CLINICAL CLASSIFICATION OF JAUNDICE



A logical first step in the study of a jaundiced patient is to determine whether there is an un­conjugated or a conjugated hyperbilirubinemia. This question is usually easUy resolved by testing the urine for bilirubin. If positive, conjugated hy­perbilirubinemia is present and is confirmed by finding greater than 50 per cent conjugated bili­rubin on serum testing.

Classification of jaundice according to this dis­tinction is shown in. Mechanisms contributing to predominantly unconjugated hy­perbilirubinemia include (1) overproduction, (2) decreased hepatic uptake, and (3) decreased con­jugation.

Conjugated hyperbilirubinemia implies either (1) a defect in hepatocellular secretion of bilirubin or (2) mechanical obstruction to the major extrahepatic bile ducts. Apart from hemol­ysis and rare conditions, such as Crigler-Najjar syndrome (decreased or absent conjugation) and Dubin-Johnson syndrome (defective hepatocel­lular excretion of bilirubin), defects in the path­way of bilirubin production to excretion leading to jaundice are more likely to be multiple than isolated ones. For example, the jaundice occur­ring in patients with hepatocellular disease (i.e., hepatitis, cirrhosis) may result from a combina­tion of diminished red cell survival and impair­ment of all three stages of hepatocellular bilirubin transport and metabolism.

Unconjugated Hyperbilirubinemia Overproduction. Hemolysis from a variety of causes may lead to bilirubin production sufficient to exceed the clearing capacity of the liver with subsequent development of jaundice. This he­molytic jaundice is characteristically mild; serum bilirubin levels rarely exceed 5 mg/dl. Up to 15 per cent of the serum bilirubin may be direct-re­acting, a phenomenon that mainly reflects an ar­tifact of the van den Bergh reaction. Ineffective erythropoiesis, which may be substantially in­creased in megaloblastic anemias, may also lead to mild jaundice.

Impaired Hepatic Uptake. Impaired uptake is very rarely encountered as an isolated cause for clinical jaundice, but may play a role in the mild jaundice following administration of radiographic contrast media (competition for bilirubin uptake) and in Gilbert’s syndrome (see below).

Impaired Conjugation. A genetically deter­mined decrease or absence of UDP-glucuronyl-transferase is encountered in the CriglerNajjar syndrome, whereas mild, acquired defects in the enzyme may be produced by drugs (e.g., chlor­amphenicol).
Pieonatal Jaundice. All steps of hepatic bili­rubin metabolism are incompletely developed in the neonatal period, while increased production is also present. The major defect is in conjugation, however, leading to unconjugated hyperbilirubi­nemia between the second and fifth days of life. When increased production of bilirubin occurs in the neonatal period, usually as a result of hemo­lytic disease secondary to bloodgroup incompat­ibility, severe unconjugated hyperbilirubinemia may occur, carrying the risk of neurological dam­age (kernicterus).

Gilbert’s Syndrome. This very common dis­order affects up to 7 per cent of the population, with a marked male predominance. It commonly manifests during the second or third decade of life as a mild unconjugated hyperbilirubinemia, ex­acerbated by fasting, and noted clinically or as an incidental laboratory finding. The mechanism ap­pears to involve increased production, dimin­ished uptake, and defective conjugation of bili­rubin to varying proportions in different individuals. Nonspecific gastrointestinal symp­toms and fatigue are commonly associated, but this condition is entirely benign. The diagnosis is strongly suggested by unconjugated hyperbiliru­binemia with normal hepatic enzymes and the ab­sence of overt hemolysis. Liver biopsy is always normal and is rarely, if ever, indicated to confirm the diagnosis.