Four inherited hyperbilirubinemias: Crigler-Najjar, Gilbert, Dubin-Johnson and Rotor syndromes
Posted Dec 12 2011 7:00am
Here are a few syndromes that are easy to mix up: Crigler-Najjar, Gilbert, Dubin-Johnson, and Rotor syndromes. All are inherited disorders in which there is a high bilirubin – but there are important differences. Pay attention to the inheritance pattern (hint: all are autosomal recessive except Gilbert syndrome), the type of bilirubinemia (conjugated or unconjugated), the specific molecular defect, and the clinical picture (hint: all of them are innocuous except type II CN).
There are actually two types of Crigler-Najjar, and boy are they different clinically. Type I CN is a super rare, autosomal recessive disorder in which patients have no UGT1A1 activity. UGT1A1 is a liver enzyme that participates in bilirubin processing (it conjugates bilirubin with one or two molecules of glucuronic acid, if you must know). The bile is colorless, with only trace amounts of unconjugated bilirubin. So the unconjugated bilirubin backs up into the blood, producing severe jaundice and icterus. The liver, by the way, looks totally normal under the microscope. Type 1 CN is fatal in the neonatal period unless the baby gets a liver transplant.
Type II CN is an autosomal dominant disorder in which patients have some UGT1A1 activity, but it’s decreased (the enzyme is only capable of forming monoglucuronidated bilirubin). The disorder is not fatal; in fact, the major consequence is simply really really yellow skin.
This syndrome is common – it’s estimated that 5-10% of the population has it. Wow! It’s an autosomal recessive disorder in which patients have a decreased activity of UGT1A1. Wait a minute, that sounds just like type II CN! Yes, that’s true – both have decreased UGT1A1 activity. However, in Gilbert syndrome, the level of UGT1A1 activity is about 30% of normal, which is quite a bit higher than the amount of activity you see in CN. Patients usually have only mild hyperbilirubinemia (unconjugated, of course), and there is no clinical consequence (other than an increased sensitivity to drugs that are metabolized by UGT1A1. Oh, and the anxiety that occurs when your skin turns yellow.).
This one is an autosomal recessive disorder in which patients have an increase in conjugated bilirubin in the blood. It’s caused by a defect in secretion of bilirubin glucuronides (already conjugated!) across the canalicular membrane (patients are missing a canalicular protein that transports bilirubin glucuronides into bile). The liver looks funny in this disorder: it is darkly pigmented because of coarse granules within the hepatocyte cytoplasm. Most patients are asymptomatic (other than some jaundice here and there).
Here’s another autosomal recessive disorder in which patients have an increase in conjugated bilirubin in the blood. The exact molecular defect is unknown – but it seems these patients have multiple defects in hepatocyte uptake and excretion of bilirubin pigments. The liver looks normal, and as in Dubin-Johnson syndrome, most patients are asymptomatic (other than some jaundice).