Definition of jaundice
The term jaundice or icterus describe the yellow pigmentation of skin, sclerae, and mucous membranes produced by increased serum bilirubin (hyperbilirubinemia). Jaundice, the most colourful and often the earliest sign of a variety of liver and biliary disease, is a starting point for evaluating many of these disorders. Serum bilirubin normally ranges from 0.5 to 1.0 mg/dl. Jaundice usually becomes clinically evident at levels exceeding 2.5 mg/dl and is most readily detected in the sclerae.
About 4mg/kg of bilirubin is produced each day, mainly (80 to 85 per cent) derived from the catabolism of the hemoglobin heme group of senescent red blood cells. The heme ring is cleaved in the reticuloendothelial system to bilirubin, a water-insoluble tetra pyrrole. A smaller proportion of bilirubin (15 to 20 per cent) is derived from the destruction of maturing erythroid cells in the bone marrow (ineffective erythropoiesis) and from the heme groups of predominantly hepatic hemoproteins such as cytochrome P-450 and cytochrome c (Figure 1).
Bilirubin liberated into the plasma is transported to the liver bound tightly but reversibly to albumin. Three phases of hepatic bilirubin metabolism are recognized: (1) uptake, (2) conjugation and (3) excretion into the bile, the last step being overall rate-limiting. Uptake is reversible and follows dissociation of bilirubin from albumin. Unconjugated bilirubin is insoluble in water and is virtually incapable of being excreted in bile. This apolar molecule, however, dissolves in lipid-rich environments and readily traverses the blood-brain barrier and placenta.
Bilirubin is rendered water-soluble and hence capable of being excreted in the aqueous bile by its conjugation with a sugar, glucuronic acid. Mono- and diglucuronides of bilirubin are formed in the hepatic endoplasmic reticulum catalyzed by the enzyme UDP glucuronyl transferase. If the biliary excretion of conjugated bilirubin is impaired, the pigment from hepatocytes regurgitates into plasma. Conjugated bilirubin is both water-soluble and less tightly bound to albumin than unconjugated pigment, so that it is readily filtered by the glomerulus and appears in the urine when its plasma levels are increased (Figure 1). Unconjugated bilirubin is not excreted in urine. With sustained conjugated hyperbilirubinemia (e.g., obstructive jaundice), a proportion of the conjugated bilirubin becomes covalently bound to albumin and is therefore unavailable for renal or biliary excretion.
Conjugated bilirubin excreted in the bile is not reabsorbed by the intestine but is converted by bacterial action in the gut to colourless tetrapyrroles termed urobilinogens. Up to 20 per cent of urobilinogen is reabsorbed and undergoes an enterohepatic circulation, a proportion being excreted in the urine. Thus, both impaired hepatocellular excretion and marked over production of bilirubin lead to increased appearance of urobilinogen in the urine.
Figure 1. The pathway of bilirubin formation, metabolism, and excretion.
Laboratory Tests for Bilirubin
The van den Bergh reaction is the most commonly used test for bilirubin in biological fluids. When carried out in an aqueous medium, the test shows a coloured reaction only with water-soluble bilirubin derivatives (called the direct van den Bergh fraction). The addition of methanol enables a coloured reaction to take place with water-insoluble bilirubin (called the indirect van deb Bergh fraction). Direct and indirect van den Bergh fractions provide clinically useful estimations of conjugated and unconjugated bilirubin, respectively.
However, the correlation between actual levels of conjugated bilirubin and levels estimated by the direct reacting fraction is poor. Normal plasma actually contains more than 95 per cent unconjugated bilirubin.
Qualitative estimation of bilirubin in urine is carried out with Ictotest tablets or dipsticks, which are positive in cases of conjugated hyperbilirubinemia.
Dr. Afsaneh Jeddi