Two-thirds of the organic materials in bile are bile salts, which are formed by the conjugation of bile acids with taurine or glycine. Bile acids, the major catabolic products of cholesterol, are a family of water-soluble sterols with carboxylated side chains. The primary human bile acids are cholic acid and chenodeoxycholic acid. Bile acids are highly effective detergents. Their primary physiologic role is to solubilize water-insoluble lipids secreted by hepatocytes into bile, and also to solubilize dietary lipids in the gut lumen. Ninety-five percent of secreted bile acids, conjugated or unconjugated, are reabsorbed from the gut lumen and recirculate to the liver (enterohepatic circulation), thus helping to maintain a large endogenous pool of bile acids for digestive and excretory purposes.
Both unconjugated bilirubin and conjugated bilirubin (bilirubin glucuronides) may accumulate systemically. As discussed earlier, unconjugated bilirubin is virtually insoluble and tightly bound to albumin. As a result, it cannot be excreted in the urine, even when blood levels are high. Normally, a very small amount of unconjugated bilirubin is present as a free anion in plasma. If unconjugated bilirubin levels rise, this unbound fraction may diffuse into tissues, particularly the brain in infants, and produce toxic injury. The unbound plasma fraction increases in severe hemolytic disease or when protein-binding drugs displace bilirubin from albumin. Hence, hemolytic disease of the newborn (erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can  cause severe neurologic damage, referred to as kernicterus
Fig. 16.22 Bilirubin metabolism and elimination.
(Chapter 7). In contrast, conjugated bilirubin is water-soluble, nontoxic, and only loosely bound to albumin. Because of its solubility and weak association with albumin, excess conjugated bilirubin in plasma can be excreted in urine.
Serum bilirubin levels in the normal adult vary between 0.3 and 1.2 mg/dL. Jaundice becomes evident when the serum bilirubin levels rise above 2 to 2.5 mg/dL; levels as high as 30 to 40 mg/dL can occur with severe disease. Causes of conjugated and unconjugated hyperbilirubinemia differ, and so measurement of both forms is of value in evaluating a patient with jaundice.
Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, termed neonatal jaundice or physiologic jaundice of the newborn. This may be exacerbated by breastfeeding, due to the action of bilirubindeconjugating enzymes in breast milk. Nevertheless, sustained jaundice in the newborn is abnormal and is discussed later in the “ ” section.
Jaundice also may result from inborn errors of metabolism, including the following: • Gilbert syndrome is a common (7% of the population) inherited condition that manifests as fluctuating unconjugated hyperbilirubinemia of variable severity. The primary cause is mildly decreased hepatic levels of glucuronosyltransferase attributed to a mutation in the encoding gene, UGT1A1; polymorphisms in the gene may play a role in the variable expression of this disorder. Gilbert syndrome is not associated with any morbidity. By contrast, severe glucuronosyltransferase deficiency causes a rare disorder called Crigler-Najjar Syndrome Type 1 that is fatal in infancy.