Insight (PreClin and Clinical): Production of Bilirubin

Every haem molecule will produce one molecule of bilirubin. These molecules are found in haemoglobin and myoglobin. Also, cytochrome enzymes will also produce one molecule of bilirubin.The production of bilirubin from haem occurs mainly in the spleen (macrophages) and liver (Kupfer cells), but also all over the body by macrophages, and in renal tubular cells. The cells that perform this job are known collectively as the reticuloendothelial system.

1. Bilirubin-forming molecules (i.e. haem) are taken up by reticuloendothelial cells.

2. Inside these cells, Haem oxygenase enzymes break down the haem, removing iron (which is recycled) and carbon monoxide, leaving biliverdin. The detection of carbon monoxide in breath can be used to determine how much haem is being turned into biliverdin. Biliverdin is very water soluble, whilst bilirubin is not.

3. Biliverdin is then converted to bilirubin, whilst still in the reticuloendothelial cell. This is done by the enzyme biliverdin reductase.

   1. Bilirubin is not just a waste product. It takes up free radicals, and thus is an antioxidant. This is perhaps the benefit of not directly secreting biliverdin, but converting it to bilirubin first.

4. After bilirubin is released from reticuloendothelial cells, it travels in the blood, bound to albumin. This ensures no bilirubin is excreted in the urine. At very high concentrations, bilirubin can slowly diffuse into the peripheral tissues where it is toxic.

5. Bilirubin is then removed from circulation in the sinusoids by hepatocytes. This is a passive process, which occurs down a concentration gradient. The fact that hepatocytes are in direct contact with the sinusoidal fluid helps this process.

6. As soon as bilirubin enters the hepatocyte, it will become bound to glucuronyl transferase which conjugates the bilirubin ready for excretion. Bilirubin is joined with glucuronic acid in the conjugation process. Very small amounts of bilirubin will somehow evade this process and end up in bile as unconjugated bilirubin.

7. It requires energy to secrete conjugated bilirubin into the canniculi.

   1. The process of conjugation makes the bilirubin water soluble, and thus easier to excrete.

Bilirubin that is deconjugated by bacteria in the gut will be reabsorbed in the colon. This process is more likely in the presence of increased bile-acids – i.e. when there is bile acid malabsorption. Bile acid malabsorption occurs in cases of intestinal disease and resection. in these patients, as a compensatory mechanism, the body excretes higher concentrations of bile salts, and this increases the risk of gallstones. Normal bilirubin level is 1-20 µmol/lIt is usually detectable when bilirubin concentrations reach 50µmol/LJaundice is the clinical sign of hyperbilirubinaemia. It indicates disease of the liver or biliary tree.Jaundice will first be visible in the sclera, and more subtly in the skin.

Cholestatic (Obsturctive) Jaundice

• This results from an obstruction in the bile duct. The liver is able to conjugate the bilirubin but not able to excrete it

• It will result in lots of conjugated bilirubin – causing very dark urine and pale stools.

Because of the fact that there is an Obstruction to bile flow, and the level of the Obstruction.

Let us know if this was of use! This was an endeavour to display how every concept is linked, the veritable interplay between the pathophysiology and etiology of a condition, in this case Obstructive Jaundice.