Bilirubin, a breakdown product of the porphyrin ring of heme-containing proteins, is found in the blood in two fractions—conjugated and unconjugated. The uncon- jugated fraction, also termed the indirect fraction, is insoluble in water and is bound to albumin in the blood. The conjugated (direct) bilirubin fraction is water-soluble and can therefore be excreted by the kidney. Normal values of total serum bilirubin are reported between 1 and 1.5 mg/dL with 95% of a normal population falling between 0.2 and 0.9 mg/dL. If the direct-acting fraction is <5% of the total, the biliru- bin can be considered to all be indirect. The most frequently reported upper limit of normal for conjugated bilirubin is 0.3 mg/dL. Elevation of the unconjugated fraction of bilirubin is rarely due to liver disease. An isolated elevation of unconjugated bilirubin is seen primarily in hemolytic disorders and in a number of genetic conditions such as Crigler-Najjar and Gilbert’s syndromes (Chap. 45). Isolated unconjugated hyperbilirubinemia (bilirubin elevated but <5% direct) should prompt a workup for hemolysis (Fig. 330-1). In the absence of hemolysis, an isolated, unconjugated hyperbilirubinemia in an other- wise healthy patient can be attributed to Gilbert’s syndrome, and no further evaluation is required. In contrast, conjugated hyperbilirubinemia almost always implies liver or biliary tract disease. The rate-limiting step in bilirubin metab- olism is not conjugation of bilirubin, but rather the transport of conju- gated bilirubin into the bile canaliculi. Thus, elevation of the conjugated fraction may be seen in any type of liver disease including fulminant liver failure. In most liver diseases, both conjugated and unconjugated fractions of the bilirubin tend to be elevated. Except in the presence of a purely unconjugated hyperbilirubinemia, fractionation of the bilirubin is rarely helpful in determining the cause of jaundice. Although the degree of elevation of the serum bilirubin has not been critically assessed as a prognostic marker, it is important in a number of conditions. In viral hepatitis, the higher the serum bilirubin, the greater is the hepatocellular damage. Total serum bilirubin correlates with poor outcomes in alcoholic hepatitis. It is also a critical compo- nent of the Model for End-Stage Liver Disease (MELD) score, a tool used to estimate survival of patients with end-stage liver disease and assess operative risk of patients with cirrhosis. An elevated total serum bilirubin in patients with drug-induced liver disease indicates more severe injury. Unconjugated bilirubin always binds to albumin in the serum and is not filtered by the kidney. Therefore, any bilirubin found in the urine is conjugated bilirubin; the presence of bilirubinuria implies the presence of liver disease. A urine dipstick test can theoretically give the same information as fractionation of the serum bilirubin. This test is almost 100% accurate. Phenothiazines may give a false-positive reading with the Ictotest tablet. In patients recovering from jaundice, the urine biliru- bin clears prior to the serum bilirubin.