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Bilirubin Metabolism

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Original Author(s): Neera Chaudhary
Last updated: 16th July 2023
Revisions: 18

Original Author(s): Neera Chaudhary
Last updated: 16th July 2023
Revisions: 18

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Bilirubin is a yellow bile pigment produced through the breakdown of red blood cells, which is known as haemolysis. Bilirubin is metabolised prior to excretion through the faeces and urine.

In this article, we will explore the different types of bilirubin, the process of enteric bilirubin metabolism, and we will briefly explore the relevance of bilirubin to clinical practice.

Forms of Bilirubin

Bilirubin exists in two forms; unconjugated and conjugated. Unconjugated bilirubin is insoluble in water. This means it can only travel in the bloodstream if bound to albumin and it cannot be directly excreted from the body.

In contrast, conjugated bilirubin is water soluble. This allows it to travel through the bloodstream without requiring transport proteins like albumin, which means that it can also be excreted out of the body.

In the next section, we will explore the metabolic pathway of bilirubin in more detail.

Bilirubin Metabolism

1 – Creation of Bilirubin

Reticuloendothelial cells are macrophages which are responsible for the maintenance of the blood, through the destruction of old or abnormal cells. They take up red blood cells and metabolise the haemoglobin present into its individual components; haem and globin. Globin is further broken down into amino acids which are subsequently recycled.

Meanwhile, haem is broken down into iron and biliverdin, a process which is catalysed by haem oxygenase. The iron gets recycled, while biliverdin is reduced to create unconjugated bilirubin.

2 – Bilirubin Conjugation

In the bloodstream, unconjugated bilirubin binds to albumin to facilitate its transport to the liver. Once in the liver, glucuronic acid is added to unconjugated bilirubin by the enzyme glucuronyl transferase. This forms conjugated bilirubin, which is soluble. This allows conjugated bilirubin to be excreted into the duodenum in bile.

3 – Bilirubin Excretion

Once in the colon, colonic bacteria deconjugate bilirubin and convert it into urobilinogen. Around 80% of this urobilinogen is further oxidised by intestinal bacteria and converted to stercobilin and then excreted through faeces. It is stercobilin which gives faeces their colour.

Around 20% of the urobilinogen is reabsorbed into the bloodstream as part of the enterohepatic circulation. It is carried to the liver where some is recycled for bile production, while a small percentage reaches the kidneys. Here, it is oxidised further into urobilin and then excreted into the urine.

Fig 1 – Bilirubin metabolism

Clinical Relevance – Jaundice

Jaundice describes a yellow discolouration of the sclera and/or skin in response to elevated bilirubin levels. Causes of jaundice can be categorised as pre-hepatic, hepatic, or post-hepatic;

  • Pre-hepatic jaundice is caused by increased haemolysis. This results in the increased presence of unconjugated bilirubin in the blood as the liver is unable to conjugate it all at the same rate. This is caused by
    • Tropical disease, e.g. malaria, yellow fever
    • Genetic disorders, e.g. sickle-cell anaemia, Gilbert’s syndrome
    • Haemolytic anaemias
  • Hepatic jaundice is caused by liver impairment. This causes the decreased ability of the liver to conjugate bilirubin, resulting in the presence of conjugated and unconjugated bilirubin in the blood. Liver damage can result from:
    • Viral hepatitis
    • Hepatotoxic drugs, e.g. paracetamol overdose, alcohol abuse
  • Post-hepatic jaundice is caused by the blockage of bile ducts. This results in backflow of conjugated bilirubin into the blood as it cannot move past the obstruction. Bile duct obstruction can be caused by:
    • Gallstones
    • Hepatic tumours
    • Pancreatic tumours

Clinical Relevance – Gilbert’s Syndrome

Gilbert’s syndrome is an inherited disorder where there is hyperbilirubinaemia (excess bilirubin in the bloodstream) due to a fault in the UGT1A1 gene leading to a deficiency in UDP-gluconoryltransferase. This faulty gene results in slower conjugation of bilirubin in the liver and so it builds up in the bloodstream instead of being excreted through the biliary ducts.

When well, patients are usually asymptomatic and have normal bilirubin levels. However, under physiological stressors such as illness, alcohol abuse and extreme exercise, patients can become markedly jaundiced.