Episode 62 – Connected Bilirubin

Why do patients with liver injury or dysfunction have conjugated hyperbilirubinemia?

On this episode of the podcast, we discuss another paradox: why does the liver’s ability to conjugate remain even in the setting of severe severe inflammation or fibrosis? It might make sense to see a dramatic elevation in unconjugated bilirubin in these situations, but the fact that conjugated bilirubin is the main form that rises when the liver is not working requires explanation.

One study reported that the normal fraction of the measured bilirubin that is conjugated is approximately 3%. In chronic alcohol-related cirrhosis, it rises to 20%. And in chronic viral hepatitis, it is 64%. And even as the liver fails, its ability to conjugate bilirubin remains intact. In another study examining liver failure secondary to hepatitis B, patients still had elevated conjugated bilirubin levels averaging about 10 mg/dL.

A brief review of hemoglobin metabolism will help explain the answer to this paradox. First, senescent red blood cells are destroyed in the spleen. When hemoglobin is metabolized, the heme moiety is converted to bilirubin and shipped into the blood. It has not yet been conjugated by the liver, so this form is called unconjugated bilirubin. It is insoluble in water and generally bound to albumin.

The unconjugated bilirubin is taken up by hepatocytes via facilitated and simple diffusion. It is then conjugated (i.e., attached to) glucuronic acid by uridine diphosphate glycosyltransferase (UGT). More specifically, the 1A1 subtype (UGT1A1) moving forward. This is done within the endoplasmic reticulum of the hepatocyte.

A few notes about UGT1A1. First, this is the enzyme that is poorly functioning in those with Gilbert’s. That’s why they present with unconjugated hyperbilirubinemia. Amazingly, phenobarbitol upregulates the function of UGT1A1. This means it can be used this to treat Gilbert’s, though this is rarely done.

Returing to bilirubin metabolism, the now soluble conjugated bilirubin is transported into bile via an ATP-dependent channel called the multidrug resistance-associated protein 2 (MRP2). The conjugated bilirubin is then excreted from the body in our stool.

Here, again, is the paradox: Because conjugation occurs within the liver, one needs working hepatocytes to produce a conjugated hyperbilirubinemia. In the setting of liver injury or dysfunction, we find evidence of poorly functioning hepatocytes when we identify an increased INR and decreased albumin. But the specific liver function of conjugation continues unabated. Why?

It turns out that in some liver diseases, there is upregulation of UGT enzyme content in the remaining viable hepatocytes. And the levels of the specific isoform of UGT that conjugates bilirubin – UGT1A1 –  remain stable as the degree of liver fibrosis progresses. Even in severe fibrosis and cirrhosis. We know this is not simply a reflection of released from damaged hematocytes because many levels of mRNA are increased as well. This suggests the remaining hepatocytes are working to ensure UGT remains functional by inducing more transcription. There are probably other factors at play. For example, one study found that alcohol upregulated UGT1A1 by 177%. And bilirubin itself seems to upregulate UGT1A1, modulating its own metabolism. This makes sense if we see bilirubin as a potential toxin.

This initial explanation uncovers another paradox: If the ability to conjugate bilirubin remains intact in acute and chronic liver disease, why isn’t the bilirubin released into the bile in the normal manner? As it turns out, although conjugation remains unaffected in liver disease, the remaining steps necessary for excretion are severely affected. First, MRP2 (the transporter that moves conjugated bilirubin from the hepatocyte into the bile) is downregulated in liver disease. This is best described in primary biliary cholangitis.

The conjugated bilirubin that cannot be moved in the bile must now make its way into the blood. Apparently, conjugated bilirubin is routinely secreted back into the sinusoidal blood by MRP3 (not to be confused with MRP2). It is almost all reclaimed by hepatocytes via organic anion-transporting polypeptides (OATP). This process of secretion into the blood and reabsorption back into the hepatocyte is known as “bilirubin hopping.” Why the liver does this isn’t clear.

Source: Sticova E. New insights in bilirubin metabolism and their clinical implications. World Journal of Gastroenterology. 2013;19(38):6398. doi:10.3748/wjg.v19.i38.6398

In liver disease, we see alterations in MRP3 and OATP as well. Something is amiss with bilirubin hopping. Alongside the decrease in the usual portal of exit from the hepatocyte into the bile via MRP2, there is a concomitant increase in MRP3. This means that more is secreted back into the blood. But there is a decrease in OATP, meaning that the conjugated bilirubin can’t hop back into the hepatocytes and is stuck in the blood.

Where we can measure it! And we’ll say the patient has conjugated hyperbilirubinemia. In many ways, this represents a situation where this liver function test demonstrates both an intact – or even augmented – ability and one that’s reduced. The liver keeps on conjugating even while losing the ability to transport the bilirubin where it ought to go.

Take Home Points

  1. UGT1A1 is the enzyme responsible for bilirubin conjugation. Its function remains stable – or even increases – in liver disease.
  2. MRP2 transports conjugated bilirubin from hepatocytes into bile. This channel is decreased in liver disease, limiting the transport of bilirubin into the bile.
  3. As an alternative exit, conjugated bilirubin enters sinusoidal blood. We see this as conjugated hyperbilirubinemia.


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Listen to the episode


Credits & Citation

◾️Episode and show notes written by Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com

Breu AC, Cooper AZ, Abrams HR. Connected bilirubin. The Curious Clinicians Podcast. December 21, 2022.

Image credit: https://geekymedics.com/neonatal-jaundice/

Published by Tony Breu

Tony Breu, MD is an internist/hospitalist who loves asking ‘why’?

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