Conjugated vs. unconjugated hyperbilirubinemia

Today, we talked about the things that cause an elevation in serum bilirubin (hyperbilirubinemia). We also talked about how it’s useful to know whether the patient has an elevation in conjugated or unconjugated bilirubin (because that helps you narrow down the possible causes). Here’s a question and explanation to get you thinking about this a bit more.

While examining the gums of a 25 year old patient, a yellowish discoloration of the oral mucosa and sclera is noted.  Laboratory tests show a significant increase in unconjugated bilirubin.  Which of the following disorders is most likely the cause of this patient’s abnormalities?

A. A stone in the bile duct
B. Carcinoma of the head of the pancreas
C. Pancreatic pseudocyst
D. Sickle cell disease
E. Hepatocellular carcinoma

Let’s review a little before we get to the question.

Bilirubin is a breakdown product of heme (which, in turn is part of the hemoglobin molecule that is in red blood cells). It is a yellow pigment that is responsible for the yellow color of bruises, and the yellowish discoloration of jaundice.

When old red cells pass through the spleen, macrophages eat them up and break down the heme into unconjugated bilirubin (which is not water soluble). The unconjugated bilirubin is then sent to the liver, which conjugates the bilirubin with glucuronic acid, making it soluble in water. Most of this conjugated bilirubin goes into the bile and out into the small intestine. (An interesting aside: some of the conjugated bilirubin remains in the large intestine and is metabolized into urobilinogen, then sterobilinogen, which gives the feces its brown color! Now you know.)

So: if you have an increase in serum bilirubin, it could be either because you’re making too much bilirubin (usually due to an increase in red cell breakdown) or because you are having a hard time properly removing bilirubin from the system (either your bile ducts are blocked, or there is a liver problem, like cirrhosis, hepatitis, or an inherited problem with bilirubin processing).

The lab reports the total bilirubin, and also the percent that is conjugated (this is usually called the “direct” bilirubin). You can easily figure out, then, how much unconjugated bilirubin you have (it’s just the total bilirubin minus the direct bilirubin).

If you have a lot of bilirubin around and it is mostly unconjugated, that means that it hasn’t been through the liver yet – so either you’ve got a situation where you’ve got a ton of heme being broken down (and it’s exceeding the pace of liver conjugation), or there’s something wrong with the conjugating capacity of the liver (for example, the patient has hepatitis and it’s interfering with the liver’s ability to conjugate bilirubin).

If you have a lot of bilirubin around and it’s mostly conjugated, that means it’s been through the conjugation process in the liver – so there’s something preventing the secretion of bilirubin into the bile (for example, there’s something blocking the bile duct, or the patient has hepatitis and it’s interfering with bilirubin excretion), and the bilirubin is backing up into the blood.

Back to our question. Let’s go through each answer and see what kind of hyperbilirubinemia these disorders would cause.

A. A stone in the bile duct – if big enough, a stone here could block the excretion of bilirubin into the bile. The bilirubin would already be conjugated, so this would be a conjugated bilirubinemia.

B. Carcinoma of the head of pancreas – this could also cause biliary obstruction, similar to A. (An important aside: it’s nice when pancreatic carcinomas announce themselves this way, because it may allow for earlier detection of the tumor. Unfortunately, this is uncommon. Pancreatic adenocarcinoma is usually silent until the tumor is very large and possibly metastatic.)

C. Pancreatic pseudocyst – same idea as A and B.

D. Sickle cell disease – Sickle cell anemia is a type of hemolytic anemia. Hemolytic anemias can cause unconjugated bilirubinemia if the hemolysis is massive enough. If it’s just a low level of hemolysis, the liver can often keep up, in which case you’d excrete the conjugated bilirubin normally (through the poopy).

E. Hepatocellular carcinoma – this would fall into the category of blocking excretion of bilirubin. The bilirubin would already be conjugated – so this would be a conjugated hyperbilirubinemia.

So: since A, B, C and E produce only conjugated hyperbilirubinemia, the answer is D, sickle cell disease.

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