There are five major groups of inherited defects in bilirubin metabolism: Gilbert’s syndrome, Crigler-Najjar syndrome (type I), Arias syndrome (Crigler-Najjar syndrome type II), Dubin-Johnson syndrome, and Rotor syndrome.

Gilbert’s syndrome. Gilbert’s syndrome is a congenital partial defect in unconjugated bilirubin clearance due to decreased function of the enzyme bilirubin uridine diphosphate-glucuronate glucuronyl transferase (UDP-GT). Males are affected 1.5-7.3 times more than females. In one study 27%-55% of the siblings of persons with Gilbert’s disease also had mild features of the syndrome. The disorder clinically consists entirely of elevated total bilirubin level, usually less than 3 mg/100 ml (4 mg in some reports) (SI 51.3-68.4 µmol/L). Ninety percent or more of the bilirubin is nonconjugated. The bilirubin level can fluctuate, with about 25% of patients having values within reference range at some time. Patients may or may not have mild jaundice. Liver function tests or liver biopsy does not show significant abnormality. The problem is differentiating the benign bilirubin level elevation of Gilbert’s syndrome from more serious conditions such as a hemolytic process or active liver disease.

There is no really satisfactory diagnostic test at present. Some physicians follow the patient for only 12-18 months and feel that persistent nonconjugated hyperbilirubinemia without development of other abnormal liver function tests is diagnostic of Gilbert’s syndrome. The other method being used (to some extent) is bilirubin response to caloric deprivation. If caloric intake is restricted to 400 calories for 24 hours, persons with Gilbert’s syndrome usually have a rise in total bilirubin greater than 0.8 mg/100 ml (13.7 µmol/L), whereas non-Gilbert’s syndrome patients have increases less than this. However, 8%-13% of Gilbert’s syndrome patients do not have increases greater than 0.8 mg. Most investigators agree there is considerable overlap between Gilbert’s and non-Gilbert’s syndrome persons both in baseline bilirubin and in response to provocative tests such as fasting or caloric restriction.

Crigler-Najjar syndrome (type I). In Crigler-Najjar syndrome type I, the unconjugated bilirubin is increased due to absence of the liver cell microsomal enzyme bilirubin UDP-GT, which adds glucuronide to unconjugated bilirubin to form bilirubin monoglucuronide. Newborns and infants display marked hyperbilirubinemia with jaundice, and death may occur. There is autosomal recessive inheritance. The jaundice does not respond to phenobarbital therapy.

Arias syndrome (Crigler-Najjar type II). In Arias syndrome (Crigler-Najjar type II), the unconjugated bilirubin level is increased, but the defect is still somewhat uncertain. The usual stated etiology is partial defect of liver cell microsomal enzyme UDP-GT, but others believe it may be due to a deficiency in hepatic cell wall transglucuronide enzyme. Patients have moderate hyperbilirubinemia (6-20 mg/100 ml), and the jaundice responds well to phenobarbital therapy.

Dubin-Johnson syndrome. In Dubin-Johnson syndrome, both conjugated and unconjugated bilirubin levels are increased, with conjugated type predominating, due to a defect in transport of bilirubin from the liver cells to the bile ducts. Hyperbilirubinemia is usually mild, and jaundice may be precipitated by other illness or by pregnancy. Inheritance is autosomal recessive. Serum BSP excretion levels are normal 45 minutes after injection but characteristically become elevated 90-120 minutes after injection. Serum bile acid levels are normal. The gallbladder usually does not visualize on oral cholecystography.

Urine coproporphyrin analysis may be helpful for diagnosis. Normally, urine coproporphyrin is predominantly (about two-thirds) type III. In Dubin-Johnson syndrome, the predominant isomer in urine becomes type I, even though total urinary coproporphyrin excretion levels are frequently normal. Some (not all) asymptomatic carriers may also have predominantly type I.

Rotor syndrome. Rotor syndrome is associated with an increase in conjugated bilirubin levels due to defect in liver cell excretion of bilirubin. Inheritance is autosomal recessive. There usually is mild hyperbilirubinemia; jaundice may be induced by other illness. Liver uptake and storage of BSP is decreased (BSP retention in serum at 45 minutes after injection is increased), and serum bile acid levels are increased.