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Bilirubin Metabolism and Jaundice

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.
In situations where the liver cannot excrete conjugated bilirubin, the kidneys will take over this job, however once plasma concentrations are high enough (above 600µmol/L) – the kidneys cannot conjugate bilirubin –  only excrete it after this process has occurred.
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.
More bilirubin is also re-absorbed during fasting.
Much of the bilirubin in the colon will also be turned into stercobilogens and urobilogens. Generally, urobilogens is colourless, and stercobilogens give faeces its colour.
Some of the urobilogens will be absorbed and enter the circulation, where they will be removed mainly by the liver, but also by the kidney.
In liver disease and excessive haemolysis, the liver may not be able to remove all excess urobilogens, and so more is removed by the kidney.
Note that bilirubin will oxidise back to biliverdin after excretion – hence the green colour of bile.

Jaundice

This is a condition where there is yellowing of the skin, sclera and mucous membranes as a result of increased bilirubin concentration in bodily fluids.
Normal bilirubin level is 1-20 µmol/l
It is usually detectable when bilirubin concentrations reach 50µmol/L
Jaundice 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. Urine is also likely to be dark. Sputum and saliva are not affected. Occasionally, carotenemia may mimic jaundice (usually caused by eating too many carrots or vitamin A), however, the yellowness is usually more visible in the palms than the sclera if this is the case.
Jaundice with scleral icterus. This file is taken from wikimedia commons and is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Haemolytic Jaundice (pre-hepatic jaundice)

Hepatocellular Jaundice

Cholestatic Jaundice

Familial hyperbiliruninaemia

Neonatal jaundice

See also Basic Liver Physiology

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