22 Jaundice

Bilirubin is a byproduct of heme metabolism. Heme, which is largely derived from the hemoglobin in senescent red blood cells, is oxidized in the spleen, liver, and other organs by two isoforms of the enzyme, heme oxygenase, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen, to form biliverdin, carbon monoxide, and iron.¹ Subsequently, biliverdin is converted into bilirubin by the phosphoprotein, biliverdin reductase, which also uses NADPH as a cofactor.

Bilirubin is lipophilic molecule. To be excreted, bilirubin that is produced in extrahepatic organs is bound to albumin and transported to the liver. The liver takes up the bilirubin-albumin complex through an albumin receptor. Bilirubin, but not albumin, is transferred across the hepatocyte membrane and transported through the cytoplasm to the smooth endoplasmic reticulum bound primarily to ligandin or Y protein, a member of the glutathione S-transferase gene family of proteins. Within hepatocytes, bilirubin is converted to water-soluble derivatives, bilirubin monoglucuronide, and bilirubin diglucuronide by the enzyme, uridine diphosphate-glucuronosyl transferase. These conjugated forms of bilirubin are secreted across the canalicular membrane into bile via an energy-dependent process. Conjugated bilirubin is excreted in the bile into the intestine, where it is broken down by gut flora to urobilinogen and stercobilin.

Total serum bilirubin consists of an unconjugated fraction and a conjugated fraction. The conjugated forms of bilirubin exist both free in the serum and bound covalently to albumin; the latter is known as delta-bilirubin.² Conjugated bilirubin is water soluble and reacts directly when certain dyes are added to the serum specimen. The unconjugated bilirubin does not react with the colorimetric reagents until a solvent is added. Accordingly, the conjugated and unconjugated forms of bilirubin are often referred to as “direct” and “indirect” bilirubin. The sum of these two measurements is “total” bilirubin. The normal total bilirubin concentration in adults is less than 18 µmol/L (1.0 mg/dL). Although any total bilirubin concentration higher than the upper limit of normal constitutes hyperbilirubinemia, jaundice (i.e., yellow discoloration of the sclerae, mucous membranes, and skin) is usually not clinically apparent unless the serum total bilirubin level is greater than 50 µmol/L (2.8 mg/dL). Unconjugated or indirect hyperbilirubinemia is present when the total serum bilirubin concentration is above the upper limit of normal, and less than 15% of the total is in the direct or conjugated form.

Differential Diagnosis

The long list of diagnoses depicted in Box 22-1 divides the causes of hyperbilirubinemia into two large groups according to whether the predominant abnormality is an increase in the circulating concentration of unconjugated (indirect) bilirubin or an increase in the concentration of conjugated (direct) bilirubin. Although this classification scheme is useful under some circumstances, many of the diagnoses listed in Box 22-1 are extremely rare and very unlikely to be encountered by the intensivist caring for critically ill (adult) patients. A more useful classification scheme is depicted in Box 22-2. In this scheme, the causes of jaundice are lumped into three primary categories: extrahepatic obstruction to bile flow, increased bilirubin production, or impaired excretion secondary to hepatocellular necrosis and/or intrahepatic cholestasis and/or hepatitis. Often multiple mechanisms are involved at once.

Box 22-1

Differential Diagnosis of Hyperbilirubinemia