Four inherited hyperbilirubinemias: Crigler-Najjar, Gilbert, Dubin-Johnson and Rotor syndromes

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 type II CN), the type of bilirubinemia (conjugated or unconjugated), the specific molecular defect, and the clinical picture (hint: all of them are innocuous except type I CN).

Crigler-Najjar syndrome

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.

Gilbert syndrome

This syndrome is common – it’s estimated that 5-10% of the population has it. Wow! In this disorder, 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, Gilbert syndrome (which is an autosomal recessive syndrome) has a UGT1A1 activity level of 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.).

Dubin-Johnson syndrome

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).

Rotor syndrome

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).

Which direction does blood flow through the ductus arteriosus?

Q. I just had a quick question for you. Our notes say that a ductus arteriosus allows flow from the pulmonary artery to the aorta, which I knew.
However, they also say that it’s a left to right shunt, and that it can become right to left. This confuses me, since from what I know, flow would be going from right (pulmonary artery) to left (aorta).

A. When we talk about the ductus allowing flow from the pulmonary artery (right) to aorta (left), we’re talking about intrauterine flow through the ductus. Before birth, the pressure on the right side of the heart is greater than the pressure on the left – so blood flows from pulmonary artery to aorta (through the ductus).

After birth, though, the pressure on the left becomes greater than the pressure on the right. In most babies, the ductus closes (probably in response to the new levels of oxygen in the blood). In some babies it remains patent, in which case flow would now be from the aorta (left; higher pressure) to the pulmonary artery (right; lower pressure).

If the ductus is widely patent, then after a while, that left to right shunt can put enough pressure on the lungs that they react by closing down vessels, effectively making it more difficult to push blood through. Now the right heart has to work really hard to push blood through the lungs – and it can get to the point where the right heart is actually bigger and stronger than the left, making the shunt reverse and go from pulmonary artery (right; higher pressure) to aorta (left; lower pressure).