Î Direct and indirect Î Direct
0-4 mg/24 h Increased
Decreased if microobstruction is present Absent
Present if microobstruction occurs
Trace to absent
1The 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.
Urobilinogen & Bilirubin in Urine Are Clinical Indicators
Normally, there are mere traces of urobilinogen in the urine. In complete obstruction of the bile duct, no urobilinogen is found in the urine, since bilirubin has no access to the intestine, where it can be converted to urobilinogen. In this case, the presence of bilirubin (conjugated) in the urine without urobilinogen suggests obstructive jaundice, either intrahepatic or posthepatic.
In jaundice secondary to hemolysis, the increased production of bilirubin leads to increased production of urobilinogen, which appears in the urine in large amounts. Bilirubin is not usually found in the urine in hemolytic jaundice (because unconjugated bilirubin does not pass into the urine), so that the combination of increased urobilinogen and absence of bilirubin is suggestive of hemolytic jaundice. Increased blood destruction from any cause brings about an increase in urine urobilinogen.
Table 32-3 summarizes laboratory results obtained on patients with three different causes of jaundice—he-molytic anemia (a prehepatic cause), hepatitis (a hepatic cause), and obstruction of the common bile duct (a posthepatic cause). Laboratory tests on blood (evaluation of the possibility of a hemolytic anemia and measurement of prothrombin time) and on serum (eg, elec-trophoresis of proteins; activities of the enzymes ALT, AST, and alkaline phosphatase) are also important in helping to distinguish between prehepatic, hepatic, and posthepatic causes of jaundice.
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