The importance of recognizing congenital hyperbilirubinemia lies mainly in distinguishing it from other, more serious hepatobiliary disease: congenital conjugated hyperbilirubinemia or hepatobiliary diseases. Except for Crigler-Najjar syndrome, congenital hyperbilirubinemia does not impair either the quality of life or the life expectancy of affected subjects. By definition, patients with familial hyperbilirubinemia have normal standard liver tests, and the liver histology is also normal (except for the pigment accumulation in Dubin-Johnson syndrome). With the exception of Gilbert's syndrome, these syndromes are uncommon and are divided into two groups on the basis of the type of the serum hyperbilirubinemia.

3.1.1 GILBERT'S SYNDROME

Gilbert's syndrome is the most common congenital hyperbilirubinemia syndrome, occurring in about 5% of Caucasians. It is probably transmitted through an autosomal dominant mode. Its pathogenesis is related to a partial deficiency in hepatic UDPglucuronyl transferase, the enzyme responsible for the glucuronidation of bilirubin. In addition, some patients have reduced bilirubin uptake by the hepatocytes, as observed with diagnostic substances (BSP, indocyanine green) and drugs (tolbutamide). The syndrome is usually detected in adolescents and young adults, most commonly in male persons; the possibility that testosterone inhibits whereas estrogen and progesterone augment the action of UDPglucuronyl transferase may provide the explanation. Complaints leading to the diagnosis are various (fatigue, nausea, vague abdominal discomfort) and unrelated to the condition. Scleral icterus may be present and fluctuating, but the physical examination is otherwise normal. Liver tests and hemogram (to exclude hemolysis) are normal except for unconjugated serum bilirubin, which is elevated between 20 and 100 µmol/L and conjugated bilirubin, which is often unrecordably low. Diagnostic tests are available but usually not necessary: fasting for two days or intravenous administration of nicotinic acid significantly increases serum unconjugated bilirubin, while phenobarbital significantly decreases it. No treatment is warranted and prognosis is excellent.

This syndrome may present in two types. Type I is a very rare and serious disease characterized by unconjugated hyperbilirubinemia often greater than 400-500 µmol/L. It is due to an absolute deficiency of UDPglucuronyl transferase. Jaundice occurs almost immediately after birth and may lead to kernicterus with consequent neurologic damage and mental retardation. Kernicterus involves damage to the basal ganglia and cerebral cortex because unconjugated bilirubin is able to penetrate the immature blood-brain barrier of infants. The syndrome is inherited in an autosomal recessive fashion, often with a family history of consanguinity. Phenobarbital treatment is ineffective in inducing UDPglucuronyl transferase activity; an early death occurs. The treatment of choice appears to be hepatic transplantation.

Crigler-Najjar syndrome type II is a much more benign condition in which the unconjugated hyperbilirubinemia usually does not exceed 400 µmol/L. Kernicterus rarely develops in these patients (except with prolonged fasting, in which bilirubin can rise). Hepatic UDPglucuronyl transferase activity is very low or undetectable, but phenobarbital therapy lowers serum bilirubin levels. (Phenobarbital presumably induces even the low levels of this enzyme.) Prognosis is very good despite a lifelong persistent unconjugated hyperbilirubinemia.

Two conditions characterized by congenital conjugated hyperbilirubinemia without cholestasis have been described. Both syndromes are inherited as autosomal recessive traits. Both are uncommon disorders believed to result from specific defects in the hepatobiliary excretion of bilirubin. These conditions are benign, and their accurate diagnosis provides reassurance to the patient. Plasma bilirubin levels are usually in the range of 35-85 µmol/L, although occasionally levels may be as high as 400 µmol/L. Plasma bilirubin may further increase in both conditions during intercurrent infection, pregnancy or use of oral contraceptives. Pruritus is absent and serum bile acid levels are normal, as are routine biochemical liver tests, except for serum bilirubin concentration. Bilirubinuria is usually present. No treatment is necessary.

Some distinctive features allow differential diagnosis between the two syndromes.

Patients with the Dubin-Johnson syndrome have a black liver, which results from the accumulation of a melanin-like pigment in lysosomes. Visualization of the gallbladder during oral cholecystography is usually delayed or absent. Urinary excretion of total coproporphyrin is normal, whereas the proportion of isomer I is higher than in normal controls (>80%). Finally, the BSP plasma retention test is normal in its initial phase, but there is a secondary rise in plasma BSP concentration at 90 minutes due to reflux of BSP from the hepatocyte to the plasma.

In patients with Rotor's syndrome, the appearance and histology of the liver are normal. Oral cholecystography usually visualizes the gallbladder. Total coproporphyrin excretion is greater than normal, as in other hepatobiliary disorders, and isomer I makes a smaller proportion (<80%) than in Dubin- Johnson patients. The plasma disappearance of injected BSP is delayed, with no secondary rise.